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Projects

Projects

The scientific research is structurally divided into two project areas:

Project area A: Strengthening GvL effects

Project area B: Prevention and treatment of GvHD.

This division has proven to be successful and constructive. Collaborative activities between the project areas have transformed the TRR 221 into a tight network in which it is clearly recognized that each GvL-modulating strategy must take into account its influence on GvHD (and vice versa). 

What are A-Projects?

Research projects that focus on the amplification of the graft-versus-leukemia (GvL) effect are grouped as A-projects. Briefly, they explore T cell redirection tools (i.e. T cell receptors (TCRs; A01), chimeric antigen receptors (CARs; A02, A03), tri-specific antibodies (A04) for the enhancement of hematopoiesis-restricted GvL activity and examine the reactivation of silenced GvL responses through improved functional and reproductive “fitness” of donor immune cells. The latter approaches include the amelioration of metabolic stress (A06), the transfer of T memory stem cells (A07) and the co-activation of innate nucleic acid receptor pathways (A08).

Whats is Project B

Prevention and treatment of GvHD by targeting cell signaling and metabolic pathways, by strengthening immune regulatory networks and by modulating GvHD-promoting co- factors The B-projects focus on the investigation of cell signaling and metabolic pathways (B02-04, B12, B14), immune regulatory/suppressive cells and networks in acute and chronic GvHD (B01, B07- B10, B15) and GvHD-promoting co-factors (B11-B13, B15). Based on their pathophysiological findings, they aim to develop and/or advance novel immunomodulatory strategies for effective prophylaxis and therapy of severe GvHD.  

Taken together, the B-projects tackle the GvHD problem from different angles with the aim to jointly develop innovative complementary or synergistic strategies. The coordinated time- and event-driven biopsy program on gut GvHD in Regensburg provides several B-projects with clinical samples and data of patients for research analyses. All PIs have proven unrestricted willingness to share their expertise, models, technologies and reagents with all other investigators. Promising strategies in GvL projects have been evaluated with respect to their influence on GvHD by the cooperating partners (and vice versa) and all participating institutions supported translational studies evolving from the TRR 221 projects (e.g. B01, B07, B10, B13, MAGIC trial).

Whats is Service Project

Information Infrastructure Project (INF), Service Projects (Z), and Integrated Research Training Group (IRTG) The A/B projects have been strongly supported by the newly established INF project (T. Dandekar, E. Holler, B. Kehr, M. Kunz) that provides the data infrastructure backbone, supporting large-scale omics, imaging, and clinical data. The INF PIs have developed a bioinformatics and data management platform, enabling mechanistic insights into GvHD and GvL immune responses and supporting translational and educational activities. Their broad and diverse expert knowledge was invaluable and contributed significantly to several TRR 221 publications (e.g., INF, refs. 1,10,23). As an outstanding INF achievement the clinical data integration system (DIS) BITCARE has been established at all three sites. Indispensable service was also provided by the pathology project Z01 (M. B¸ttner-Herold, M. Evert, A. Rosenwald), that performs the coordinated sampling and processing of human and murine tissues at each site and employs standardized consensus diagnosis and grading of experimental and human GvHD. The latter has been clearly improved by the TRR 221 owned virtual pathology platform and online CaseCentre (Sysmex/HP), that are both used to jointly evaluate digitized GvHD cases across sites. The project leaders conducted a Round Robin test on human colonic GvHD biopsies to ensure harmonization of the diagnostic approach by the involved pathologists (Z01, ref. 1). A variety of tissue-based histochemical, immunohistochemical, ultrastructural and molecular methods were performed as requested by TRR 221 projects (e.g., refs. 6,7). Service project Z02 by P. Hoffmann, T. Winkler, and A. Beilhack supports the A/B-projects by the generation and cross-breeding of numerous genetically modified mouse strains (e.g. loxP flank in Klf6 gene for conditional deleter mice, IL3 & Csf2 knockout mice, and novel split-cre mice for specific deletion of target genes by a combinatorial expression of the cre recombinase) and assists the projects on-site in the performance of complex mouse ASCT experiments and the conduction of sophisticated in vivo and ex vivo imaging studies. To study the role of the intestinal microbiome in ASCT, Z02 utilizes the proprietary germfree (GF) mouse facility in Regensburg and has performed several ASCT experiments investigating the course of GvHD under GF conditions in coop with B07, B03, B09, and B12. Moreover, a central human biomaterial repository supported by Z03 funds collected samples from hematologic neoplasias, which were provided to A/B-projects as required. To advance ASCT, talented early career researchers (ECRs) require training in their specific field as well as in the basic biology and clinical problems of ASCT. For this purpose, PIs M. Edinger, A. Kremer and F. Berberich-Siebelt further developed and strengthened the cross-site IRTG for doctoral students (PhD, MD) and for MDs (Dr. med.). All IRTG students are enrolled in local graduate programs and the IRTG focuses on complementary ASCT training modules detailed in the IRTG chapter. The joined training of doctoral candidates in medicine (Dr. med.) and natural sciences (Dr. rer. nat./PhD) as well as human biology (Dr. rer. biol. hum./Dr. rer. physiol.) has fostered the 14General information interdisciplinary cooperation and exchange of ideas between scientists and physicians to bridge the gap between laboratory and clinical research. During the 2nd FP, TRR 221 project leaders published 139 peer-reviewed publications on TRR specific topics (w/o reviews and clinical studies; only first and last authorships counted), of which 81 publications list project leaders of at least two different TRR projects as authors (evaluation period: 01/2022 to 04/2025; see also Fig. 3, cooperation array). Of these joint publications, 23 include project leaders from two and 9 from three TRR sites, respectively. Many more joint manuscripts are currently submitted for publication or are in preparation. Notably, joint publications (i.e., from at least two different projects) in the 1st FP (evaluation period: 01/2018 to 07/2021) were 74, of which 12 included project leaders from two and 3 from three TRR 221 sites (as detailed in our last proposal). This strong increase of joint cross-site publications from the 1st to 2nd FP clearly demonstrates that the TRR 221 has evolved into a strongly interacting and intensely collaborating research consortium during the first two FPs.

Project A01

Deciphering the role of DM-sensitive and DM-resistant antigens in immune responses after allogeneic stem cell transplantation (ASCT)
Site: Erlangen
Principal Investigator: Dr. rer. nat. Hannah Reimann, and Prof. Dr. med. Andreas Mackensen

DM-sensitive antigens are promising targets for selective GvL effects without GvHD. We isolated CD4+ T-cell clones targeting these antigens in mismatched HLA-DP, recognizing primary AML blasts while sparing non-hematopoietic cells. For clinical translation, we aim to develop scalable, GMP-grade T-cell products and assess their GvL and GvHD potential using AML blasts and patient-derived organoids. Preliminary post-ASCT data suggest a link between T-cell responses to DM-resistant antigens and GvHD. To elucidate this relationship, we will longitudinally track T-cell clones targeting DM-sensitive /-resistant antigens in ASCT patients.

1. Kretschmann S, Herda S, Bruns H, Russ J, van der Meijden ED, Schlotzer-Schrehardt U, Griffioen M, Na IK, Mackensen A, Kremer AN. Chaperone protein HSC70 regulates intercellular transfer of Y chromosome antigen DBY. J Clin Invest 2019;129(7):2952-63. doi:10.1172/JCI123105.

2. Kremer AN, van der Meijden ED, Honders MW, Goeman JJ, Wiertz EJ, Falkenburg JH, Griffioen M. Endogenous HLA class II epitopes that are immunogenic in vivo show distinct behavior toward HLA-DM and its natural inhibitor HLA-DO. Blood 2012;120(16):3246-55. doi:10.1182/blood-2011-12-399311.

3. Kremer AN, van der Meijden ED, Honders MW, Pont MJ, Goeman JJ, Falkenburg JH, Griffioen M. Human leukocyte antigen-DO regulates surface presentation of human leukocyte antigen class II-restricted antigens on B cell malignancies. Biol Blood Marrow Transplant 2014; 20(5):742-7. doi:10.1016/j.bbmt.2014.02.005.

4. Bernhardt AL*, Zeun J*, Marecek M*, Reimann H, Kretschmann S, Bausenwein J, van der Meijden ED, Karg MM, Haug T, Meintker L, Lutzny-Geier G, Mackensen A, Kremer AN. Influence of DM-sensitivity on immunogenicity of MHC class II restricted antigens. J Immunother Cancer 2021;9(7):e002401. doi: 10.1136/jitc-2021-002401.

5. Zeun J, Bernhardt AL, Neubeck S, Lang V, Korn K, Nagel L, Kunert T, Brey S, Atreya I, Denzin L, Bäuerle T, Hidner K, Büttner-Herold M, Winkler T, Mackensen A, Reimann H*, Kremer AN*. Selective H2-O tissue expression reduces risk for graft-versus-host disease in an in vivo transplantation model. Transpl Cell Therapy 2025; accepted

6. Mackensen A*, Muller F*, Mougiakakos D*, Boltz S, Wilhelm A, Aigner M, Völkl S, Simon D, Kleyer A, Munoz L, Kretschmann S, Kharboutli S, Gary R, Reimann H, Rosler W, Uderhardt S, Bang H, Herrmann M, Ekici AB, Buettner C, Habenicht KM, Winkler TH, Kronke G*, Schett G*. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022;28(10):2124-32. doi:10.1038/s41591-022-02017-5.

7. Müller F*, Taubmann J*, Bucci L, Wilhelm A, Bergmann C, Völkl S, Aigner M, Rothe T, Minopoulou I, Tur C, Knitza J, Kharboutli S, Kretschmann S, Vasova I, Spoerl S, Reimann H, Munoz L, Gerlach RG, Schäfer S, Grieshaber-Bouyer R, Korganow AS, Farge-Bancel D, Mougiakakos D, Bozec A, Winkler T, Krönke G, Mackensen A*, Schett G*. CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up. N Engl J Med 2024;390(8):687-700. doi:10.1056/NEJMoa2308917.

8. Kretschmann S*, Völkl S*, Reimann H, Krönke G, Schett G, Achenbach S, Lutzny-Geier G, Müller F, Mougiakakos D, Dingfelder J, Flamann C, Hanssens L, Gary R, Mackensen A, Aigner M. Successful generation of CD19 chimeric antigen receptor (CAR) T cells from patients with advanced Systemic Lupus Erythematosus (SLE). Transplant Cell Ther 2023;29(1):27-33. doi: 10.1016/j.jtct.2022.10.004.

9. Reimann H, Moosmann C, Schober K, Lang V, Verhagen J, Zeun J, Mackensen A, Kremer AN, Völkl S, Aigner M. Identification and characterization of T-cell receptors with therapeutic potential showing conserved specificity against all SARS-CoV 2 strains. Immunobiology 2023;228(5):152720. doi:10.1016/j.imbio.2023.152720.

10. Reimann H*, Nguyen A*, Sanborn JZ, Vaske CJ, Benz SC, Niazi K, Rabizadeh S, Spilman P, Mackensen A, Ruebner M, Hein A, Beckmann MW, van der Meijden ED, Bausenwein J, Kretschmann S, Griffioen M, Schlom J, Gulley JL, Lee KL, Hamilton DH, Soon-Shiong P, Fasching PA*, Kremer AN*. Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy. J Immunother Cancer 2021; 9(6):e002605. doi: 10.1136/jitc-2021-002605.

 

  • Dr. rer. nat. Hannah Reimann
    Universitätsklinikum Erlangen
    Medizinische Klinik 5
    Hartmannstraße 14
    91052 Erlangen
    T: +49 9131 85-36287
    hannah.reimann(at)uk-erlangen.de

 

Prof. Dr. med. Andreas Mackensen
Universitätsklinikum Erlangen
Medizinische Klinik 5
Hartmannstraße 14
91052 Erlangen

T+49 9131 85-35954

med5-direktion(at)uk-erlangen.de

Project IRTG

Integrated Research Training Group of CRC/TRR 221
Principal Investigators:Prof. Dr. med. Matthias Edinger, Prof. Dr. Krystelle Nganou-Makamdop, PhD, Prof. Dr. med. Sophia Danhof

The Integrated Research Training Group (IRTG) of the TRR 221 supports the participating doctoral researchers by providing well-structured and interdisciplinary training and qualification modules. The program focusses on basic and translational science in the area of allogeneic stem cell transplantation and cell therapy, but covers all topics and technologies of current biomedical research. Through close supervision and mentoring programs, the early career researchers are well supported for a successful graduation in an innovative research field.

Prof. Dr. Matthias Edinger
University Hospital Regensburg
Department of Internal Medicine III
Franz-Josef-Strauß-Allee 11
93053 Regensburg
T: +49 941 944-5580
matthias.edinger(at)ukr.de

PD Dr. Anita Kremer
University Hospital Erlangen
Department of Medicine 5
Ulmenweg 18
91054 Erlangen
T: +49 9131 85-43183
anita.kremer(at)uk-erlangen.de

PD Dr. Friederike Berberich-Siebelt
University Würzburg
Institute for Pathology
Josef-Schneider-Str. 2
97080 Würzburg
T: +49 931 3181208
path230@mail.uni-wuerzburg.de

Prof. Dr. med. Sophia Danhof, MHBA
University Hospital Würzburg
Department of Internal Medicine II
Oberdürrbacher Straße 6
97080 Würzburg / Germany
T: +49 931 / 201-44922
danhof_s@ukw.de

Project A02

Efficacy and safety of HLA-DPB1-specific chimeric antigen receptors (CAR) as mediators of graft-versus-leukemia (GvL) effect
Site: Regensburg
Principal Investigators: Prof. Dr. med. Simone Thomas, Prof. Dr. med. Wolfgang Herr, PD Dr. Patrick Schlegel

We developed a combinatorial ‘Logic-AND-Gating’ CAR that requires the simultaneous binding to alloHLA-DPB1 of patient origin and to the hematopoiesis-restricted antigen CD45 on leukemia cells for T cell activation. This new approach is thought to prevent HLA-DP-specific alloreactivity toward non-hematopoietic (CD45neg) tissues upon CAR treatment. We will now test this CAR and a novel alloHLA-A2/CD45 CAR for efficacy and toxicity in humanized NSG mouse models to show that this combinatorial ‘Logic-AND-gating’ CAR approach allows the induction of a selective GvL effect in the absence of GvHD.

  1. Jetani H, Garcia-Cadenas I, Nerreter T, Thomas S, Rydzek J, Meijide JB, Bonig H, Herr W, Sierra J, Einsele H, Hudecek M. CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia 2018;32(5):1168-79. doi:10.1038/s41375-018-0009-0.
  2. Herr W*, Eichinger Y*, Beshay J*, Bloetz A*, Vatter S, Mirbeth C, Distler E, Hartwig UF, Thomas S. HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation. Leukemia 2017;31(2):434-45. doi:10.1038/leu.2016.210.
  3. Klobuch S, Hammon K, Vatter-Leising S, Neidlinger E, Zwerger M, Wandel A, Neuber LM, Heilmeier B, Fichtner R, Mirbeth C, Herr W, Thomas S. HLA-DPB1 Reactive T Cell Receptors for Adoptive Immunotherapy in Allogeneic Stem Cell Transplantation. Cells 2020;9(5):1264. doi:10.3390/cells9051264.
  4. Hammon K*, Renner K*, Althammer M, Voll F, Babl N, Decking S-M, Siska PJ, Matos C, Conejo ZEC, Mendes K, Einwag F, Siegmund H, Iberl S, Berger RS, Dettmer K, Schoenmehl R, Brochhausen C, Herr W, Oefner PJ, Rehli M, Thomas S*, Kreutz M*. D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells. Haematologica 2024;109(8):2500-14. doi:10.3324/haematol.2023.283597.
  5. Seitz CM, Mittelstaet J, Atar D, Hau J, Reiter S, Illi C, Kieble V, Engert F, Drees B, Bender G, Krahl A-C, Knopf P, Schroeder S, Paulsen N, Rokhvarguer A, Scheuermann S, Rapp E, Mast AS, Rabsteyn A, Schleicher S, Grote S, Schilbach K, Kneilling M, Pichler B, Lock D, Kotter B, Dapa S, Miltenyi S, Kaiser A, Lang P, Handgretinger R*, Schlegel P*. Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting. Oncoimmunology 2021;10(1):2003532. doi:10.1080/2162402X.2021.2003532.
  6. Atar D, Mast AS, Scheuermann S, Ruoff L, Seitz CM, Schlegel P. Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas. Biomedicines 2022;10(10);2420. doi:10.3390/biomedicines10102420.
  7. Atar D, Ruoff L, Mast AS, Krost S, Moustafa-Oglou M, Scheuermann S, Kristmann B, Feige M, Canak A, Wolsing K, Schlager L, Schilbach K, Zekri L, Ebinger M, Nixdorf D, Subklewe M, Schulte J, Lengerke C, Jeremias I, Werchau N, Mittelstaet J, Lang P, Handgretinger R, Schlegel P, Seitz CM. Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia. Leukemia 2024;38(10):2183-95. doi:10.1038/s41375-024-02351-2.
  8. Wehler TC, Nonn M, Brandt B, Britten CM, Gröne M, Todorova M, Link I, Khan SA, Meyer RG, Huber C, Hartwig UF, Herr W. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 2007;109(1):365-73. doi:10.1182/blood-2006-04-014100.
  9. Distler E, Wölfel C, Köhler S, Nonn M, Kaus N, Schnürer E, Meyer RG, Wehler TC, Huber C, Wölfel T, Hartwig UF, Herr W. Acute myeloid leukemia (AML)-reactive cytotoxic T lymphocyte clones rapidly expanded from CD8(+) CD62L((high)+) T cells of healthy donors prevent AML engraftment in NOD/SCID IL2Rgamma(null) mice. Exp Hematol 2008;36(4):451-63. doi:10.1016/j.exphem.2007.12.011.
  10. Thomas S, Klobuch S, Sommer M, van Ewijk R, Theobald M, Meyer RG, Herr W. Human CD8+ memory and EBV-specific T cells show low alloreactivity in vitro and in CD34+ stem cell-engrafted NOD/SCID/IL-2Rγc null mice. Exp Hematol 2014;42(1):28-38.e1-2. doi:10.1016/j.exphem.2013.09.013.
  • Prof. Dr. med. Simone Thomas
    LIT – Leibniz Institute for Immunotherapy
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5501
    simone.thomas@ukr.de
  • Prof. Dr. med. Wolfgang Herr
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5142
    wolfgang.herr@ukr.de
  • PD Dr. Patrick Schlegel
    University Hospital Regensburg
    Department of Pediatric Hematology
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-2101
    patrick.schlegel@ukr.de

Project A03

Advanced CAR T cell engineering to augment the GvL effect of ASCT
Site: Würzburg
Principal Investigators: Prof. Dr. med. Michael Hudecek, Prof. Dr. med. Sophia Danhof, Prof. Dr. med. Hermann Einsele

We have developed CAR-T cells as ‘bridge to transplant’ (pre-ASCT) or as ‘CAR donor lymphocyte infusion’ (post-ASCT) in AML and multiple myeloma. Here, we will investigate the effect of glucocorticoids on CAR-T cells and render them resistant through gene-editing to maintain anti-tumor functionality during GvHD and/or CRS (Aim 1); we will accomplish serial antigen targeting for enhanced GvL effect (Aim 2); and we will analyze how alloreactivity and inflammation may cause AML resistance and/or neurotoxicity during CAR-T cell therapy (Aim 3) to improve the outcome of ASCT and integrate CAR-T therapy into the treatment algorithm.

 

  1. Roex MCJ, van Balen P, Germeroth L, Hageman L, van Egmond E, Veld SAJ,Hoogstraten C, van Liempt E, Zwaginga JJ, Wreede LC, Meij P, Vossen ACTM, Danhof S, Einsele H, Schaafsma MR, Veelken H, Halkes CJM, Jedema I, Falkenburg JHF. Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation-a phase I/II study. Leukemia 2020;34(3):831-44. doi:10.1038/s41375-019-0600-z. 
  1. San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, Fernández de Larrea C, Martínez-López J, Moreau P, Touzeau C, Leleu X, Avivi I, Cavo M, Ishida T, Kim SJ, Roeloffzen W, van de Donk NWCJ, Dytfeld D, Sidana S, Costa LJ, Oriol A, Popat R, Khan AM, Cohen YC, Ho PJ, Griffin J, Lendvai N, Lonardi C, Slaughter A, Schecter JM, Jackson CC, Connors K, Li K, Zudaire E, Chen D, Gilbert J, Yeh TM, Nagle S, Florendo E, Pacaud L, Patel N, Harrison SJ, Einsele H*. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med 2023;389(4):335-47. doi:10.1056/NEJMoa2303379. 
  1. García-Guerrero E, Rodríguez-Lobato LG, Sierro-Martínez B, Danhof S, Bates S, Frenz S, Haertle L, Götz R, Sauer M, Rasche L, Kortüm KM, Pérez-Simón JA, Einsele H, Hudecek M, Prommersberger SR. All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells. Haematologica 2023;108(2):568-80. doi:10.3324/haematol.2022.281339. 
  1. Vera-Cruz S, Jornet Culubret M, Konetzki V, Alb M, Friedel SR, Hudecek M, Einsele H,Danhof S, Scheller L. Cellular Therapies for Multiple Myeloma: Engineering Hope. Cancers (Basel) 2024;16(22):3867. doi: 10.3390/cancers16223867. 
  1. Gogishvili T, Danhof S, Prommersberger S, Rydzek J, Schreder M, Brede C, Einsele H, Hudecek M*. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes. Blood 2017;130(26):2838-47. doi:10.1182/blood-2017-04-778423
  2. Jetani H, Garcia-Cadenas I, Nerreter T, Thomas S, Rydzek J, Meijide JB, Bonig H, Herr W, Sierra J, Einsele H, Hudecek M*. CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia 2018;32(5):1168-79. doi:10.1038/s41375-018-0009-0.Mestermann K, Giavridis T, Weber J, Rydzek J, Frenz S, Nerreter T, Mades A, Sadelain M, Einsele H, Hudecek M*. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med 2019;11(499):eaau5907. doi:10.1126/scitranslmed.aau5907.
  3. Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, Klein M, Wempe A, Leister H, Raifer H, Picard F, Muhammad K, Ohl K, Romero R, Fischer F, Bauer CA, Huber M, Gress TM, Lauth M, Danhof S, Bopp T, Nerreter T, Mulder IE, Steinhoff U, Hudecek M, Visekruna A. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 2021;12(1):4077. doi:10.1038/s41467-021-24331-1. 
  1. Staudt S, Nikolka F, Perl M, Franz J, Leblay N, Yuan XK, Larrayoz M, Lozano T, Warmuth L, Fante MA, Skorupskaitė A, Fei T, Bromberg M, Martin-Uriz PS, Rodriguez-Madoz JR, Ziegler-Martin K, Adil-Gholam N,, Benz P, Tran Huu P, Freitag F, Riester Z, Stein-Thoeringer C, Schmitt M, Kleigrewe K, Weber J, Mangold K, Ho P, Einsele H, Prosper F, Ellmeier W, Busch D, Visekruna A, Slingerland J, Shouval R, Hiller K, Lasarte JJ, Martinez-Climent JÁ, Pausch P, Neri P, van den Brink M, Poeck H, Hudecek M, Luu M. Metabolization of microbial postbiotic pentanoate drives anti-cancer CAR T cells. bioRxiv2025:2024.08.19.608538. doi:10.1101/2024.08.19.608538. 
  1. Schauer MP, Weber J, Altieri B, Spieler P, Gehrke L, Sbiera S, Kircher S, Kurlbaum M, Kroiss M, Kiseljak-Vassiliades K, Wierman ME, Nerreter T, Einsele H, Fassnacht M, Landwehr LS, Hudecek M*. Autocrine signaling in hormonally active cancer induces antigen expression for immunotherapy. Published online on bioRxiv January 29, 2025:2025.01.28.632923. doi:10.1101/2025.01.28.632923.
  • Prof. Dr. med. Michael Hudecek
    University Hospital Würzburg
    Department of Medicine III
    Oberdürrbacher Straße 6
    97080 Würzburg
    T: +49 931 201-71091
    hudecek_m@ukw.de

 

  • Prof. Dr. med. Hermann Einsele
    University Hospital Würzburg
    Department of Medicine III
    Oberdürrbacher Straße 6
    97080 Würzburg
    T: +49 931 201-40001
    einsele_h@ukw.de
  • Prof. Dr. med. Sophia Danhof, MHBA
    University Hospital Würzburg
    Department of Internal Medicine II
    Oberdürrbacher Straße 6
    97080 Würzburg / Germany
    T: +49 931 / 201-44922
    danhof_s@ukw.de

Project A06

Advanced CAR T cell engineering to augment the GvL effect of ASCT
Site: Erlangen
Principal Investigators: Prof. Dr. med. Dimitrios Mougiakakos, Prof. Dr. rer. nat. Maik Luu

Previously, we demonstrated that ASCT patients exhibit increased oxidative stress compared to healthy controls and autologous SCT patients. Oxidative DNA damage in reconstituting T cells correlated with their functional impairment, and an increased relapse risk. Targeting DNA repair mechanisms and mitochondrial health with microbial postbiotics indicates their potential to restore T cell fitness. We aim to: (i) investigate the link between mitochondrial fitness, DNA damage repair, and GvL efficacy, (ii) synergize postbiotics with DNA repair mechanisms to enhance GvL activity, and (iii) translate these insights into a CAR T cell-based approach.

  1. Baur R, Karl F, Böttcher-Loschinski R, Stoll A, Völkl S, Gießl A, Flamann C, Bruns H, Schlötzer-Schrehardt U, Böttcher M, Schewe DM, Fischer T, Jitschin R, Mackensen A, Mougiakakos D. Accumulation of T-cell-suppressive PD-L1high extracellular vesicles is associated with GvHD and might impact GvL efficacy. J Immunother Cancer 2023;11(3):e006362. doi: 10.1136/jitc-2022-006362.
  2. Mougiakakos D, Johansson CC, Kiessling R. Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 2009;113(15):3542-5. doi: 10.1182/blood-2008-09-181040.
  3. Karl F, Stoll A, Böttcher-Loschinski R, Böttcher M, Baur R, Jacobs B, Völkl S, Jitschin R, Rösler W, Mackensen A, Mougiakakos D. Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients. Leukemia 2021;35(3):910-5. doi:10.1038/s41375-020-0956-0.
  4. Karl F, Liang C, Böttcher-Loschinski R, Stoll A, Flamann C, Richter S, Lischer C, Völkl S, Jacobs B, Böttcher M, Jitschin R, Bruns H, Fischer T, Holler E, Rösler W, Dandekar T, Mackensen A, Mougiakakos D. Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT. Blood 2023;141(13):1626-39. doi: 10.1182/blood.2022017267.
  5. Richter S, Böttcher M, Stoll A, Zeremski V, Völkl S, Mackensen A, Ekici AB, Jacobs B, Mougiakakos D. Increased PD-1 expression on circulating T cells correlates with inferior outcome after autologous stem cell transplantation. Transplant Cell Ther 2024; 30(6):628.e1-628.e9. doi: 10.1016/j.jtct.2024.03.005. 
  6. Jetani H, Navarro-Bailón A, Maucher M, Frenz S, Verbruggen C, Yeguas A, Vidriales MB, González M, Rial Saborido J, Kraus S, Mestermann K, Thomas S, Bonig H, Luu M, Monjezi R, Mougiakakos D, Sauer M, Einsele H, Hudecek M. Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia. Blood 2021;138(19):1830-42. doi: 10.1182/blood.2020009192.
  7. Jitschin R, Saul D, Braun M, Tohumeken S, Völkl S, Kischel R, Lutteropp M, Dos Santos C, Mackensen A, Mougiakakos D. CD33/CD3-bispecific T-cell engaging (BiTE®) antibody construct targets monocytic AML myeloid-derived suppressor cells. J Immunother Cancer 2018;6(1):116. doi: 10.1186/s40425-018-0432-9.
  8. Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, Klein M, Wempe A, Leister H, Raifer H, Picard F, Muhammad K, Ohl K, Romero R, Fischer F, Bauer CA, Huber M, Gress TM, Lauth M, Danhof S, Bopp T, Nerreter T, Mulder IE, Steinhoff U, Hudecek M*, Visekruna A*. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 2021;12(1):4077. doi: 10.1038/s41467-021-24331
  9. Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, Hofmann J, Raifer H, Vachharajani N, Carrascosa LC, Lamp B, Nist A, Stiewe T, Shaul Y, Adhikary T, Zaiss MM, Lauth M, Steinhoff U, Visekruna A. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun 2019;10(1):760. doi: 10.1038/s41467-019-08711-2. 
  10. Staudt S, Nikolka F, Perl M, Franz J, Leblay N, Yuan X, Larrayoz M, Lozano M, Warmuth L, Fante MA, Skorpskaite A, Fei T, Bromberg Maria, San Martin-Uriz P, Rodriguez-Madoz JR, Ziegler-Martin K, Adil Gholam N, Benz P, Tran Huu P, Freitag F, Riester R, Stein-Thoeringer C, Schmitt M, Kleigrewe K,  Weber J, Mangold K, Ho P, Einsele H, Prosper P, Ellmeier W, Busch D, Visekruna V, Slingerland J, Shouval R, Hiller H, Juan José Lasarte, Jose Angel Martinez-Climent, Pausch P, Neri P, van den Brink M, Poeck H, Hudecek M, Luu M. Metabolization of microbial postbiotic pentanoate drives anti-cancer CAR T cells. bioRxiv  2025; 2024.08.19.608538. doi: 10.1101/2024.08.19.608538. 
  • Prof. Dr. rer. nat. Maik Luu
    University Hospital Würzburg
    Medical Clinic & Polyclinic II
    Versbacher Straße 5
    97078 Würzburg
    T: +49 931 201-71098
    luu_m@ukw.de

Project A07 

Enhancing GvL responses by donor-derived CAR-modified CD8+ T memory stem cells
Site: Regensburg
Principal Investigator: Prof. Dr. med. Luca Gattinoni, Priv.-Doz. Dr. med. Dennis Harrer

IL-10 is emerging as a critical Achilles´ heel limiting the functionality of donor-derived CD19-CAR CD8+ T memory stem cells (TSCM) in the treatment of B-cell malignancies relapsing after ASCT. In this project, we seek to elucidate the role of IL-10 in CAR TSCM cell biology and develop strategies to overcome IL-10-mediated immunosuppression. Specifically, we will engineer CAR TSCM with (i) dominant-negative IL-10 receptors, (ii) IL-10 switch receptors converting IL-10 immunosuppressive signaling into T-cell supportive signals, and (iii) synthetic intramembrane proteolysis receptors designed to sustain stemness in response to IL-10.

  1. Harrer DC, Schenkel C, Bezler V, Kaljanac M, Hartley J, Barden M, Pan H, Holzinger A, Herr W, Abken H. CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop. Cells 2022;11(23):3839. doi: 10.3390/cells11233839.
  2. Harrer DC, Bezler V, Hartley J, Herr W, Abken H. IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities. Front Immunol 2023;14:1185618. doi: 10.3389/fimmu.2023.1185618.
  3. Baldwin JG, Heuser-Loy C, Saha T, Schelker RC, Slavkovic-Lukic D, Strieder N, Hernandez-Lopez I, Rana N, Barden M, Mastrogiovanni F, Martín-Santos A, Raimondi A, Brohawn P, Higgs BW, Gebhard C, Kapoor V, Telford WG, Gautam S, Xydia M, Beckhove P, Frischholz S, Schober K, Kontarakis Z, Corn JE, Iannacone M, Inverso D, Rehli M, Fioravanti J, Sengupta S, Gattinoni L. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell 2024;187(23):6614-30.e21. doi: 10.1016/j.cell.2024.08.029. 
  4. Schelker RC, Fioravanti J, Mastrogiovanni F, Baldwin JG, Rana N, Li P, Chen P, Vadász T, Spolski R, Heuser-Loy C, Slavkovic-Lukic D, Noronha P, Damiano G, Raccosta L, Maggioni D, Pullugula S, Lin JX, Oh J, Grandinetti P, Lecce M, Hesse L, Kocks E, Martín-Santos A, Gebhard C, Telford WG, Ji Y, Restifo NP, Russo V, Rehli M, Herr W, Leonard WJ, Gattinoni L. LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling. Signal Transduct Target Ther 2024;9(1):199. doi: 10.1038/s41392-024-01915-z.
  5. Gattinoni L*, Zhong XS*, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Garvin LM, Paulos CM, Muranski P, Restifo NP. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 2009;15(7):808-13. doi: 10.1038/nm.1982.
  6. Gattinoni L*, Lugli E*, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP. A human memory T cell subset with stem cell-like properties. Nat Med 2011;17(10):1290-7. doi: 10.1038/nm.2446.
  7. Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP*, Gattinoni L*. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 2013;123(10):4479-88. doi: 10.1172/JCI69589.
  8. Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V, Hocker JD, Dougherty S, Qin H, Klebanoff CA, Fry TJ, Gress RE, Kochenderfer JN, Stroncek DF, Ji Y, Gattinoni L. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 2016;128(4):519-28. doi: 10.1182/blood-2015-11-683847. 
  9. Gattinoni L*, Speiser DE*, Lichterfeld M*, Bonini C*. T memory stem cells in health and disease. Nat Med 2017;23(1):18-27. doi: 10.1038/nm.4241. 

 

  • Dr. med. Dennis Harrer
  • Universitätsklinikum Regensburg
    Klinik und Poliklinik für Innere Medizin III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-15557
    dennis.harrer(at)ukr.de
  • Prof. Dr. med. Luca Gattinoni
    LIT – Leibniz Institute for Immunotherapy
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38131
    luca.gattinoni(at)ukr.de

Project A08

Harnessing tissue homeostasis-promoting functions of specialized regulatory T cells in GvHD
Site: Regensburg
Prof. Dr. med. Markus Feuerer, Prof. Dr. Frederik Graw, PhD

Regulatory T cells (Treg) perform two distinct functions: they maintain self-tolerance and support tissue-repair and organ homeostasis by differentiation into specialized tissue-Treg cells. To harness the tissue-repair functions of these cells for preventing or treating GvHD after ASCT, we will combine in vitro organoid and in vivo mouse experiments with mathematical modelling with the aim of engineering ‘tissue smart’ Treg cells for the therapy of GvHD. We will translate these findings to human Treg cells to establish novel Treg cell therapy formats.

 

  1. Fischer JC, Bscheider M, Eisenkolb G, Lin CC, 
Wintges A, Otten V, Lindemans CA, Heidegger S, Rudelius M, Monette S, Porosnicu Rodriguez KA, Calafiore M, Liebermann S, Liu C, Lienenklaus S, Weiss S, Kalinke U, Ruland J, Peschel C, Shono Y, Docampo M, Velardi E, Jenq RR, Hanash AM, Dudakov JA, Haas T, van den Brink MRM, Poeck H. RIG-I/MAVS and STING signaling promote gut integrity during irradiation and immune-mediated tissue injury. Sci Transl Med 2017;9(386):eaag2513. doi: 10.1126/scitranslmed.aag2513.. 
  2. Heidegger S, Stritzke F, Dahl S, Daßler-Plenker J, Joachim L, Buschmann D, Fan K, Sauer CM, Ludwig N, Winter C, Enssle S, Li S, Perl M, Görgens A, Haas T, Orberg ET, Göttert S, Wölfel C, Engleitner T, Cortés-Ciriano I, Rad R, Herr W, Giebel B, Ruland J, Bassermann F, Coch C, Hartmann G, Poeck H. Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy. Cell Rep Med 2023;19;4(9):101171. doi: 10.1016/j.xcrm.2023.101171. 
  3. Thiele-Orberg E*, Meedt E*, Hiergeist A*, Xue J, Heinrich P, Ru J, Ghimire S, Miltiadous O, Lindner S, Tiefgraber M, Göldel S, Eismann T, Schwarz A, Göttert S, Jarosch S, Steiger K, Schulz C, Gigl M, Fischer JC, Janssen KP, Quante M, Heidegger S, Herhaus P, Verbeek M, Ruland J, van den Brink MRM, Weber D, Edinger M, Wolff D, Busch DH, Kleigrewe K, Herr W, Bassermann F, Gessner A, Deng L, Holler E, Poeck H. Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation. Nat Cancer 2024;5(1):187-208. doi: 10.1038/s43018-023-00669-x. 
  4. Joachim L, Göttert S, Sax A, Steiger K, Neuhaus K, Heinrich P, Fan K, Orberg ET, Kleigrewe K, Ruland J, Bassermann F, Herr W, Posch C, Heidegger S, Poeck H. The microbial metabolite desaminotyrosine enhances T-cell priming and cancer immunotherapy with immune checkpoint inhibitors. EBioMedicine 2023;97:104834. doi: 10.1016/j.ebiom.2023.104834. 
  5. Fischer JC, Göttert S, Heinrich P, Walther CN, Fan K, Eisenkolb G, Nefzger SM, Giller M, Khalid O, Ruben T, Jarosch S, Klostermeier L, Engleitner T, Strieder N, Gebhard C, Diederich S, Schmid NA, Lansink Rotgerink L, Joachim L, Ghimire S, Steiger K, Öllinger R, Rad R, Wolff D, Feuerer M, Hoffmann P, Edinger M, Rehli M, Tschurtschenthaler M, Kepp O, Kroemer G, Thiele Orberg E, Combs SE, Herr W, Bassermann F, Busch DH, Holler E, Heidegger S, Poeck H. Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury. bioRxiv 2025; doi: 10.1101/2024.10.21.617518. 
  6. Rendeiro AF, Krausgruber T, Fortelny N, Zhao F, Penz T, Farlik M, Schuster LC, Nemc A, Tasnády S, Réti M, Matrái Z, Alpár D, Bödör C, Schmidl C, Bock C. Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL. Nat Commun 2020; 11, 577. doi: 10.1038/s41467-019-14081-6. 
  7. Göttert S, Orberg ET, Fan K, Heinrich P, Matthe D, Khalid O, Klostermeier L, Suriano C, Strieder N, Gebhard C, Vonbrunn E, Mamilos A, Hirsch D, Meedt E, Kleigrewe K, Hiergeist A, Ghimire S, Joachim L, Voll F, Neuhaus K, Janssen KP, Perl M, Ruland J, Kreutz M, Weber D, Schmidl C, Köhler N, Tschurtschenthaler M, Hoffmann P, Edinger M, Wolff D, Bassermann F, Rehli M, Haller D, Evert M, Hildner K, Büttner-Herold M, Herr W, Gessner A, Heidegger S, Holler E*, Poeck H*. A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration. bioRxiv 2025. doi: 10.1101/2025.04.08.647747 
  8. Riegel D, Romero-Fernández E, Simon M, Adenugba AR, Singer K, Mayr R, Weber F, Kleemann M, Imbusch CD, Kreutz M, Brors B, Ugele I, Werner JM, Siska PJ, Schmidl C. Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells. Mol Cell 2023;83(4):622-36.e10. doi: 10.1016/j.molcel.2022.12.029. 
  9. Delacher M, Imbusch CD, Hotz-Wagenblatt A, Mallm JP, Bauer K, Simon M, Riegel D, Rendeiro AF, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband KL, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C*, Feuerer M*. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity 2020;52(2):295-312 e211. doi: 10.1016/j.immuni.2019.12.002. 
  10. Schmidl C*, Rendeiro AF*, Sheffield NC, Bock C. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat Methods 2015;12(10):963-65. doi: 10.1038/nmeth.3542. 
  • Prof. Dr. med. Hendrik Poeck
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5542
    hendrik.poeck(at)ukr.de
  • Dr. rer. nat. Christian Schmidl
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-18176
    christian.schmidl(at)ukr.de

Project B02

Targeting of TNFR2 and related molecules to separate graft-versus-host disease (GvHD) from the GvL effect
Site: Würzburg
Principal Investigator: Prof. Dr. rer. nat. Harald Wajant , Dr. rer. nat. Isabell Lang

We developed two novel human (hu) TNFR2 agonists with high specific activity and excellent stability and productivity: i) a nanobody-based agonist showing anti-GvHD activity in huTNFR2 knockin (ki) mice and ii) a huTNFR2-specific huTNF-based agonist whose murine surrogate exerts anti-GvHD activity in wild type mice. The two human agonists will now be compared head-to-head in huTNFR2 ki mice with regard to their anti-GvHD- and GvHD/GvL-separating activity to identify the lead candidate for clinical translation.

 

  1. Siegmund D, Wajant H. TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond. Nat Rev Rheumatol 2023;19(9):576-91. doi: 10.1038/s41584-023-01002-7.
  2. Prada JP, Wangorsch G, Kucka K, Lang I, Dandekar T, Wajant H. A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2. Bioinformatics 2021;37(5):669-76. doi: 10.1093/bioinformatics/btaa844.
  3. Kucka K, Lang I, Zhang T, Siegmund D, Medler J, Wajant H. Membrane lymphotoxin-α(2)β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist. Cell Death Dis 2021;12(4):360. doi: 10.1038/s41419-021-03633-8.
  4. Lang I, Füllsack S, Wajant H. Lack of Evidence for a Direct Interaction of Progranulin and Tumor Necrosis Factor Receptor-1 and Tumor Necrosis Factor Receptor-2 From Cellular Binding Studies. Front Immunol 2018;9:793. doi: 10.3389/fimmu.2018.00793.
  5. Medler J, Nelke J, Weisenberger D, Steinfatt T, Rothaug M, Berr S, Hünig T, Beilhack A, Wajant H. TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity. Cell Death Dis 2019;10(3):224. doi: 10.1038/s41419-019-1456-x.
  6. Vargas JG, Wagner J, Shaikh H, Lang I, Medler J, Anany M, Steinfatt T, Mosca JP, Haack S, Dahlhoff J, Büttner-Herold M, Graf C, Viera EA, Einsele H, Wajant H*, Beilhack A*. A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity. Front Immunol 2022;13:888274. doi: 10.3389/fimmu.2022.888274.
  7. Anany MA, Haack S, Lang I, Dahlhoff J, Vargas JG, Steinfatt T, Päckert L, Weisenberger D, Zaitseva O, Medler J, Kucka K, Zhang T, Van Belle T, van Rompaey L, Beilhack A, Wajant H. Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 2024;14(2):496-509. doi: 10.7150/thno.84404.
  8. Medler J, Kucka K, Melo V, Zhang T, von Rotenhan S, Ulrich J, Bremer E, Hudecek M, Beilhack A, Wajant H. CD40- and 41BB-specific antibody fusion proteins with PDL1 blockade-restricted agonism. Theranostics 2022;12(4):1486-99. doi: 10.7150/thno.66119.
  9. Zaitseva O, Anany M, Wajant H*, Lang I*. Basic characterization of antibodies targeting receptors of the tumor necrosis factor receptor superfamily. Front Immunol 2023;14:1115667. doi: 10.3389/fimmu.2023.1115667.
  10. Hesen N, Anany M, Freidel A, Baker M, Siegmund D, Zaitseva O, Wajant H, Lang I. Genetically engineered IgG1 and nanobody oligomers acquire strong intrinsic CD40 agonism. Bioengineered 2024.15(1);2302246. doi: 10.1080/21655979.2024.2302246.
  • Prof. Dr. rer. nat. Harald Wajant
    University Hospital Würzburg
    Department of Medicine II
    Molecular Internal Medicine
    Röntgenring 11
    97070 Würzburg
    T: +49 931 201-71000
    harald.wajant@mail-uni-wuerzburg.de
  • Dr. rer. nat. Isabell Lang
    University Hospital Würzburg
    Department of Internal Medicine II
    Division of Molecular Internal Medicine
    Auverahaus, Grombühlstraße 12
    97080 Würzburg
    T: +49 931 201-71040
    Lang_I@ukw.de

 

Project B03

Generation, molecular characteristics and effector mechanisms of CSF2+ T cells in GvHD
Site: Erlangen
Principal Investigator: Prof. Dr. med. Kai Hildner, Prof. Dr. Krystelle Nganou-Makamdop, PhD

Based on our preliminary work we hypothesize that distinct microbial signatures foster a subtle immunological milieu shift thereby promoting CSF2+ T cell-mediated GvHD. To test this systematically, we link immune, microbial and clinical profiles of CSF2-driven intestinal pathology in preclinical models. Moreover, we perform in depth characterizations of blood and gut CSF-2+ T cells in ASCT patients to explore the mechanisms of T cell differentiation. Lastly, our microbiome analysis seeks to identify drivers of CSF2 in ASCT patients. Overall, we aim to identify key mechanisms underlying CSF2+ T cell driven GvHD.

 

  1. Thiagarajan S, Neurath MF, Hildner K. Resolution of acute intestinal graft-versus-host disease. Semin Immunopathol 2019;41(6):655-64. doi: 10.1007/s00281-019-00769-w. 
  2. Ullrich E, Abendroth B, Rothamer J, Huber C, Büttner-Herold M, Buchele V, Vogler T, Longerich T, Zundler S, Völkl S, Beilhack A, Rose-John S, Wirtz S, Weber GF, Ghimire S, Kreutz M, Holler E, Mackensen A, Neurath MF, Hildner K. BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease. J Clin Invest 2018;128(3):916-30. doi: 10.1172/JCI89242. 
  3. Buchele V, Abendroth B, Büttner-Herold M, Vogler T, Rothamer J, Ghimire S, Ullrich E, Holler E, Neurath MF, Hildner K. Targeting Inflammatory T Helper Cells via Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis. Front Immunol 2018;9:1138. doi: 10.3389/fimmu.2018.01138. 
  4. Enderle K, Dinkel M, Spath EM, Schmid B, Zundler S, Tripal P, Neurath MF, Hildner K*, Neufert C*. Dynamic Imaging of IEL-IEC Co-Cultures Allows for Quantification of CD103-Dependent T Cell Migration. Int J Mol Sci 2021;22(10).: 5148. doi: 10.3390/ijms22105148.*shared senior authorship 
  5. Matthe DM, Dinkel M, Schmid B, Vogler T, Neurath MF, Poeck H, Neufert C, Büttner-Herold M, Hildner K. Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease. Front Immunol 2023;14:1253514. doi: 10.3389/fimmu.2023.1253514. 
  6. Buchele V, Konein P, Vogler T, Kunert T, Enderle K, Khan H, Büttner-Herold M, Lehmann CHK, Amon L, Wirtz S, Dudziak D, Neurath MF, Neufert C, Hildner K. Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner. Front Immunol 2020;11:590893. doi: 10.3389/fimmu.2020.590893. 
  7. Nganou-Makamdop K, Douek DC. The Gut and the Translocated Microbiomes in HIV Infection: Current Concepts and Future Avenues. Pathog Immun 2024;9(1):168-94. doi: 10.20411/pai.v9i1.693. 
  8. Morou A, Brunet-Ratnasingham E, Dube M, Charlebois R, Mercier E, Darko S, Brassard N, Nganou-Makamdop K, Arumugam S, Gendron-Lepage G, Yang L, Niessl J, Baxter AE, Billingsley JM, Rajakumar PA, Lefebvre F, Johnson RP, Tremblay C, Routy JP, Wyatt RT, Finzi A, Douek DC, Kaufmann DE. Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease. Nat Immunol 2019;20(8):1059-70. doi: 10.1038/s41590-019-0418-x. 
  9. Nganou-Makamdop K*, Talla A*, Sharma AA*, Darko S, Ransier A, Laboune F, Chipman JG, Beilman GJ, Hoskuldsson T, Fourati S, Schmidt TE, Arumugam S, Lima NS, Moon D, Callisto S, Schoephoerster J, Tomalka J, Mugyenyi P, Ssali F, Muloma P, Ssengendo P, Leda AR, Cheu RK, Flynn JK, Morou A, Brunet-Ratnasingham E, Rodriguez B, Lederman MM, Kaufmann DE, Klatt NR, Kityo C, Brenchley JM, Schacker TW, Sekaly RP, Douek DC. Translocated microbiome composition determines immunological outcome in treated HIV infection. Cell 2021;184(15):3899-914 e16. doi: 10.1016/j.cell.2021.05.023. 
  10. Kiessling M, Cole JJ, Kübel S, Klein P, Korn K, Henry AR, Laboune F, Fourati S, Harrer E, Harrer T, Douek DC, Überla K, Nganou-Makamdop K. Chronic inflammation degrades CD4 T cell immunity to prior vaccines in treated HIV infection. Nat Commun 2024;15(1):10200. doi: 10.1038/s41467-024-54605-3. 
  • Prof. Dr. med. Kai Hildner
    University Hospital Erlangen
    Department of Medicine 1
    Ulmenweg 18
    91054 Erlangen
    T: +49 9131 85-35000 o. 85-45173
    kai.hildner@uk-erlangen.de

Project B07

GvHD therapy with donor regulatory T cells
Site: Regensburg
Principal Investigators: PD Dr. rer. nat. Petra Hoffmann, Prof. Dr. rer. nat. Michael Rehli, Prof. Dr. med. Matthias Edinger

We initially demonstrated that donor CD4+CD25+Foxp3+ regulatory T cells (Treg) prevent acute GvHD after MHC-mismatched ASCT. We then showed that they are also efficacious in the treatment of aGvHD and revealed that donor Treg rapidly adapt their phenotype and gene expression to the local environment, especially in the gastrointestinal tract. We now explore whether the microbiome contributes to organ-specific Treg adaptation, examine the mechanisms underlying their immune and tissue regenerating effects and determine, whether their therapeutic efficacy can be enhanced by targeting tissue-specific or ubiquitous antigens.

 

 

  1. Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Schmidleithner L, Bittner S, Pant A, Ritter U, Hehlgans T, Riegel D, Schneider V, Groeber-Becker FK, Eigenberger A, Gebhard C, Strieder N, Fischer A, Rehli M, Hoffmann P, Edinger M, Strowig T, Huehn J, Schmidl C, Werner JM, Prantl L, Brors B, Imbusch CD, Feuerer M. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells. Immunity 2021;54(4):702-20 e17. DOI: 10.1016/j.immuni.2021.03.007.
  2. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002;196(3):389-99. DOI: 10.1084/jem.20020399.
  3. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9(9):1144-50. DOI: 10.1038/nm915.
  4. Riegel C, Boeld TJ, Doser K, Huber E, Hoffmann P*, Edinger M*. Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells. Leukemia 2020;34(3):895-908. DOI: 10.1038/s41375-019-0625-3.
  5. Dittmar DJ*, Pielmeier F*, Strieder N, Fischer A, Herbst M, Stanewsky H, Wenzl N, Röseler E, Eder R, Gebhard C, Schwarzfischer-Pfeilschifter L, Albrecht C, Herr W, Edinger M*, Hoffmann P*, Rehli M*. Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease. Nat Commun 2024;15(1):3224. DOI: 10.1038/s41467-024-47575-z.
  6. Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, Edinger M. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 2006;108(13):4260-7. DOI: 10.1182/blood-2006-06-027409.
  7. Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood 2004;104(3):895-903. DOI: 10.1182/blood-2004-01-0086.
  8. Hoffmann P, Boeld TJ, Eder R, Albrecht J, Doser K, Piseshka B, Dada A, Niemand C, Assenmacher M, Orsó E, Andreesen R, Holler E, Edinger M. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant 2006;12(3):267-74. DOI: 10.1016/j.bbmt.2006.01.005.
  9. Schmidl C, Hansmann L, Lassmann T, Balwierz PJ, Kawaji H, Itoh M, Kawai J, Nagao-Sato S, Suzuki H, Andreesen R, Hayashizaki Y, Forrest AR, Carninci P, Hoffmann P, Edinger M, Rehli M, consortium F. The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations. Blood 2014;123(17):e68-78. DOI: 10.1182/blood-2013-02-486944.
  10. Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 2009;19(7):1165-74. DOI: 10.1101/gr.091470.109.
  • PD Dr. rer. nat. Petra Hoffmann
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38492
    petra.hoffmann(at)ukr.de
  • Prof. Dr. rer. nat. Michael Rehli
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38487
    michael.rehli(at)ukr.de
  • Prof. Dr. med. Matthias Edinger
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5582
    matthias.edinger(at)ukr.de

Project B08

Harnessing tissue homeostasis-promoting functions of specialized regulatory T cells in graft-versus-host disease.
Site: Regensburg, Erlangen-Nürnberg
Principal Investigator: Prof. Dr. med. Markus Feuerer Prof., Dr. Frederik Graw PhD

Regulatory T cells (Treg) perform two distinct functions: they maintain self-tolerance and support organ homeostasis by differentiation into specialized tissue Treg cells. We aim to harness the tissue-repair, organ-homeostasis promoting function of tissue-resident Treg cells to prevent or treat graft-versus-host disease after allogeneic bone marrow transplantation. In this respect, we study a TH2-biased tissue Treg population that is present in virtually all organs. We will use loss-of-function and gain-of-function experiments to understand how these cells function during GvHD. Finally, we want to translate these findings into the human context.

 

  1. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D.  Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009;15(8):930-9. doi: 10.1038/nm.2002.
  2. Delacher M, Imbusch CD, Weichenhan D, Breiling A, Hotz-Wagenblatt A, Träger U, Hofer AC, Kägebein D, Wang Q, Frauhammer F, Mallm JP, Bauer K, Herrmann C, Lang PA, Brors B, Plass C, Feuerer M. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat Immunol 2017;18(10):1160-72. doi: 10.1038/ni.3799.
  3. Delacher M, Imbusch CD, Hotz-Wagenblatt A, Mallm JP, Bauer K, Simon M, Riegel D, Rendeiro AF, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband KL, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C, Feuerer M. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity 2020;52(2):295-312.e11. doi: 10.1016/j.immuni.2019.12.002. 
  4. Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Schmidleithner L, Bittner S, Pant A, Ritter U, Hehlgans T, Riegel D, Schneider V, Groeber-Becker FK, Eigenberger A, Gebhard C, Strieder N, Fischer A, Rehli M, Hoffmann P, Edinger M, Strowig T, Huehn J, Schmidl C, Werner JM, Prantl L, Brors B, Imbusch CD, Feuerer M. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells. Immunity 2021;54(4):702-20.e17. doi: 10.1016/j.immuni.2021.03.007.
  5. Delacher M, Schmidleithner L, Simon M, Stüve P, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Ruhland B, Hofmann V, Bittner S, Ritter U, Pant A, Helbich SS, Voss M, Lemmermann NA, Bessiri-Schake L, Bohn T, Eigenberger A, Menevse AN, Gebhard C, Strieder N, Abken H, Rehli M, Huehn J, Beckhove P, Hehlgans T, Junger H, Geissler EK, Prantl L, Werner JM, Schmidl C, Brors B, Imbusch CD, Feuerer M. The effector program of human CD8 T cells supports tissue remodeling. J Exp Med 2024;221(2):e20230488. doi: 10.1084/jem.20230488.
  6. Simon M, Stüve P, Schmidleithner L, Bittner S, Beumer N, Strieder N, Schmidl C, Pant A, Gebhard C, Eigenberger A, Rehli M, Prantl L, Hehlgans T, Brors B, Imbusch CD, Delacher M, Feuerer M. Single-cell chromatin accessibility and transposable element landscapes reveal shared features of tissue-residing immune cells. Immunity 2024;57(8):1975-93.e10. doi: 10.1016/j.immuni.2024.06.015. 
  7. Bittner S, Ruhland B, Hofmann V, Schmidleithner L, Schambeck K, Pant A, Stüve P, Delacher M, Echtenacher B, Edinger M, Hoffmann P, Rehli M, Gebhard C, Strieder N, Hehlgans T, Feuerer M. Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy. Proc Natl Acad Sci U S A 2022;119(40):e2208436119. doi: 10.1073/pnas.2208436119.
  8. Bittner S, Hehlgans T, Feuerer M. Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond. Trends Immunol 2023;44(6):468-83. doi: 10.1016/j.it.2023.04.005. 
  9. Raach B, Bundgaard N, Haase MJ, Starruß J, Sotillo R, Stanifer ML, Graw F. Influence of cell type specific infectivity and tissue composition on SARS-CoV-2 infection dynamics within human airway epithelium. PLoS Comput Biol 2023;9(8):e1011356. doi: 10.1371/journal.pcbi.1011356.
  10. Frank R, Gabel M, Heiss K, Mueller AK, Graw F. Varying Immunizations With Plasmodium Radiation-Attenuated Sporozoites Alter Tissue-Specific CD8(+) T Cell Dynamics. Front Immunol 2018;9:1137. doi: 10.3389/fimmu.2018.01137. 
  • Prof. Dr. med. Markus Feuerer
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38121
    markus.feuerer@ukr.de
  • Prof. Dr. Frederik Graw
    FAU Erlangen-Nürnberg/University Hospital Erlangen
    Department of Medicine 5
    Kussmaulallee 12
    91054 Erlangen
    T: +49 9131 85-47601
    frederik.graw@fau.de

Project B09

Regulation of tissue—resident myeloid cells controlling acute and chronic GvHD
Site: Würzburg
Principal Investigator: Prof. Dr. med. Dr. med. univ. Andreas Beilhack, Dr. rer. nat. Mercedes Gomez de Agüero

Acute GvHD primarily affects the gut, liver, and skin, while sparing organs like the kidney through unclear mechanisms. We identified perivascular PD-L1hi intestinal macrophages (MPs) as key regulators of acute GvHD. While renal MPs lose PD-L1 expression following microbial priming, conditioning-induced microbial translocation rapidly recruits PD-L1+Ly6C+ monocytes that restore the renal PD-L1+ MP network. This project investigates how microbial shifts – whether induced by conditioning or through eubiotic restoration – govern organ-specific myeloid resilience, thereby suppressing GvHD while preserving GvL effects

 

1. Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Pena Mosca J, Arellano Viera E, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022;7(22):e154250. doi: 10.1172/jci.insight.154250.  

2. Erny D, Dokalis N, Mezo C, Castoldi A, Mossad O, Staszewski O, Frosch M, Villa M, Fuchs V, Mayer A, Neuber J, Sosat J, Tholen S, Schilling O, Vlachos A, Blank T, Gomez de Agüero M, Macpherson AJ, Pearce EJ, Prinz M. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metab 2021;33(11):2260-76 e7. doi: 10.1016/j.cmet.2021.10.010. 

3. Gomez de Agüero M, Ganal-Vonarburg SC, Fuhrer T, Rupp S, Uchimura Y, Li H, Steinert A, Heikenwalder M, Hapfelmeier S, Sauer U, McCoy KD, Macpherson AJ. The maternal microbiota drives early postnatal innate immune development. Science 2016;351(6279):1296-302. doi: 10.1126/science.aad2571. 

4. Jakob MO, Spari D, Sanchez Taltavull D, Salm L, Yilmaz B, Doucet Ladeveze R, Mooser C, Pereyra D, Ouyang Y, Schmidt T, Mattiola I, Starlinger P, Stroka D, Tschan F, Candinas D, Gasteiger G, Klose CSN, Diefenbach A, Gomez de Agüero M*, Beldi G.* ILC3s restrict the dissemination of intestinal bacteria to safeguard liver regeneration after surgery. Cell Rep 2023;42(3):112269. doi: 10.1016/j.celrep.2023.112269. 

5. Castelo J, Araujo-Aris S, Barriales D, Tanner Pasco S, Seoane I, Pena-Cearra A, Palacios A, Simo C, Garcia-Canas V, Khamwong M, Martin-Ruiz I, Gonzalez-Lopez M, Barcena L, Martin Rodriguez JE, Lavin JL, Gutiez N, Marcos R, Atondo E, Cobela A, Plaza-Vinuesa L, Plata A, Santos-Fernandez E, Fernandez-Tejada A, Villaran MC, Mancheno JM, Maria Flores J, Maria Aransay A, Pellon A, de Las Rivas B, Munoz R, Margolles A, Ruas-Madiedo P, Victoria Selma M, Gomez de Agüero M, Abecia L, Anguita J, Rodriguez H. The microbiota metabolite, phloroglucinol, confers long-term protection against inflammation. Gut Microbes 2024;16(1):2438829. doi: 10.1080/19490976.2024.2438829. 

6. Obata Y, Castano A, Boeing S, Bon-Frauches AC, Fung C, Fallesen T, Gomez de Agüero M, Yilmaz B, Lopes R, Huseynova A, Horswell S, Maradana MR, Boesmans W, Vanden Berghe P, Murray AJ, Stockinger B, Macpherson AJ, Pachnis V. Neuronal programming by microbiota regulates intestinal physiology. Nature 2020;578(7794):284-9. doi: 10.1038/s41586-020-1975-8. 

7. Brandl A, Solimando AG, Mokhtari Z, Tabares P, Medler J, Manz H, Da Via MC, Croci GA, Kurzwart M, Thusek S, Schneider T, Ebert R, Jakob F, Einsele H, Beilhack A. Junctional adhesion molecule C expression specifies a CD138low/neg multiple myeloma cell population in mice and humans. Blood Adv 2022;6(7):2195-2206. doi: 10.1182/bloodadvances.2021004354. 

8. Haake M, Haack B, Schäfer T, Harter PN, Mattavelli G, Eiring P, Vashist N, Wedekink F, Genssler S, Fischer B, Dahlhoff J, Mokhtari F, Kuzkina A, Welters MJP, Benz TM, Sorger L, Thiemann V, Almanzar G, Selle M, Thein K, Späth J, Gonzalez MC, Reitinger C, Ipsen-Escobedo A, Wistuba-Hamprecht K, Eichler K, Filipski K, Zeiner PS, Beschorner R, Goedemans R, Gogolla FH, Hackl H, Rooswinkel, RW, Thiem A, Roche PR, Joshi H, Puhringer D, Wöckel A, Diessner JE, Rüdiger M, Leo E, Cheng PF, Levesque MP, Goebeler M, Sauer M, Nimmerjahn F, Schuberth-Wagner C, von Felten S, Mittelbronn M, Mehling M, Beilhack A, van der Burg SH, Riedel A, Weide B, Dummer R, Wischhusen J. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun 2023;14(1):4253. doi: 10.1038/s41467-023-39817-3. 

9. Nava Lauson CB, Tiberti S, Corsetto PA, Conte F, Tyagi P, Machwirth M, Ebert S, Loffreda A, Scheller L, Sheta D, Mokhtari Z, Peters T, Raman AT, Greco F, Rizzo AM, Beilhack A, Signore G, Tumino N, Vacca P, McDonnell LA, Raimondi A, Greenberg PD, Huppa JB, Cardaci S, Caruana I, Rodighiero S, Nezi L, Manzo T. Linoleic acid potentiates CD8(+) T cell metabolic fitness and antitumor immunity. Cell Metab 2023;35(4):633-50.e9. doi: 10.1016/j.cmet.2023.02.013. 

10. Flamann C*, Shaik H*, Matos C, Kreutz M, Ali H, Kern MAG, Büttner-Herold M, Jacobs B, Völkl S, Lischer C, Kellner C, Berges J, Bitterer K, Saul D, Goel M, L, Link-Rachner CS, Zernecke A, Weber D, Mougiakakos D, Mackensen A, Beilhack A, Bruns H. Augmented CD47 expression impairs alloreactive T cell clearance after allo-HCT. Blood 2025;2023-023056R2. doi: In press. 

Prof. Dr. med. Dr. med. univ. Andreas Beilhack

Universitätsklinikum Würzburg

Medizinische Klinik und Poliklinik II

ZEMM Zentrum für Experimentelle Molekulare Medizin

Zinklesweg 10

97078 Würzburg

T: 0931 201-44040

beilhack_a(at)ukw.de

Dr. rer. nat. Mercedes Gomez de Agüero

Julius-Maximilians-University Würzburg

Würzburg Institute für Systemimmunologie

Versbacher Straße 9

97078 Würzburg

T: +49 931 80303

mercedes.gomez(at)uni-wuerzburg.de

Project B10

Dysregulation of the B cell compartment leading to chronic GvHD Summary:
Sites: Erlangen & Regensburg
Principal Investigators: Prof. Dr. med. Fabian Müller, Prof. Dr. med. Daniel Wolff

In prior work we described elevated circulating IgA+ plasmablasts as early predictors of chronic GvHD. These plasmablasts home to the gut and produce commensal-binding IgA potentially modulating the microbiota. Aiming to identify biological processes that predict treatment response, we analyze peripheral blood and tissues for dynamic therapy-induced effects on plasmablasts and B cell trajectories, inflammatory pathways, BCR-repertoire reconstitution, and alterations of T follicular helper cells. The dynamic changes will be correlated with clinical response to standard of care and to CD19 CAR T cell therapy within a clinical trial.

  1. Wolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, Hamadani M, Arai S, Salhotra A, Perez-Simon JA, Alousi A, Choe H, Kwon M, Bermúdez A, Kim I, Socié G, Chhabra S, Radojcic V, O’Toole T, Tian C, Ordentlich P, DeFilipp Z, Kitko CL, AGAVE-201 Investigators. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med 2024;391(11):1002-14. doi: 10.1056/NEJMoa2401537.
  2. Langer R, Lelas A, Rittenschober M, Piekarska A, Sadowska-Klasa A, Sabol I, Desnica L, Greinix H, Dickinson A, Inngjerdingen M, Lawitschka A, Vrhovac R, Pulanic D, Güneş S, Klein S, Moritz Middeke J, Grube M, Edinger M, Herr W, Wolff D. Retrospective analysis of the incidence and outcome of late acute and chronic graft-versus-host disease-an analysis from transplant centers across Europe. Front Transplant 2024;3:1332181. doi: 10.3389/frtra.2024.1332181.
  3. Habenicht KM, Wanzek A, Bootz A, Schäfer S, Vollmer L, Hiergeist A, Fante M, Hasenbank J, Schneider A, Spoerl S, Brandt A, Rehli M, Hoffmann P, Wirtz S, Gerlach R, Gessner A, Mackensen A, Winkler J, Wolff D, Winkler TH. Expansions of circulating plasmablasts producing commensal-reactive IgA antibodies are predictors for chronic GVHD. Blood 2025;.doi: 10.1182/blood.2024027301 (2025).
  4. Scheidler L, Hippe K, Ghimire S, Weber D, Weber M, Meedt E, Hoffmann P, Lehn P, Burkhardt R, Mamilos A, Edinger M, Wolff D, Poeck H, Evert M, Gessner A, Herr W, Holler E. Intestinal IgA-positive plasma cells are highly sensitive indicators of alloreaction early after allogeneic transplantation and associate with both graft-versus-host disease and relapse-related mortality. Haematologica 2023;108(11):2993-3000. doi: 10.3324/haematol.2022.282188.
  5. Schett G, Müller F, Taubmann J, Mackensen A, Wang W, Furie RA, Gold R, Haghikia A, Merkel PA, Caricchio R, D’Agostino MA, Locatelli F, June CH, Mougiakakos D. Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nat Rev Rheumatol 2024;20(9):531-44. doi: 10.1038/s41584-024-01139-z.
  6. Klobuch S, Weber D, Holler B, Edinger M, Herr W, Holler E, Wolff D. Long-term follow-up of rituximab in treatment of chronic graft-versus-host disease-single center experience. Ann Hematol 2019;98(10):2399-2405. doi: 10.1007/s00277-019-03768-x.
  7. Auth J, Müller F, Völkl S, Bayerl N, Distler JHW, Tur C, Raimondo MG, Chenguiti Fakhouri S, Atzinger A, Coppers B, Eckstein M, Liphardt AM, Bäuerle T, Tascilar K, Aigner M, Kretschmann S, Wirsching A, Taubmann J, Hagen M, Gyorfi AH, Kharboutli S, Krickau T, Dees C, Spörl S, Rothe T, Harrer T, Bozec A, Grieshaber-Bouyer R, Fuchs F, Kuwert T, Berking C, Horch RE, Uder M, Mackensen A, Schett G, Bergmann C. CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series. Lancet Rheumatol 2025;7(2):e83-e93. doi: 10.1016/S2665-9913(24)00282-0.
  8. Liang C, Spoerl S, Xiao Y, Habenicht KM, Haeusl SS, Sandner I, Winkler J, Strieder N, Eder R, Stanewsky H, Alexiou C, Dudziak D, Rosenwald A, Edinger M, Rehli M, Hoffmann P, Winkler TH, Berberich-Siebelt F. Oligoclonal CD4(+)CXCR5(+) T cells with a cytotoxic phenotype appear in tonsils and blood. Commun Biol 2024;7(1):879. doi: 10.1038/s42003-024-06563-1.
  9. Müller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Völkl S, Aigner M, Rothe T, Minopoulou I, Tur C, Knitza J, Kharboutli S, Kretschmann S, Vasova I, Spoerl S, Reimann H, Munoz L, Gerlach RG, Schafer S, Grieshaber-Bouyer R, Korganow AS, Farge-Bancel D, Mougiakakos D, Bozec A, Winkler TH, Krönke G, Mackensen A, Schett G. CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up. N Engl J Med 2024;390(8):687-700. doi: 10.1056/NEJMoa2308917.
  10. Pelzl R BG, Gsottberger F, Scholz J K, Rübner M, Yao H, Wendland K, Rejeski K, Altmann H, Petkovic S, Mellenthin L, Kübel S, Schmiedeberg M, Klein P, Petrera A, Baur R, Eckstein S, Hoepffner-Grundy S, Röllig C, Subklewe M, Huebner H, Schett G, Mackensen A, Laurenti L, Graw F, Völkl S, Nganou-Makamdop K, Müller F. Large B-cell lymphoma imprints dysfunctional immune phenotype that persists years after treatment. Blood 2025; accepted for publication.
  • Prof. Dr. Fabian Müller
    University Hospital of Erlangen
    Department of Internal Medicine 5 – Hematology and Oncology
    Ulmenweg 18
    91054 Erlangen
    T +49 9131 85-43107
    Fabian.mueller@uk-erlangen.de
  • Prof. Dr. med. Daniel Wolff
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5531
    daniel.wolff(at)ukr.de

Project B11

Targeting the reciprocal T cell-endothelial interactions after ASCT
Site: Würzburg
Principal Investigators: Prof. Dr. med. Alma Zernecke-Madsen, Prof. Dr. med. univ. Dr. med. Andreas Beilhack

We show that endothelial cells in lymphoid organs prime alloreactive T cells in vivo and trigger lethal GvHD. Early endothelial injury increases the risks of GvHD and atherosclerosis, while VEGFR1 deficiency in endothelial cells induces an anti-inflammatory phenotype and reduces the accumulation of alloreactive T cells in the gut. We will investigate how myeloablative conditioning, ASCT, and T-cell homing affect bone marrow endothelial reconstruction and modulate T-cell responses. By studying bone marrow endothelial-immune cell interactions, we aim to develop therapeutic strategies to enhance GvL and reduce GvHD

 

  1. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI, Baker EM, Cao YA, Contag CH, Negrin RS. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 2005;106(3):1113-22. doi: 10.1182/blood-2005-02-0509.
  2. Bäuerlein CA, Riedel SS, Baker J, Brede C, Garrote AL, Chopra M, Ritz M, Beilhack GF, Schulz S, Zeiser R, Schlegel PG, Einsele H, Negrin RS, Beilhack A. A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model. BMC Med 2013;11:134. doi: 10.1186/1741-7015-11-134.
  3. Bundalo M, Vorlova S, Ulrich J, Barbieri R, Richter L, Höna L, Egg M, Bock J, Schäfer S, Solé NA, Rosa A, Rizzo G, Cochain C, Kastenmüller W, Henke E, Skryabin BV, Rozhdestvensky TS, Wildgruber M, Lorenz K, Kuhn M, Zernecke A. Redirecting full-length FLT1 expression towards its soluble isoform. promotes postischemic angiogenesis. bioRxiv 2024:2024.2009.2019.613989. doi: 10.1101/2024.09.19.613989
  4. Cochain C, Koch M, Chaudhari SM, Busch M, Pelisek J, Boon L, Zernecke A. CD8+ T Cells Regulate Monopoiesis and Circulating Ly6Chigh Monocyte Levels in Atherosclerosis in Mice. Circ Res 2015:117(3):244-53. doi: 10.1161/CIRCRESAHA.117.304611.
  5. Gil-Pulido J, Amézaga N, Jorgacevic I, Manthey HD, Rösch M, Brand T, Cidlinsky P, Schäfer S, Beilhack A, Saliba AE, Lorenz K, Boon L, Prinz I, Waisman A, Korn T, Cochain C, Zernecke A. Interleukin-23 receptor expressing gammadelta T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice. Cardiovasc Res 2022;118(14):2932-945. doi: 10.1093/cvr/cvab359.
  6. Zernecke A, Erhard F, Weinberger T, Schulz C, Ley K, Saliba AE, Cochain C. Integrated single-cell analysis based classification of vascular mononuclear phagocytes in mouse and human atherosclerosis. Cardiovasc Res 2023;119(8):1676-89. doi: 10.1093/cvr/cvac161.
  7. Zernecke A, Winkels H, Cochain C, Williams JW, Wolf D, Soehnlein O, Robbins CS, Monaco C, Park I, McNamara CA, Binder CJ, Cybulsky MI, Scipione CA, Hedrick CC, Galkina EV, Kyaw T, Ghosheh Y, Dinh HQ, Ley K. Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas. Circ Res 2020;127(3):402-26. doi: 10.1161/CIRCRESAHA.120.316903.
  8. Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Pena Mosca J, Arellano Viera E, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022;7(22):e154250. doi: 10.1172/jci.insight.154250.
  9. Beilhack A, Schulz S, Baker J, Beilhack GF, Nishimura R, Baker EM, Landan G, Herman EI, Butcher EC, Contag CH, Negrin RS. Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. Blood 2008;111(5):2919-28. doi: 10.1182/blood-2007-09-112789.
  10. Majumder S, Jugovic I, Saul D, Bell L, Hundhausen N, Seal R, Beilhack A, Rosenwald A, Mougiakakos D, Berberich-Siebelt F. Rapid and Efficient Gene Editing for Direct Transplantation of Naive Murine Cas9(+) T Cells. Front Immunol 2021;12:683631. doi: 10.3389/fimmu.2021.683631.
  • Prof. Dr. med. Alma Zernecke-Madsen
    University Hospital Würzburg
    Department of Experimental Biomedicine II
    Josef-Schneider-Straße 2
    97080 Würzburg
    T: +49 931 201-48331
    alma.zernecke(at)uni-wuerzburg.de
  • Prof. Dr. med. Dr. med. univ. Andreas Beilhack
    University Hospital Würzburg
    Department of Medicine II
    ZEMM Center for Experimental Molecular Medicine
    Zinklesweg 10
    97078 Würzburg
    T: +49 931 201-44040
    beilhack_a(at)ukw.de

Project B12

Regulation of the immune balance during ASCT by vitamin D3
Sites: Regensburg & Erlangen
Principal Investigators: Prof. Dr. rer. nat. Marina Kreutz, Dr. rer. nat. Carina Matos, Priv.-Doz. Dr. rer. nat. Heiko Bruns

We identified low vitamin D receptor (VDR) expression as an independent risk factor for mortality following ASCT. In a murine ASCT model, VDR-KO recipients showed reduced GvHD severity, likely due to elevated vitamin D3 levels modulating incoming immune cells. Myeloid cells emerged as key vitamin D3 targets and gut analyses showed VDR-dependent shifts in gene expression and microbiota. Next, we will confirm our data in an independent murine model, study VDR’s role in GvL and test local VDR agonists, including engineered probiotics producing vitamin D3 metabolites, to modulate GvHD and improve transplant outcomes.

 

 

  1. Flamann C, Peter K, Kreutz M, Bruns H. Regulation of the Immune Balance During Allogeneic Hematopoietic Stem Cell Transplantation by Vitamin D. Front Immunol 2019; 10: 2586; doi:10.3389/fimmu.2019.02586
  2. Peter K, Siska PJ, Roider T, Matos C, Bruns H, Renner K, Singer K, Weber D, Güllstorf M, Kröger N, Wolff D, Herr W, Ayuk F, Holler E, Stark K, Heid IM, Kreutz M. 1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation. Bone Marrow Transplant 2021 Feb;56(2):419-433. doi: 10.1038/s41409-020-01031-w.
  3. Bruns H, Böttcher M, Qorraj M, Fabri M, Jitschin S, Dindorf J, Busch L, Jitschin R, Mackensen A, Mougiakakos D. CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D. Leukemia 2017 Apr;31(4):985-988. doi: 10.1038/leu.2016.378.
  4. Bruns H, Büttner M, Fabri M, Mougiakakos D, Bittenbring JT, Hoffmann MH, Beier F, Pasemann S, Jitschin R, Hofmann AD, Neumann F, Daniel C, Maurberger A, Kempkes B, Amann K, Mackensen A, Gerbitz A. Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma. Sci Transl Med 2015 Apr 8;7(282):282ra47. doi: 10.1126/scitranslmed.aaa3230.
  5. Matos C, Renner K, Peuker A, Schoenhammer G, Schreiber L, Bruss C, Eder R, Bruns H, Flamann C, Hoffmann P, Gebhard C, Herr W, Rehli M, Peter K, Kreutz M. Physiological levels of 25-hydroxyvitamin D3 induce a suppressive CD4+ T cell phenotype not reflected in the epigenetic landscape. Scand J Immunol 2022 May;95(5):e13146. doi: 10.1111/sji.13146.
  6. Matos C, Peter K, Weich L, Peuker A, Schoenhammer G, Roider T, Ghimire S, Babl N, Decking S, Güllstorf M, Kröger N, Hammon K, Herr W, Stark K, Heid IM, Renner K, Holler E, Kreutz M. Anti-Thymocyte Globulin Treatment Augments 1,25-Dihydroxyvitamin D3 Serum Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation. Front Immunol 2022 Jan 4;12:803726. doi: 10.3389/fimmu.2021.803726.
  7. Busch L, Mougiakakos D, Büttner-Herold M, Müller MJ, Volmer DA, Bach C, Fabri M, Bittenbring JT, Neumann F, Boxhammer R, Nolting J, Bisht S, Böttcher M, Jitschin S, Hoffmann MH, Balzer H, Beier F, Gezer D, Dudziak D, Gelse K, Hennig FF, Pallasch CP, Spriewald B, Mackensen A, Bruns H. Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway. Leukemia 2018 Nov;32(11):2445-2458. doi: 10.1038/s41375-018-0114-0.
  8. Matos C, Mamilos A, Shah PN, Meedt E, Weber D, Ghimire S, Hiergeist A, Gessner A, Dickinson A, Dressel R, Walter L, Stark K, Heid IM, Poeck H, Edinger M, Wolff D, Herr W, Holler E, Kreutz M, Ghimire S. Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation. Front Immunol 2022 Oct 20;13:1028850. doi: 10.3389/fimmu.2022.1028850.
  9. Schreiber L, Ghimire S, Hiergeist A, Renner K, Althammer M, Babl N, Peuker A, Schoenhammer G, Hippe K, Gessner A, Albrecht C, Pielmeier F, Büttner-Herold M, Bruns H, Hoffmann P, Herr W, Holler E, Peter K, Kreutz M, Matos C. Strain specific differences in vitamin D3 response: impact on gut homeostasis. Front Immunol 2024 Mar 1;15:1347835. doi: 10.3389/fimmu.2024.1347835. 
  10. Flamann C, Shaikh H, Matos C, Kreutz M, Ali H , Kern M, Büttner-Herold M, Jacobs B, Völkl S, Lischer C, Kellner C, Berges J, Bitterer K, Saul D, Goel M, Link-Rachner C, Zernecke A, Weber D, Mougiakakos D, Mackensen A , Beilhack A and Bruns H. Augmented CD47 expression  impairs alloreactive T cell clearance after allo-HCT. Blood 2025; accepted
  • Prof. Dr. rer. nat. Marina Kreutz
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5577
    marina.kreutz(at)ukr.de
  • PD Dr. rer. nat Heiko Bruns
    University Hospital Erlangen
    Department of Medicine 5
    Ulmenweg 18
    91052 Erlangen
    T: +49 9131 85-43163
    heiko.bruns(at)uk-erlangen.de
  • Dr. rer. nat. Carina Matos
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38477
    carina.matos@ukr.de

Project B13

Enterococci in ASCT: Indicators of loss of diversity or true GvHD pathogens?
Site: Regensburg
Principal Investigators: Prof. Dr. med. Daniela Weber, Dr. med. Elisabeth Meedt, Prof. Dr. med. Dr. rer. nat. André Gessner

Our studies suggest a causal link between enterococci and acute GvHD. Genomic and functional analyses reveal consistent differences between enterococcal strains isolated from ASCT patients and healthy controls, as well as between GvHD and non-GvHD patients. Various strains and associated metabolites and the effects of microbiota transfer will be tested in organoid and animal models. We will also investigate the enterococci translocation into intestinal tissue and their interaction with the immune system, focusing on T and B cell responses both locally in the gut and systemically.

 

  1. Stein-Thoeringer CK, Nichols KB, Lazrak A, Docampo MD, Slingerland AE, Slingerland JB, Clurman AG, Armijo G, Gomes ALC, Shono Y, Staffas A, Burgos da Silva M, Devlin S, Markey KA, Bajic D, Pinedo R, Tsakmaklis A, Littmann ER, Pastore A, Taur Y, Monette S, Arcila ME, Pickard AJ, Maloy M, Wright RJ, Amoretti LA, Fontana E, Pham D, Jamal MA, Weber D, Sung AD, Hashimoto D, Scheid C, Xavier JB, Messina JA, Romero K, Lew M, Bush A, Bohannon L, Hayasaka K, Hasegawa Y, Vehreschild MJGT, Cross JR, Ponce DM, Perales MA, Giralt SA, Jenq RR, Teshima T, Holler E, Chao NJ, Pamer EG, Peled JU, van den Brink MRM. Lactose drives Enterococcus expansion to promote graft-versus-host disease. Science 2019; 366, 1143–1149. doi:10.1126/science.aax3760.
  2. Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, Weber D, Hashimoto D, Slingerland AE, Slingerland JB, Maloy M, Clurman AG, Stein-Thoeringer CK, Markey KA, Docampo MD, Burgos da Silva M, Khan N, Gessner A, Messina JA, Romero K, Lew MV, Bush A, Bohannon L, Brereton DG, Fontana E, Amoretti LA, Wright RJ, Armijo GK, Shono Y, Sanchez-Escamilla M, Castillo Flores N, Alarcon Tomas A, Lin RJ, Yáñez San Segundo L, Shah GL, Cho C, Scordo M, Politikos I, Hayasaka K, Hasegawa Y, Gyurkocza B, Ponce DM, Barker JN, Perales M-A, Giralt SA, Jenq RR, Teshima T, Chao NJ, Holler E, Xavier JB, Pamer EG, van den Brink MRM. Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation. N Engl J Med 2020; 382, 822–834. doi:10.1056/NEJMoa1900623.
  3. Meedt E, Hiergeist A, Gessner A, Dettmer K, Liebisch G, Ghimire S, Poeck H, Edinger M, Wolff D, Herr W, Holler E, Weber D. Prolonged Suppression of Butyrate-Producing Bacteria Is Associated With Acute Gastrointestinal Graft-vs-Host Disease and Transplantation-Related Mortality After Allogeneic Stem Cell Transplantation. Clin Infect Dis 2022; 74, 614–621. doi:10.1093/cid/ciab500.
  4. Thiele Orberg E*, Meedt E*, Hiergeist A*, Xue J*, Heinrich P, Ru J, Ghimire S, Miltiadous O, Lindner S, Tiefgraber M, Göldel S, Eismann T, Schwarz A, Göttert S, Jarosch S, Steiger K, Schulz C, Gigl M, Fischer JC, Janssen K-P, Quante M, Heidegger S, Herhaus P, Verbeek M, Ruland J, Van Den Brink MRM, Weber D, Edinger M, Wolff D, Busch DH, Kleigrewe K, Herr W, Bassermann F, Gessner A, Deng L, Holler E*, Poeck H*. Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation. Nat Cancer 2024; 5, 187–208. doi:10.1038/s43018-023-00669-x.
  5. Weber D, Meedt E, Poeck H, Thiele-Orberg E, Hiergeist A, Gessner A, Holler E. Fecal Microbiota Transfer in Acute Graft-versus-Host Disease following Allogeneic Stem Cell Transplantation. Visc Med 2024; 1–6. doi:10.1159/000538303.
  6. DeFilipp Z, Damania AV, Kim HT, Chang C-C, El-Jawahri A, McAfee SL, Bottoms AS, Toncheva V, Smith MM, Dolaher M, Perry L, White M, Diana B, Connolly S, Dey BR, Frigault MJ, Newcomb RA, O’Donnell PV, Spitzer TR, Mansour MK, Weber D, Ajami NJ, Hohmann E, Jenq RR, Chen Y-B. Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract. Blood Adv 2024; 8, 2074–2084. doi:10.1182/bloodadvances.2024012556.
  7. DeFilipp Z, Damania AV, Kim HT, Chang C-C, El-Jawahri A, McAfee SL, Bottoms AS, Toncheva V, Smith MM, Dolaher M, Perry L, White M, Diana B, Connolly S, Dey BR, Frigault MJ, Newcomb RA, O’Donnell PV, Spitzer TR, Mansour MK, Weber D, Ajami NJ, Hohmann E, Jenq RR, Chen Y-B. Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract. Blood Adv 2024; 8, 2074–2084. doi:10.1182/bloodadvances.2024012556
  8. Jarosch S, Köhlen J, Ghimire S, Orberg ET, Hammel M, Gaag D, Evert M, Janssen K-P, Hiergeist A, Gessner A, Weber D, Meedt E, Poeck H, D’Ippolito E, Holler E, Busch DH. Multimodal immune cell phenotyping in GI biopsies reveals microbiome-related T cell modulations in human GvHD. Cell Rep Med 2023; 4, 101125.  doi:10.1016/j.xcrm.2023.101125.
  9. Weber D, Weber M, Meedt E, Ghimire S, Wolff D, Edinger M, Poeck H, Hiergeist A, Gessner A, Ayuk F, Roesler W, Wölfl M, Kraus S, Zeiser R, Bertrand H, Bader P, Ullrich E, Eder M, Gleich S, Young R, Herr W, Levine JE, Ferrara JLM, Holler E. Reg3α concentrations at day of allogeneic stem cell transplantation predict outcome and correlate with early antibiotic use. Blood Adv 2023; 7, 1326–1335. doi:10.1182/bloodadvances.2022008480.
  10. Weber D, Hiergeist A, Weber M, Ghimire S, Salzberger B, Wolff D, Poeck H, Gessner A, Edinger M, Herr W, Meedt E, Holler E. Restrictive versus permissive use of broad-spectrum antibiotics in patients receiving allogeneic SCT and early fever due to cytokine release syndrome: Evidence for beneficial microbiota protection without increase of infectious complications. Clin Infect Dis 2023; ciad389. doi:10.1093/cid/ciad389.
  11. Turner AM, Li L, Monk IR, Lee JYH, Ingle DJ, Portelli S, Sherry NL, Isles N, Seemann T, Sharkey LK, Walsh CJ, Reid GE, Nie S, Eijkelkamp BA, Holmes NE, Collis B, Vogrin S, Hiergeist A, Weber D, Gessner A, Holler E, Ascher DB, Duchene S, Scott NE, Stinear TP, Kwong JC, Gorrie CL, Howden BP, Carter GP. Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin. Nature 2024. doi:10.1038/s41586-024-08095-4.
  • PD Dr. med. Daniela Weber
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5510
    daniela.weber@ukr.de
  • Prof. Dr. med. Dr. rer. nat. André Gessner
    University Hospital Regensburg
    Department of Clinical Chemistry and Laboratory Medicine
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-6401
    andre.gessner@ukr.de

Project INF

Data integration platform and systems medicine efforts to foster GvL and GvHD research
Site: Regensburg, Erlangen, Würzburg
Principal Investigator: Prof. Dr. rer. nat. Katrin Heinze, Prof. Dr. rer. nat. Birte Kehr, Priv.-Doz. Dr. rer. nat. Leila Taher, Dr. med. Elisabeth Meedt

The information infrastructure project provides systematic data management and bioinformatics data analysis support for the TRR 221. We will continue to develop and link our previously established databases for GvL/GvHD research data and clinical data. Furthermore, we will offer support to all TRR 221 subprojects for biomedical data analysis with existing and newly developed bioinformatics software, and will actively collaborate on systems biological analyses of signatures, markers and interactions in GvHD/GvL research.

  1. Liang M, Dickel N, Györfi A, SafakTümerdem B, Li Y, Rigau AR, Liang C, Hong X, Shen L, Matei A, Trinh-Minh T, Tran-Manh C, Zhou X, Zehender A, Kreuter A, Zou H, Schett G, Kunz M, Distler JHW. Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis. Sci Transl Med 2024;16(740):eadd6570. doi: 10.1126/scitranslmed.add6570. 
  2. Karl F, Liang C, Böttcher-Loschinski R, Stoll A, Flamann C, Richter S, Lischer C, Völkl S, Jacobs B, Böttcher M, Jitschin R, Bruns H, Fischer T, Holler E, Rösler W, Dandekar T, Mackensen A, Mougiakakos D. Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT. Blood 2023;141(13):1626-39. doi: 10.1182/blood.2022017267. 
  3. Lainscsek X, Taher L. Predicting chromosomal compartments directly from the nucleotide sequence with DNA-DDA. Brief Bioinform 2023;24(4):bbad198.doi: 10.1093/bib/bbad198.  
  4. Mirus T, Lohmayer R, Döhring C, Halldórsson BV, Kehr B. GGTyper: genotyping complex structural variants using short-read sequencing data. Bioinformatics 2024;40(Suppl_2):ii11-ii19. doi: 10.1093/bioinformatics/btae391. 
  5. Cao K, Elfaramawy N, Weidlich M, Kehr B. From Program Chains to Exploratory Workflows: PopinSnake for Genomic Insertion Detection. 2023 IEEE 19th International Conference on e-Science (e-Science) 2023. doi: 10.1109/e-science58273.2023.10254924. 
  6. Ascheid D, Baumann M, Pinnecker J, Friedrich M, Szi-Marton D, Medved C, Bundalo M, Ortmann V, Öztürk A, Nandigama R, Hemmen K, Ergün S, Zernecke A, Hirth M, Heinze KG, Henke E. A vascularized breast cancer spheroid platform for the ranked evaluation of tumor microenvironment-targeted drugs by light sheet fluorescence microscopy. Nat Commun 2024;15(1):3599. doi: 10.1038/s41467-024-48010-z. 
  7. Peulen T, Hemmen K, Greife A, Webb BM, Felekyan S, Sali A, Seidel CAM, Sanabria H, Heinze KG. tttrlib: modular software for integrating fluorescence spectroscopy, imaging, and molecular modeling. Bioinformatics 2025;41(2):btaf025. doi: 10.1093/bioinformatics/btaf025. 
  8. Breitenbach T, Englert N, Osmanoglu Ö, Rukoyatkina N, Wangorsch G, Heinze K, Friebe A, Butt E, Feil R, Dittrich M, Gambaryan S, Dandekar T. A modular systems biological modelling framework studies cyclic nucleotide signaling in platelets. Jl Theor Biol 2022;550:111222. doi: 10.1016/j.jtbi.2022.111222. 
  9. Thiele Orberg E*, Meedt E*, Hiergeist A*, Xue J, Heinrich P, Ru J, Ghimire S, Miltiadous O, Lindner S, Tiefgraber M, Göldel S, Eismann T, Schwarz A, Göttert S, Jarosch S, Steiger K, Schulz C, Gigl M, Fischer JC, Janssen K, Quante M, Heidegger S, Herhaus P, Verbeek M, Ruland J, van den Brink MRM, Weber D, Edinger M, Wolff D, Busch DH, Kleigrewe K, Herr W, Bassermann F, Gessner A, Deng L, Holler E, Poeck H. Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation. Nat Cancer 2024;5(1):187-208. doi: 10.1038/s43018-023-00669-x. 
  10. Meedt E, Hiergeist A, Gessner A, Dettmer K, Liebisch G, Ghimire S, Poeck H, Edinger M, Wolff D, Herr W, Holler E, Weber D. Prolonged Suppression of Butyrate-Producing Bacteria Is Associated With Acute Gastrointestinal Graft-vs-Host Disease and Transplantation-Related Mortality After Allogeneic Stem Cell Transplantation. Clin Infect Dis 2021;74(4):614-21. doi: 10.1093/cid/ciab500. 
  • Prof. Dr. rer. nat. Birte Kehr
    LIT – Leibniz Institute for Immunotherapy
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944 18161
    birte.kehr(at)ukr.de
  • Dr. Leila Taher
    Head of the Core Unit for Bioinformatics, Data Integration and Analysis (CUBiDA)
    Medical Centre for Information and Communication Technology (MIK)
    Erlangen University Hospital
    Krankenhausstraße 12
    91054 Erlangen
    Phone: +49 (9131) 85-48260
    E-Mail: Leila.Taher@uk-erlangen.de

Project Z01

Pathology and multi-omics work-up of GvHD and GvL in mice and men
Principal Investigators: Prof. Dr. med. Daniela Hirsch, Prof. Dr. Zoltan Takats, PhD, Prof. Dr. med. Andreas Rosenwald, Prof. Dr. med. Maike Büttner-Herold

This service project will continue providing expert (immuno-)histological and tissue-based molecular analyses on human and murine tissue samples to all members of TRR 221. The project will offer spatial multi-omics assays in the next funding period, comprising spatial transcriptomics, proteomics, metabolomics and lipidomics at single cell resolution. In addition, live cell and in vivo tissue metabolomics will also become available through the project.

 

  1. Hippe K, Kreft A, Reu-Hofer S, Rosenwald A, Ferrazzi F, Daniel C, Amann K, Kraus S, Holler E, Kandulski A, Hirsch D, Buttner A, Rosler W, Hildner K, Winkler J, Büttner-Herold M. Round-Robin test for the histological diagnosis of acute colonic Graft-versus-Host disease validating established histological criteria and grading systems. Virchows Arch 2023;483(1):47-58. doi: 10.1007/s00428-023-03544-3. 
  2. Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Pena Mosca J, Arellano Viera E, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022;7(22):e154250. doi: 10.1172/jci.insight.154250. 
  3. Biedermann A, Patra-Kneuer M, Mougiakakos D, Büttner-Herold M, Mangelberger-Eberl D, Berges J, Kellner C, Altmeyer S, Bittenbring JT, Augsberger C, Ilieva-Babinsky K, Haskamp S, Beier F, Lischer C, Vera J, Lührmann A, Bertz S, Völkl S, Jacobs B, Steidl S, Mackensen A, Bruns H. Blockade of the CD47/SIRPalpha checkpoint axis potentiates the macrophage-mediated anti-tumor efficacy of tafasitamab. Haematologica 2024; 109(12):3928-40. doi: 10.3324/haematol.2023.284795. 
  4. Schreiber L, Ghimire S, Hiergeist A, Renner K, Althammer M, Babl N, Peuker A, Schoenhammer G, Hippe K, Gessner A, Albrecht C, Pielmeier F, Büttner-Herold M, Bruns H, Hoffmann P, Herr W, Holler E, Peter K, Kreutz M, Matos C. Strain specific differences in vitamin D3 response: impact on gut homeostasis. Front Immunol 2024;15:1347835. doi: 10.3389/fimmu.2024.1347835. 
  5. Matthe DM, Dinkel M, Schmid B, Vogler T, Neurath MF, Poeck H, Neufert C, Büttner-Herold M, Hildner K. Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease. Front Immunol 2023;14:1253514. doi: 10.3389/fimmu.2023.1253514. 
  6. Hirsch D, Wangsa D, Zhu YJ, Hu Y, Edelman DC, Meltzer P S, Heselmeyer-Haddad K, Ott C, Kienle P, Galata C, Horisberger K, Ried T, Gaiser T. Dynamics of Genome Alterations in Crohn’s Disease-Associated Colorectal Carcinogenesis. Clin Cancer Res 2018;24(20):4997–5011. doi: 10.1158/1078-0432.CCR-18-0630. 
  7. Hirsch D, Hardt J, Sauer C, Heselmeyer-Hadded K, Witt SH, Kienle P, Ried T, Gaiser T. Molecular characterization of ulcerative colitis-associated colorectal carcinomas. Mod Pathol 2021;34(6);1153-66. doi: 10.1038/s41379-020-00722-5. 
  8. Takáts Z, Wiseman JM, Gologan B, Cooks RG. Mass spectrometry sampling under ambient conditions with desorption electrospray ionization. Science 2004;306(5695):471-3. doi: 10.1126/science.1104404. 
  9. Jones EA, Simon D, Karancsi T, Balog J, Pringle SD, Takats Z. Matrix Assisted Rapid Evaporative Ionization Mass Spectrometry. Anal Chem 2019;6;91(15):9784-91. doi: 10.1021/acs.analchem.9b01441. 
  10. Strittmatter N, Lovrics A, Sessler J, McKenzie JS, Bodai Z, Doria ML, Kucsma N, Szakacs G, Takats Z. Shotgun Lipidomic Profiling of the NCI60 Cell Line Panel Using Rapid Evaporative Ionization Mass Spectrometry. Anal Chem 2016, 2;88(15):7507-14. doi: 10.1021/acs.analchem.6b00187. 
  • Prof. Dr. med. Daniela Hirsch
    University of Regensburg
    Institute of Pathology
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-6643
    daniela.hirsch@ur.de
  • Prof. Dr. med. Maike Büttner-Herold
    University Hospital Erlangen
    Department of Nephropathology
    Krankenhausstraße 8-10
    91054 Erlangen
    T: +49 9131 85-22605
    maike.buettner(at)uk-erlangen.de
  • Prof. Dr. med. Andreas Rosenwald
    Julius-Maximilians-University Würzburg
    Department of Pathology
    Josef-Schneider-Str. 2
    97080 Würzburg
    T: +49 931 31-81199
    rosenwald(at)uni-wuerzburg.de

Project Z02

Animal engineering and complex transplantation models
Regensburg, Würzburg, Erlangen
Principal Investigators: Priv.-Doz. Dr. rer. nat. Petra Hoffmann, Dr. rer. nat. Franziska Pielmeier, Prof. Dr. med. univ. Dr. med. Andreas Beilhack, Prof. Dr. rer. nat. Thomas Winkler

Due to the complexity of GvH and GvL immune reactions their basic biology as well as novel intervention strategies can only be examined in adequate preclinical in vivo models. In addition to providing general support in all experimental and regulatory issues, this service project continues to generate valuable new genetically modified mouse strains for the consortium and provides an experimental platform to investigate GvHD in germfree and gnotobiotic mice. We aim for informative, cross-validated, reproducible and predictive in vivo models at the three participating centers.

 

  1. Dittmar DJ*, Pielmeier F*, Strieder N, Fischer A, Herbst M, Stanewsky H, Wenzl N, Röseler E, Eder R, Gebhard C, Schwarzfischer-Pfeilschifter L, Albrecht C, Herr W, Edinger M*, Hoffmann P*, Rehli M*. Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease. Nat Commun 2024;15(1):3224. doi: 10.1038/s41467-024-47575-z. 
  2. Seefried M, Hundhausen N, Kroeger I, Büttner-Herold M, Hoffmann P, Edinger M, Ullrich E, Berberich-Siebelt F, Britt WJ, Mach M, Winkler TH. Murine cytomegalovirus reactivation concomitant with acute graft-versus-host disease is controlled by antibodies. JCI Insight 2023;8(5):e149648. doi: 10.1172/jci.insight.149648. 
  3. Gamboa Vargas J*, Wagner J*, Shaikh H, Lang I, Medler J, Anany M, Steinfatt T, Peña Mosca J, Haack S, Dahlhoff J, Büttner-Herold M, Graf C, Viera EA, Einsele H, Wajant H*, Beilhack A*. A TNFR2-specific TNF fusion protein with improved in vivo activity. Front Immunol 2022; 13:888274. doi: 10.3389/fimmu. 2023.1352525. 
  4. Anany MA, Haack S, Lang I, Dahlhoff J, Gamboa Vargas J, Steinfatt T, Päckert L, Weisenberger D, Zaitseva O, Medler J, Kucka K, Zhang T, Van Belle T, van Rompaey L, Beilhack A*, Wajant H*. Generic design principles for antibody based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 2024; 14(2):496-509. doi: 10.7150/thno.84404. 
  5. Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Peña Mosca J, Arellano Viera E, Kern MAG, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022; 7(22):e154250. doi: 10.1172/jci.insight.154250. 
  6. Riegel C, Boeld TJ, Doser K, Huber E, Hoffmann P, Edinger M. Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells. Leukemia 2020;4(3):895-908. doi: 10.1038/s41375-019-0625-3. 
  7. Ewendt F, Drewitz F, Althammer M, Eichler C, Brandsch C, Brey S, Winkler TH, Wilkens MR, S-Arnaud R, Kreutz M, Stangl GI. Vitamin D stimulates Il-15 synthesis in rodent muscle. Biochem Biophys Rep 2025; 41:101925.DOI: 10.1016/j.bbrep.2025.101925. 
  8. Mueller JPJ, Dobosz M, O’Brien N, Abdoush N, Giusti AM, Lechmann M, Osl F, Wolf AK, Arellano-Viera E, Shaikh H, Sauer M, Rosenwald A, Herting F, Umana P, Colombetti S, Pöschinger T, Beilhack A. ROCKETS – a novel one-for-all toolbox for light sheet microscopy in drug discovery. Front Immunol 2023; 14:1034032. doi: 10.3389/fimmu.2023.1034032. 
  • PD Dr. rer. nat. Petra Hoffmann
    University Hospital Regensburg
    Department of Internal Medicine III
    LIT – Leibniz Institute for Immunotherapy
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5592
    petra.hoffmann(at)ukr.de
  • Prof. Dr. rer. nat. Thomas Winkler
    FAU Erlangen-Nürnberg
    Department of Biology
    Nikolaus-Fiebiger-Center for Molecular Medicine
    Glückstraße 6
    91054 Erlangen
    T: +49 9131 85-29136
    thomas.winkler(at)fau.de
  • Prof. Dr. med. Dr. med. univ. Andreas Beilhack
    University Hospital Würzburg
    Department of Medicine II
    ZEMM Center for Experimental Molecular Medicine
    Zinklesweg 10
    97078 Würzburg
    T: +49 931 201-44040
    beilhack_a(at)ukw.de

Project Z03

Central Tasks of the Collaborative Research Centre
Principal Investigator: Prof. Dr. med. Wolfgang Herr

This project takes care of the administrative and organizational matters of the TRR 221. It manages the funds that are primarily used for the (i) recruitment and early career support of excellent young postdocs, (ii) rotation (‘Gerok’) positions for clinical project leaders and young physician scientists, (iii) gender equality measures, (iv) support of new projects that have the potential to advance the TRR 221 program, (v) project-specific workshops and guest speaker seminars, (vi)  traveling, and (vii) public relation work.

  • Prof. Dr. med. Wolfgang Herr
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 941-5501
    wolfgang.herr@ukr.de

B14

Role of EGF-like growth factors in immune regulation and tissue homeostasis during GvHD
Würzburg
Prof. Dr. rer. nat. Dietmar Zaiß, Dr. rer. nat. Haroon Shaikh

The two EGF-like growth factors, Amphiregulin and HB-EGF, are strongly upregulated in their expression during GvHD and substantially influence its development and progression. It is our aim to dissect the role these factors play during the different stages of GvHD and determine how we can tailor novel approaches for the prophylaxis and treatment of GvHD, by the selective blockade or application of recombinant Amphiregulin and / or HB-EGF.

  1. du Halgouet A, Darbois A, Alkobtawi M, Mestdagh M, Alphonse A, Premel V, Yvorra T, Colombeau L, Rodriguez R, Zaiss D, El Morr Y, Bugaut H, Legoux F, Perrin L, Aractingi S, Golub R, Lantz O, Salou M. (2023) Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing. Immunity 56:78-92.
  2. Minutti CM, Modak RV, Macdonald F, Li F, Smyth DJ, Dorward DA, Blair N, Husovsky C, Muir A, Giampazolias E, Dobie R, Maizels RM, Kendall TJ, Griggs DW, Kopf M, Henderson NC, Zaiss DM*. (2019) A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation. Immunity 50:645-654
  3. Minutti CM, Blair N, Schwartz C, Drube S, Kamradt T, Sibilia M, Sijts AJ, Fallon PG, Maizels RM, Zaiss DM*. (2017) Epidermal growth factor receptor expression licenses Th2 cells to function in a TCR-independent way. Immunity 47:710-722
  4. Minutti CM, Jackson-Jones LH, García-Fojeda B, Logan N, Rinqvist E, Guillamat-Prats R, Artigas A, Stamme C, Chroneos ZC, Zaiss DM, Casals C*, Allen JE.* (2017) Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. Science 356: 1076-8
  5. Zaiss DM*, Gause WC*, Osborne LC, Artis D* (2015) Emerging functions of Amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42: 216-26
  6. Zaiss DM*., van Loosdregt J., Gorlani A., Bekker CJ., Gröne A., Sibilia M., van Bergen en Henegouwen PM., Roovers RC, Coffer PJ, Sijts AJ. (2013) Amphiregulin enhances regulatory T cell suppressive function via the epidermal growth factor receptor. Immunity 38: 275-28
  7. van Loosdregt J., Fleskens V., Tiemessen MM., van Boxtel R., Mokry M., Meerding J., Pals CE., Kurek D., Baert MR., Delemarre EM., Gröne A., Sijts AJ., Maurice MM., van Es JH., ten Berge D., Staal FJ., Zaiss DM., Prakken BJ., and Coffer PJ.* (2013) Canonical Wnt signaling negatively modulates T regulatory cell function. Immunity 39: 298-310
  8. van Loosdregt J., Fleskens V., Fu J., Brenkman AB., Bekker CJ., Pals CE., Meerding J., Berkers CR., Barbi J., Gröne A., Sijts AJ., Maurice MM., Kalkhoven E., Prakken BJ., Ovaa H., Pan F., Zaiss DM., and Coffer PJ.* (2013) USP7/HAUSP mediated stabilization of FoxP3 increases Treg suppressive capacity. Immunity 39: 259-271
  9. Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR.* (2006) Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science 314:1746.
  10. Schubert D, Schmidt M, Zaiss D, Jungblut P, Kamradt T.* (2002) Autoantibodies against GPI and creatine kinase in rheumatoid arthritis. Nature Immunol.  3: 411
  11. Shaikh, H. *, Helal, M., Wittmann, P., Kern, M. A. G., Abboud, Z., Gamboa Vargas, J., Pezoldt, J., Mokhtari, Z., Jarick, K., Yan, H., Müller, J. P. J., Saliba, A.-E., Riedel, A., Zernecke, A., Büttner-Herold, M., Einsele, H., Huehn, J., & Beilhack, A. * (2025). Blood Endothelial Cells Prime Alloreactive CD4+ T Cells to Initiate Acute Graft-Versus-Host Disease. bioRxiv 2025.10.07.677751; doi: https://doi.org/10.1101/2025.10.07.677751
  12. Jorgacevic, I. *, Shaikh, H. *, Ali, H., Bundalo, M., Schäfer, S., Kern, M. A. G., Büttner-Herold, M., Reu-Hofer, S., Cochain, C., Bartolomaeus, H., Saliba, A.-E., Rösch, M., Rizzo, G., Arellano Viera, E., Gamboa Vargas, J., Berberich-Siebelt, F., Herr, W., Boon, L., Rosenwald, A., Butt, E., Hermanns, H., Beilhack, A., & Zernecke, A. (2025). Allogeneic hematopoietic cell transplantation initiates atherosclerosis in mice via CD8+ T cells. Cardiovascular Research, 2025 Dec 31;121(17):2668-2678.
  14. Flamann, C. *, Shaikh, H. *, Matos, C., Kreutz, M., Ali, H., Kern, M. A. G., Büttner-Herold, M., Jacobs, B., Völkl, S., Lischer, C., Kellner, C., Berges, J., Bitterer, K., Saul, D., Goel, M., Link-Rachner, C. S., Zernecke, A., Weber, D., Mougiakakos, D., Mackensen, A., Beilhack, A., & Bruns, H. (2025). Augmented CD47 expression impairs alloreactive T cell clearance after allo-HCT. Blood. 2025 Sep 11;146(11):1359-1373.
  16. Daud, M., Dasari, P., Adelfinger, M., Langenhorst, D., Lother, J., Slavkovic-Lukic, D., Berges, C., Kruhm, M., Galler, A., Schleussner, C., Luther, C. H., Alberter, K., Althammer, A., Shaikh, H., Pallmann, N., Bodem, J., El‐Mowafy, M., Beilhack, A., Dittrich, M., Topp, M. S., Zipfel, P. F., & Beyersdorf, N. (2023). Enolase 1 of Candida albicans binds human CD4⁺ T cells and modulates naïve and memory responses. European Journal of Immunology, 53(11), e2250284.
  18. Mueller, J. P. J., Dobosz, M., O’Brien, N., Abdoush, N., Giusti, A. M., Lechmann, M., Osl, F., Wolf, A.-K., Arellano-Viera, E., Shaikh, H., Sauer, M., Rosenwald, A., Herting, F., Umaña, P., Colombetti, S., Pöschinger, T., & Beilhack, A. (2023). ROCKETS – A novel one-for-all toolbox for light sheet microscopy in drug discovery. Frontiers in Immunology, 2023 Feb 7:14:1034032.
  19.  
  20. Shaikh, H., Pezoldt, J., Mokhtari, Z., Vargas, J. G., Le, D., Mosca, J. P., Viera, E. A., Kern, M. A., Graf, C., Beyersdorf, N., Lutz, M. B., Riedel, A., Büttner-Herold, M., Zernecke, A., Einsele, H., Saliba, A., Ludewig, B., Huehn, J., & Beilhack, A. (2022). Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight. 2022 Nov 22;7(22):e154250.
  21.  
  22. Ataide, M. A. *, Knöpper, K. *, De Casas, P. C. *, Ugur, M., Eickhoff, S., Zou, M., Shaikh, H., Trivedi, A., Grafen, A., Yang, T., Prinz, I., Ohlsen, K., De Agüero, M. G., Beilhack, A., Huehn, J., Gaya, M., Saliba, A., Gasteiger, G., & Kastenmüller, W. (2022). Lymphatic migration of unconventional T cells promotes site-specific immunity in distinct lymph nodes. Immunity, 55(10), 1813-1828.e9.
  24. Vargas, J. G. *, Wagner, J. *, Shaikh, H., Lang, I., Medler, J., Anany, M., Steinfatt, T., Mosca, J. P., Haack, S., Dahlhoff, J., Büttner-Herold, M., Graf, C., Viera, E. A., Einsele, H., Wajant, H., & Beilhack, A. (2022). A TNFR2-Specific TNF fusion protein with improved in vivo activity. Frontiers in Immunology, 13. 2022 Jun 13:13:888274.
  25.  
  26. Shaikh, H., Vargas, J. G., Mokhtari, Z., Jarick, K. J., Ulbrich, M., Mosca, J. P., Viera, E. A., Graf, C., Le, D., Heinze, K. G., Büttner-Herold, M., Rosenwald, A., Pezoldt, J., Huehn, J., & Beilhack, A. (2021). Mesenteric lymph node transplantation in mice to study immune responses of the gastrointestinal tract. Frontiers in Immunology, 2021 Jul 26:12:689896.
  27.  
  28. Ranjan, S., Goihl, A., Kohli, S., Gadi, I., Pierau, M., Shahzad, K., Gupta, D., Bock, F., Wang, H., Shaikh, H., Kähne, T., Reinhold, D., Bank, U., Zenclussen, A. C., Niemz, J., Schnöder, T. M., Brunner-Weinzierl, M., Fischer, T., Kalinski, T., Schraven, B., Luft, T., Huehn, J., Naumann, M., Heidel, F. H., Isermann, B. (2017). Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. Nature Communications, . 2017 Aug 21;8(1):311.

 

 

  • Prof. Dr. Dietmar M.W. Zaiss
    University Regensburg, Faculty of Medicine
    Department of Immune Medicine,
    Professor for Immune Cell Communication
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5466
    dietmar.zaiss@ukr.de
  • Dr. rer. nat. Haroon Shaikh
    University Hospital Würzburg
    Department of Medicine II
    Zinklesweg 10
    97078 Würzburg
    T: +49 931 201-44050
    shaikh_h@ukw.de

Project A09

Identification of T cell receptors and their epitopes mediating GvL responses in acute myeloid leukemia (AML)
Erlangen
Prof. Dr. med. Kilian Schober

This project aims to enhance GvL effects in AML by identifying leukemia-reactive T cell receptors (TCRs) and their target epitopes. Using advanced technologies like single-cell RNA/TCR sequencing and CRISPR-based TCR re-expression, the project screens patient- and donor-derived T cells before and after ASCT. Epitope specificity is mapped using conventional assays and genome-wide peptide-HLA libraries. The goal is to discover over 100 functional TCRs and their epitopes across five common HLA types, paving the way for targeted TCR-based AML immunotherapy after ASCT.

S. Frischholz*, E.-M. Schuster*, M. Grotz*, C. Schülein, J. Benz, K. Kocher, L. Klotz, S. Varga, T. Hiltner, R. Alsalameh, J. Esse, J. Träger, J. Held, F. Graw, J. Pahle, B. Spriewald, L. Gattinoni, V. R. Buchholz, F. Drost, B. Schubert, S. Rothenfußer, D. H. Busch, C. Bogdan & K. Schober. Metabolic quiescence of naïve-like memory T cells precedes and maintains antigen-specific T cell memory. Nature Immunology, in press.

K. Kocher*, F. Drost*, A. M. Tesfaye, C. Moosmann, C. Schuelein, M. Grotz, E. D’Ippolito, F. Graw, B. Spriewald, D. H. Busch, C. Bogdan, M. Tenbusch, B. Schubert*, K. Schober*, Quality of vaccination-induced T cell responses is conveyed by polyclonality and high, but not maximum, antigen receptor avidity. Science Immunology (2025), doi: 10.1126/sciimmunol.adu6730.

K. Kocher*, C. Moosmann*, F. Drost, C. Schülein, P. Irrgang, P. Steininger, J. Zhong, J. Träger, B. Spriewald, C. Bock, D. H. Busch, C. Bogdan, B. Schubert, T. H. Winkler, M. Tenbusch, E. M. Schuster*, K. Schober*, Adaptive immune responses are larger and functionally preserved in a hypervaccinated individual. The Lancet Infectious Diseases (2024), doi:10.1016/S1473-3099(24)00134-8

F. Drost*, E. Dorigatti*, A. Straub*, P. Hilgendorf, K. I. Wagner, K. Heyer, M. López Montes, B. Bischl, D. H. Busch*, K. Schober*, B. Schubert*, Predicting T cell receptor functionality against mutant epitopes. Cell Genomics, (2024), doi: 10.1016/j.xgen.2024.100634

A. Straub, S. Grassmann, S. Jarosch, L. Richter, P. Hilgendorf, M. Hammel, K. I. Wagner, V. R. Buchholz, K. Schober*, D. H. Busch*, Recruitment of epitope-specific T cell clones with a low-avidity threshold supports efficacy against mutational escape upon reinfection, Immunity (2023), doi:10.1016/j.immuni.2023.04.010.

P. Irrgang*, J. Gerling*, K. Kocher*, D. Lapuente, P. Steininger, K. Habenicht, M. Wytopil, S. Beileke, S. Schäfer, J. Zhong, G. Ssebyatika, T. Krey, V. Falcone, C. Schülein, A. S. Peter, K. Nganou-Makamdop, H. Hengel, J. Held, C. Bogdan, K. Überla, K. Schober*, T. H. Winkler*, M. Tenbusch*, Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination, Science Immunology (2023), doi:10.1126/sciimmunol.ade2798.

E. Vogel*, K. Kocher*, A. Priller*, C.-C. Cheng*, P. Steininger, B.-H. Liao, N. Körber, A. Willmann, P. Irrgang, J. Held, C. Moosmann, V. Schmidt, S. Beileke, M. Wytopil, S. Heringer, T. Bauer, R. Brockhoff, S. Jeske, H. Mijocevic, C. Christa, J. Salmanton-García, K. Tinnefeld, C. Bogdan, S. Yazici, P. Knolle, O. A. Cornely, K. Überla, U. Protzer*, K. Schober*, M. Tenbusch*, Dynamics of humoral and cellular immune responses after homologous and heterologous SARS-CoV-2 vaccination with ChAdOx1 nCoV-19 and BNT162b2. eBioMedicine. (2022), doi: 10.1016/j.ebiom.2022.104294

A. Purcarea*, S. Jarosch*, J. Barton, S. Grassmann, L. Pachmayr, E. D’Ippolito, M. Hammel, A. Hochholzer, K. I. Wagner, J. H. van den Berg, V. R. Buchholz, J. B. A. G. Haanen, D. H. Busch*, K. Schober*, Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity. Science Immunology (2022), doi:10.1126/sciimmunol.abm2077 (free access link)

D. S. Fischer*, M. Ansari*, K. I. Wagner*, S. Jarosch, Y. Huang, C. H. Mayr, M. Strunz, N. J. Lang, E. D. Ippolito, M. Hammel, L. Mateyka, S. Weber, L. S. Wolff, K. Witter, I. E. Fernandez, K. Milger, M. Frankenberger, L. Nowak, K. Heinig-Menhard, I. Koch, M. G. Stoleriu, A. Hilgendorff, J. Behr, A. Pichlmair, B. Schubert*, F. J. Theis*, D. H. Busch*, H. B. Schiller*, K. Schober*, Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through “reverse phenotyping.” Nature Communications (2021), doi:10.1038/s41467-021-24730-4

D. S. Fischer*, M. Ansari*, K. I. Wagner*, S. Jarosch, Y. Huang, C. H. Mayr, M. Strunz, N. J. Lang, E. D. Ippolito, M. Hammel, L. Mateyka, S. Weber, L. S. Wolff, K. Witter, I. E. Fernandez, K. Milger, M. Frankenberger, L. Nowak, K. Heinig-Menhard, I. Koch, M. G. Stoleriu, A. Hilgendorff, J. Behr, A. Pichlmair, B. Schubert*, F. J. Theis*, D. H. Busch*, H. B. Schiller*, K. Schober*, Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through “reverse
phenotyping.” Nature Communications (2021), doi:10.1038/s41467-021-24730-4

K. Schober*, F. Voit*, S. Grassmann, T. R. Müller, J. Eggert, S. Jarosch, B. Weißbrich, P. Hoffmann, L. Borkner, E. Nio, L. Fanchi, C. R. Clouser, A. Radhakrishnan, L. Mihatsch, P. Lückemeier, J. Leube, G. Dössinger, L. Klein, M. Neuenhahn, J. D. Oduro, L. Cicin-Sain, V. R. Buchholz, D. H. Busch, Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection. Nature Immunology 21, 434–441 (2020), doi:10.1038/s41590-020-0628-2

K. Schober*, T. R. Müller*, F. Gökmen, S. Grassmann, M. Effenberger, M. Poltorak, C. Stemberger, K. Schumann, T. L. Roth, A. Marson, D. H. Busch, Orthotopic replacement of T-cell receptor α- and β-chains with preservation of near-physiological T-cell function. Nature Biomedical Engineering 3, 974–984 (2019), doi:10.1038/s41551-019-0409-0.

  • Prof. Dr. med Kilian Schober
    Microbiology Institute – Clinical Microbiology, Immunology and Hygiene
    University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg
    T: 09131 85-46930
    kilian.schober@uk-erlangen.de

B15

Elucidating inflammatory remodeling of the bone marrow niche after ASCT
Würzburg
Prof. Dr. rer. nat. Dominic Grün, Priv.-Doz. Dr. med. Sabrina Kraus

Severe acute (a)GvHD is associated with long-lasting hematopoietic dysfunction, yet the underlying mechanisms remain unknown. We hypothesize that perturbed bone marrow niche interactions of HSCPs after ASCT impair regeneration of hematopoiesis in aGvHD. Using single-cell RNA-sequencing and spatial transcriptomics, we will reconstruct the spatial bone marrow architecture in patients with severe aGvHD, and compare between steroid-refractory and -responsive groups. By inferring perturbations of the bone marrow niche and underlying molecular pathways, we will identify key local cellular interactions contributing to BM failure.

  1. Chan ASF, Greiner J, Marschh√§user L, Brennan TA, Perez-Feliz S, Agrawal A, Hemmer H, Sinning K, Cheung WL, Iqbal Z, Klesen A, Vico TA, Aprea J, Hilgendorf I, Seidel T, Vaeth M, Rog-Zielinska E, Kohl P, Schneider-Warme F, Grün D (2025) Spatio-temporal dynamics of the fibrotic niche in cardiac repair. Nature Cardiovascular Research. 2025;4(11): 1550-1572. doi:10.1038/s44161-025-00739-6.
  2. Agrawal A, Thomann T, Basu S, Grün D. NiCo Identifies Extrinsic Drivers of Cell State Modulation by Niche Covariation Analysis. Nature Communications.2024; 15(1):10628. doi: 10.1038/s41467-024-54973-w
  3. Rosales-Alvarez RE, Rettkowski J, Herman JS, Dumbović G, Cabezas-Wallscheid N, Grün D. VarID2 quantifies gene expression noise dynamics and unveils functional heterogeneity of ageing hematopoietic stem cells. Genome Biology. 2023; 24(1):148. doi: 10.1186/s13059-023-02974-1
  4. Nusser A, Sagar, Swann JB, Krauth B, Diekhoff D, Calderon L, Happe C, Grün D#, Boehm T#. Developmental dynamics of two bipotent thymic epithelial progenitor types. 2022; 606(7912):165-171. doi: 10.1038/s41586-022-04752-8
  5. Zeis P, Lian M, Fan X, Herman JS, Hernandez DC, Gentek R, Elias S, Symowski C, Knöpper K, Peltokangas N, Friedrich C, Doucet-Ladeveze R, Kabat AM, Locksley RM, Voehringe D, Bajenoff M, Rudensky AY, Romagnani C, Grün D#, Gasteiger G#. In situ maturation and tissue adaptation of type 2 innate lymphoid cell progenitors. Immunity. 2020; 53(4):775-792.e9. doi: 1016/j.immuni.2020.09.002
  6. Sagar, Pokrovskii M, Herman JS, Naik S, Sock E, Lausch U, Wegner M, Tanriver Y, Littman DR, Grün D. Deciphering the Regulatory Landscape of γδ T Cell Development by Single-Cell RNA-Sequencing. EMBO Journal. 2020; 39(13): e104159. doi: 10.15252/embj.2019104159
  7. Grün D. Revealing Dynamics of Gene Expression Variability in Cell State Space. Nature Methods. 2020; 17(1): 45-49. doi: 10.1038/s41592-019-0632-3
  8. Aizarani A, Saviano A, Sagar, Mailly L, Durand S, Herman JS, Pessaux P, Baumert TF#, Grün D#. A Human Liver Cell Atlas reveals Heterogeneity and Epithelial Progenitors. 2019; 572(7768): 199-204. doi: 10.1038/s41586-019-1373-2
  9. Herman JS, Sagar, Grün D. FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data. Nature Methods. 2018; 15(5): 379-386. doi: 10.1038/nmeth.4662
  10. Grün D, Lyubimova A, Kester L, Wiebrands K, Basak O, Sasaki N, Clevers H, van Oudenaarden A. Single-cell mRNA sequencing reveals rare intestinal cell types. Nature. 2015; 525: 251-255. doi: 10.1038/nature14966
  11. Wermke M, Kraus S, Ehninger A, Bargou RC, Goebeler ME, Middeke JM, Kreissig C, von Bonin M, Koedam J, Pehl M, Bornhäuser M, Einsele H, Ehninger G, Cartellieri M. Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML. Blood 2021;137(22):3145–8. doi.org/10.1182/blood.2020009759.
  12. Lauruschkat CD, Muchsin I, Rein AF, Erhard F, Grathwohl D, Dölken L, Köchel C, Nehmer A, Falk CS, Grigoleit GU, Einsele H, Wurster S, Kraus S. Impaired T cells and “memory-like” NK-cell reconstitution is linked to late-onset HCMV reactivation after letermovir cessation. Blood Adv 2024;8(11):2967–79. doi.org/10.1182/bloodadvances.2023012008.
  13. Rein AF, Lauruschkat CD, Muchsin I, Köchel C, Tischer-Zimmermann S, Bauersfeld L, Nelde A, Lübke M, Prusty BK, Schlosser A, Halenius A, Eiz-Vesper B, Dölken L, Grigoleit GU, Einsele H, Erhard F, Kraus S. Identification of novel canonical and cryptic HCMV-specific T-cell epitopes for HLA-A∗03 and HLA-B∗15 via peptide-PRISM. Blood Adv 2024;8(3):712–24. doi.org/10.1182/bloodadvances.2023011120
  14. Lauruschkat CD, Görge H, Knies K, Weißbrich B, Dölken L, Köchel C, Imhof N, Huber M, Hengel H, Einsele H, Wurster S, Kraus S. Human cytomegalovirus control in allogeneic stem cell transplant recipients in the letermovir era – emerging humoral and cellular players. Haematologica. 2025 Nov 27. doi: 10.3324/haematol.2025.288237.
  • Prof. Dr. rer. nat. Dominic Grün
    Institute of Systems Immunology
    Julius-Maximilians-Universität Würzburg
    Versbacher Str. 9
    97078 Würzburg
    Tel.: +49 931 31-81481
    dominic.gruen@uni-wuerzburg.de
  • PD Dr. med. Sabrina Kraus
    University Hospital Würzburg
    Department of Internal Medicine II
    Oberdürrbacher Straße 6
    97080 Würzburg
    T: +49 931 201-40967
    Kraus_S3@ukw.de

Spokespersons

Within the Collaborative Research Centre/Transregio (CRC/TRR) 221 innovative immune modulation strategies will be investigated to separate GvHD from GvL effects in order to enhance the safety and efficacy of allo-HSCT in the future.

Andreas Mackensen

Wolfgang Herr

Hermann Einsele

PARTICIPATING INSTITUTIONS

UW
UE
UKR
UKW
UR
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Contact us
Tel: (0049) 0941 944 - 5501
Fax: (0049) 0941 944 - 5502
Mail: wolfgang.herr(at)ukr.de
93053 Regensburg,
Franz-Josef-Strauß-Allee 11
Let's stay in touch