Graft vs. Host Disease

Despite their critical role in eradicating cancer cells, allogeneic donor T cells in a stem cell transplant can also turn against the patient’s healthy cells resulting in Graft vs. Host Disease (GvHD) which can cause severe and often fatal side effects.  In collaboration with Dr. Jaebok Choi’s lab we focus on pathways and mechanisms of alloreactivity and graft versus leukemia.

(Dr. Steve Persaud, Dr. Ramzi Abboud, Julie Ritchey, Peter Ruminski, Dr. Michael Rettig, Dr. Ezhil Chendamarai, Aditya Yelamali)

 
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The role of the JAK/STAT system in graft-vs-host disease.  Three step model of acute GvHD.   From Abboud, et al., Ther Adv Hematol 2020, 11: 1–13

 

For patients with a variety of hematological malignancies, an allogeneic stem cell transplantation can successfully eradicate the cancer cells due to immune-mediated clearance.

 

Unfortunately, the same T cells that mediate this graft-versus-leukemia effect can also react against healthy host tissues to cause potentially fatal GvHD.  In seeking to better understand the mechanism behind this complication we, along with former lab member and continued collaborator, Dr. Jaebok Choi, are focusing on the role of the JAK/STAT signaling pathway which is central to inflammation.  Both the development and maintenance of GvHD could be attributable to pathways downstream of JAK/STAT in T cells, B cells, macrophages, neutrophils, and natural killer cells.  Drs. Ramzi Abboud and Mark Schroder are translating this work in clinical trials using itacitinib in haploidentical transplantations and baricitinib for matched related and unrelated transplantations.

To reduce GvHD we are testing not only JAK inhibitors, such as baricitinib, that have been approved by the FDA, but also proprietary reagents being generated by our medicinal chemists, such as potent small molecule VLA-4/α4β7 inhibitors  to prevent trafficking of autoreactive lymphocytes into the intestine. Our goal is not only to minimize GvHD, but also to retain anti-tumor activity.

As described elsewhere in this website, we are developing methods for conditioning patients for stem cell transplantation that avoid the use of toxic treatments such as irradiation and chemotherapy, both of which can also contribute to the pathology of GvHD.

Finally, we also collaborate with other academic or industry partners to assess proprietary molecules in preclinical studies that have the potential to alleviate GvHD.

 

 Key Publications

  •  Choi J, Ziga ED, Ritchey J, Collins L, Prior JL, Cooper ML, Piwnica-Worms D, and DiPersio JF. IFNyR signaling mediates alloreactive T cell trafficking and GvHD. Blood120(19):4093-103 2012. PMID 22972985.

  • Cooper ML, Choi J, Karpova D, Vij K, Ritchey J, Schroeder MA, and DiPersio JF.  Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo.  J Immunol 2017 May 1;198(9):346-3754.  doi: 10.4049/jimmunol.1502399. Epub 2017 Mar 22. PMID 28330901.

  • Choi J, Cooper ML, Staser K, Ashami K, Vij KR, Wang B, Marsala L, Niswonger J, Ritchey J, Alahmari B, Achilefu S, Tsunoda I, Schroeder MA, DiPersio JF.  Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease.  Leukemia 2018 Nov;32(11):2483-2494. doi:10.1038/s41375-01-0123-z. Epub 2018 Apr 2. PMID 29691471.

  • Perry JSA, Russler-Germain EV, Zhou YW, Purtha W, Cooper M, Choi J, Schroeder MA, Salazar V, Egawa T, Lee BC, Abumrad N, Kim B, Anderson M, DiPersio JF, and Hsieh CS. Transfer of Cell-Surface Antigens by Scavenger Receptor CD36 Promotes Thymic Regulatory T Cell Receptor Repertoire Development and Allo-tolerance. Immunity2018 June 19; 48(6):1271. PMID 29752065.

  • Alahmari B, Cooper ML, Vij K, Ritchey J, Ruminski P, Gao F, Choi J, DiPersio JF.  Selective targeting of α4β1 integrin attenuates murine graft versus host disease.  Leukemia. 2020 Nov;34(11):3100-3104. doi: 10.1038/s41375-020-0786-0. Epub 2020 Mar 9.  PMID: 32152466.

  • Schroeder MA, Khoury HJ, Jagasia M, Ali H, Schiller GJ, Staser K, Choi J, Gehrs L, Arbushites MC, Yan Y, Langmuir P, Srinivas N, Pratta M, Perales MA, Chen YB, Meyers G, DiPersio, JF.  A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease.  Blood Adv 2020 Apr 28;4(8):1656-1669. doi: 

  • Liu R, Gao Q, Foltz SM, Fowles JS, Yao L, Wang JT, Cao S, Sun H, Wendl MC, Sethuraman S, Weerasinghe A, Weerasinghe A, Rettig MP, Storrs EP, Yoon CJ, Wyczalkowski MA, McMichael JF, Kohnen DR, King J, Goldsmith SR, O’Neal JO, Fulton RS, Fronick CC, Ley TJ, Jaysinghe RG, Fiala MA, Oh ST, DiPersio JF, Vij R, Ding L. Co-evolution of tumor and immune cells during progression of multiple myeloma. Nat Commun 2021|

  • Alahmari B, Cooper ML, Vij K, Ritchey J, Ruminski P, Gao F, Choi  J, DiPersio JF. Selective Targeting of Alpha4beta1 Integrin Attenuates Murine Graft Versus Host Disease. Leukemia 2020 Nov;34(11):3100-3104 

  • Kim S, Ashami K, Lim S, Staser K, Vij K, Santhanam S, Ritchey J, Peterson  S, Gao F, Ciorba MA, Cooper ML, DiPersio JF, Choi J. Baricitinib Prevents GvHD by Increasing Tregs Via JAK3 and Treats Established GvHD by Promoting Intestinal Tissue Repair Via EGFR. Leukemia 2022 Jan;36(1):292-295

  • Persaud SP, Ritchey JK, Kim S, Lim S, Ruminski PG, Cooper ML, Rettig  MP, Choi J, DiPersio JF. Antibody-Drug Conjugates Plus Janus Kinase Inhibitors Enable MHC-Mismatched Allogeneic Hematopoietic Stem Cell  Transplantation. J Clin Invest 2021 Dec 15;131(24):e145501

  • Patel DA, Schroeder MA, Choi J, DiPersio JF. Mouse Models of Graft-Versus-Host Disease. Methods Cell Biol 2022;168:41-66 

  • Kim S, Lim S, Kim B, Ritchey J, Vij K, Prior J, Marsala L, Stoner A, Gao F,  Achilefu S, Cooper ML, DiPersio JF, Choi J. S100A9 Up-Regulated by IFNGR Signaling Blockade Functions as a Novel GvHD Suppressor Without Compromising GvL in Mice. Blood 2022 Dec 7:blood2021012687; [ahead of print]

  • Goldsmith SR, Ghobadi A, DiPersio JF, Hill B, Shadman M, Jain T. Chimeric Antigen Receptor T Cell Therapy Versus Hematopoietic Stem Cell Transplantation: An Evolving Perspective. Transplant Cell Ther 2022 Nov;28(11):727-736