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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 B01

Therapeutic targeting of T-follicular cells in GvHD.
Site: Würzburg, Erlangen
Principal Investigator: apl. Prof. Friederike Berberich-Siebelt, PD Dr. med. Silvia Spörl

Calcineurin inhibitors block NFAT activation and protect patients from graft-versus-host disease during bone marrow transplantation. On the other hand, they exert adverse side effects and interfere with the valuable graft-versus-leukemia effect. In contrast, NFAT deficiency maintains graft-versus-leukemia activity, although still protecting from graft-versus-host disease in mouse models. Therefore, it is planned to evaluate new NFAT inhibitors in vitro, on engineered human skin and in mouse models, as well as to ablate NFAT family members by CRISPR/Cas9 ahead of cell transfer.

  1. Vaeth M, Bauerlein CA, Pusch T, Findeis J, Chopra M, Mottok A, Rosenwald A, Beilhack A, Berberich-Siebelt F. Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity. Proc Natl Acad Sci U S A 2015;112(4):1125-30. doi: 10.1073/pnas.1409290112.
  2. 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.
  3. Koenig A*, Vaeth M*, Xiao Y, Chiarolla CM, Erapaneedi R, Klein M, Dietz L, Hundhausen N, Majumder S, Schuessler F, Bopp T, Klein-Hessling S, Rosenwald A, Berberich I, Berberich-Siebelt F. NFATc1/alphaA and Blimp-1 Support the Follicular and Effector Phenotype of Tregs. Front Immunol 2021;12:791100. doi: 10.3389/fimmu.2021.791100.
  4. Vaeth M, Muller G, Stauss D, Dietz L, Klein-Hessling S, Serfling E, Lipp M, Berberich I, Berberich-Siebelt F. Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J Exp Med 2014;211(3):545-61. doi: 10.1084/jem.20130604.
  5. 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.
  6. Hundhausen N, Majumder S, Xiao Y, Haeusl SS, Goehler H, Seal R, Chiarolla CM, Rosenwald A, Eyrich M, Cicin-Sain L, Berberich-Siebelt F. NFAT single-deficient murine T cells reduce the risk of aGvHD while controlling cytomegalovirus infection. iScience 2025;28(2):111937. doi: 10.1016/j.isci.2025.111937.
  7. Xiao Y*, Qureischi M*, Dietz L*, Vaeth M, Vallabhapurapu SD, Klein-Hessling S, Klein M, Liang C, Konig A, Serfling E, Mottok A, Bopp T, Rosenwald A, Buttmann M, Berberich I, Beilhack A, Berberich-Siebelt F. Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity. J Exp Med 2021;218(1). doi: 10.1084/jem.20181853.
  • PD Dr. rer. nat Friederike Berberich-Siebelt
    Universität Würzburg
    Institut für Pathologie
    Josef-Schneider-Straße 2
    97080 Würzburg
    T: 0931 31-81208
    path230(at)mail.uni-wuerzburg.de
  • PD Dr. med. Silvia Spörl
    University Hospital Erlangen
    Department of Medicine 5
    Ulmenweg 18
    91054 Erlangen
    T: +49 9131 8545021
    silvia.spoerl(at)uk-erlangen.de

Project B02

Targeting of TNFR2 and related molecules to separate GvHD from the GvL effect.
Site: Würzburg
Principal Investigator: Prof. Dr. rer. nat. Harald Wajant

Previously, we demonstrated in mice that targeting of TNFR2 and Fn14 allows GvL effect-sparing inhibition of GvHD by different mechanisms. Now, we will clarify whether co-targeting of TNFR2 and Fn14 yields additive or even synergistic therapeutic activity. To facilitate clinical translation of TNFR2 targeting on Tregs, we will also develop human TNFR2-specific antibody variants with Fcγ-receptor-independent agonistic activity and various IL-2 receptor targeted TNFR2 agonists. These reagents will be tested and evaluated in a variety of in vitro models but also in knockin mice in which the ectodomain of murine TNFR2 has been replaced by the corresponding domain of human TNFR2.

 

  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

Project B03

Generation, molecular characteristics and effector mechanisms of CSF2+-T-cells in graft-versus-host disease.
Site: Erlangen
Principal Investigator: Prof. Dr. med. Kai Hildner

CSF2+ T cells have been recently described to critically mediate immune-mediated tissue-damage in various autoimmune disease models. Their role within the pathogenesis of GvHD has not been studied yet. Our results indicate that CSF2+ donor T cells critically contribute to intestinal GvHD manifestation suggesting that CSF2 might represent a novel drugable target to limit GvHD. Hence, the overall goal of this research project is to molecularly and functionally define the T cell-extrinsic and -intrinsic signals that drive CSF2+ donor T cell formation and identify the characteristics and effector mechanisms of CSF2+ donor T cells in the immune pathogenesis of 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(at)uk-erlangen.de

Project B04

Aldehyde dehydrogenase 3A2 (ALDH3A2) as a novel regulator of inflammation and fibrotic tissue remodeling in sclerodermatous chronic graft-versus-host-disease.
Site: Erlangen
Principal Investigators: Prof. Dr. med. Jörg Distler, PD Dr. med. Regina Jitschin, PhD

Metabolic deregulation is emerging as a common pathogenic driver of chronic inflammatory as well as fibrosing diseases. We demonstrated in our preliminary resultsthat the expression of ALDH3A2 is deregulated in the skin of cGvHD patients in a TGFb-dependentmanner. Inactivation of ALDH3A2 prevented fibroblast activation, whereas overexpression of ALDH3A2 promoted collagen release and deposition of extracellular matrix. Moreover, inactivation of ALDH3A2 modulated leukocyte infiltration and ameliorated tissue remodelingin the murine cGvHD. With the current project, we aim to study the effects of ALDH3A2 on leukocyteinfiltration and fibroblast activation in experimental cGvHD and to decipher the molecular mechanisms, by which ALDH3A2 regulates inflammation and tissue remodeling in cGvHD.

  1. Trinh-Minh T, Chen CW, Tran Manh C, Li YN, Zhu H, Zhou X, Chakraborty D, Zhang Y, Rauber S, Dees C, Lin NY, Kah D, Gerum R, Bergmann C, Kreuter A, Reuter C, Groeber-Becker F, Eckes B, Distler O, Fabry B, Ramming A, Schambony A, Schett G, Distler JH. Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis. J Clin Invest 2024;134(10):e159884. doi: 10.1172/JCI159884.  
  2. Grönberg C, Rattik S, Tran-Manh C, Zhou X, Rius Rigau A, Li YN, Györfi AH, Dickel N, Kunz M, Kreuter A, Matei EA, Zhu H, Skoog P, Liberg D, Distler JH, Trinh-Minh T. Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2024;83(9):1156-68. doi: 10.1136/ard-2023-225158.  
  3. Liang M, Dickel N, Györfi AH, SafakTümerdem B, Li YN, Rigau AR, Liang C, Hong X, Shen L, Matei AE, 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.  
  4. Zhang Y, Shen L, Dreißigacker K, Zhu H, Trinh-Minh T, Meng X, Tran-Manh C, Dees C, Matei AE, Chen CW, Ditschkowski M, Krauss S, Winkler J, Wolff D, Ziemer M, Beilhack A, Karrer S, Herr W, Mackensen A, Schett G, Spriewald BM, Distler JHW. Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease. Blood 2021;137(17):2403-16. doi: 10.1182/blood.2020008720.  
  5. Rius Rigau A, Liang M, Devakumar V, Neelagar R, Matei AE, Györfi AH, Bergmann C, Filla T, Fedorchenko V, Schett G, Distler JHW, Li YN. Imaging mass cytometry-based characterisation of fibroblast subsets and their cellular niches in systemic sclerosis. Ann Rheum Dis 2024:ard-2024-226336. doi: 10.1136/ard-2024-226336. Online ahead of print.  
  6. Rius Rigau A, Li YN, Matei AE, Györfi AH, Bruch PM, Koziel S, Devakumar V, Gabrielli A, Kreuter A, Wang J, Dietrich S, Schett G, Distler JHW, Liang M. Characterization of Vascular Niche in Systemic Sclerosis by Spatial Proteomics. Circ Res 2024;134(7):875-91. doi: 10.1161/CIRCRESAHA.123.323299.  
  7. Zhu H, Luo H, Skaug B, Tabib T, Li YN, Tao Y, Matei AE, Lyons MA, Schett G, Lafyatis R, Assassi S, Distler JHW. Fibroblast Subpopulations in Systemic Sclerosis: Functional Implications of Individual Subpopulations and Correlations with Clinical Features. J Invest Dermatol 2024;144(6):1251-61.e13. doi: 10.1016/j.jid.2023.09.288.  
  8. Trinh-Minh T, Györfi AH, Tomcik M, Tran-Manh C, Zhou X, Dickel N, Tümerdem BS, Kreuter A, Burmann SN, Borchert SV, Hussain RI, Hallén J, Klingelhöfer J, Kunz M, Distler JHW. Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis-Specific Transcriptional Signatures in Human Skin. Arthritis Rheumatol 2024;76(5):783-95. doi: 10.1002/art.42781.  
  9. Zhou X, Trinh-Minh T, Matei AE, Györfi AH, Hong X, Bergmann C, Schett G, Atkinson J, Bowcutt R, Patel J, Johnson TS, Distler JHW. Amelioration of Fibrotic Remodeling of Human 3-Dimensional Full-Thickness Skin by Transglutamase 2 Inhibition. Arthritis Rheumatol 2023;75(9):1619-27. doi: 10.1002/art.42518.  
  10. Zhou X, Trinh-Minh T, Tran-Manh C, Gießl A, Bergmann C, Györfi AH, Schett G, Distler JHW. Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis. Arthritis Rheumatol 2022;74(5):871-81. doi: 10.1002/art.42033.  
  • Prof. Dr. med. Jörg Distler
    University Hospital Erlangen
    Department of Medicine 3
    Ulmenweg 18
    91054 Erlangen
    T: +49 9131 85-43008
    joerg.distler(at)uk-erlangen.de
  • PD Dr. med. Regina Jitschin , PhD
    University Hospital Erlangen
    Department of Medicine 5
    Ulmenweg 18
    91054 Erlangen
    T: +49 9131 8543113
    regina.jitschin(at)uk-erlangen.de

Project B07

GvHD therapy with in vitro expanded 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 previously showed that donor CD4+CD25+Foxp3+ regulatory T cells (Treg) prevent lethal acute GvHD after MHC-mismatched BMT in murine models. We now observed that they also ameliorate ongoing GvHD and the prerequisites for efficacious GvHD therapy are studied in this project. For this purpose, the migration pattern of in vitro expanded donor Treg is examined, their organ-specific T cell receptor (TCR) repertoire selection and their site-specific functional status. Finally, we investigate whether their therapeutic efficacy in GvHD can be enhanced by the overexpression of alloreactive TCRs or tissue-specific homing receptors.

 

  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
Principal Investigator: Prof. Dr. med. Markus Feuerer

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(at)ukr.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

Based on our recent findings on the spatio-temporal kinetics of graft-versus-host disease (GvHD) pathophysiology we discovered a regulatory myeloid cell population that exerts protective functions during the intestinal GvHD effector phase. Employing preclinical mouse models for GvHD and GvL we will interrogate the identity, mechanism of action, and therapeutic potential of this immune-protective myeloid cell subset to improve allo-HSCT.

 

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-lymphocyte compartments leading to chronic GvHD.
Sites: Erlangen & Regensburg
Principal Investigators: Prof. Dr. rer. nat. Thomas Winkler, Dr. med. Julia Winkler, Prof. Dr. med. Daniel Wolff

Although experimental data point to a crucial role of antibody mediated damage in chronic GvHD clinical evidence remains restricted to associations but direct proof is lacking. Within the research program we will analyse clonal B cell subpopulations directly involved in clinical chronic GvHD, characterize host specific antibodies including identification of targets and glycosylation profile, analyse T follicular helper cells mediating this process and finally characterize B cell infiltration host-and donor-antibody mediated damage of target organs.

  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. 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
  • Dr. med. Julia Winkler
    University Hospital Erlangen
    Department of Medicine 5
    Ulmenweg 18
    91054 Erlangen
    T: +49 9131 85-43112
    julia.winkler(at)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 interaction of GvHD and atherosclerosis after allogeneic HSCT.
Site: Würzburg
Principal Investigators: Prof. Dr. med. Alma Zernecke, Prof. Dr. med. Dr. med. univ. Andreas Beilhack

Patients undergoing allogeneic HSCT have an increased risk of cardiovascular disease. To address the interconnection between GvHD and atherosclerosis, we will use a GvHD-atherosclerosis mouse model and analyze GvHD activity, plaque development, as well as local and systemic immune responses. We will further focus on monocytes/macrophages and CD8+ T cells in mediating vascular inflammation and GvHD using relevant knockout mice and/or cell depletion strategies. In addition, we will investigate the potential of immunosuppressive drugs to improve GvHD-related atherosclerosis. It is our aim to define novel approaches to reduce cardiovascular events after HSCT.

 

  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 allogeneic hematopoietic stemm cell transplantation (HSCT) by vitamin D3.
Sites: Regensburg & Erlangen
Principal Investigators: Prof. Dr. rer. nat. Marina Kreutz, PD Dr. rer. nat. Heiko Bruns

To understand the underlying mechanisms for the protective effects of vitamin D3 in allogeneic HSCT patients we will investigate vitamin D3-related changes in the microbiome, epithelial barrier function and immune cell infiltration in GvHD target tissues in murine GvHD models. In vitro-analyses will prove direct effects of vitamin D3 on the function of T cells and macrophages. Results will be confirmed in murine models after selective deletion of the vitamin D receptor in T cells, macrophages and epithelial cells. Finally, effector mechanisms will be verified in human GvHD samples. Results should provide the basis for vitamin D3 supplementation of allo-HSCT patients in a prospective clinical trial.

 

  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

Project B13

Enterococci in allogeneic stem cell transplantation – indicators of loss of diversity or true GvHD pathogens?
Site: Regensburg
Principal Investigators: PD Dr. med. Daniela Weber, Prof. Dr. med. Dr. rer. nat. André Gessner, Prof. Dr. med. Ernst Holler

Based on our previous observation, that high enterococcal abundance associates with GvHD, we aim to analyze the causal relationship between enterococci and GvHD. Enterococcal strains collected from GvHD patients will be tested for pathogenicity in epithelial cell cultures as well as in murine models of colitis and GvHD: GvHD will be induced after recolonization of mice pretreated with antibiotics or of germfree mice with apathogenic and highly pathogenic strains. Full sequencing and targeted mutagenesis of specific enterococcal strains will be performed to identify strain specific pathogenicity factors. Finally, the impact of enterocccci on intestinal Treg and IgA reconstitution will be analyzed.

 

  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(at)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(at)ukr.de
  • Prof. Dr. med. Ernst Holler
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5542
    ernst.holler(at)ukr.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
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