Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host/donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD.
|Original language||English (US)|
|Number of pages||31|
|Journal||Annual Review of Immunology|
|State||Published - Apr 26 2021|
Bibliographical noteFunding Information:
B.R.B. has received funding from Kadmon Pharmaceuticals for preclinical studies, is an Advisory Board member for a KD025 cGVHD trial, has received funding from BlueRock Therapeutics, serves as a consultant for BlueRock Therapeutics and Magenta Therapeutics, and is a cofounder of Tmunity Therapeutics. L.S.K. is on the Scientific Advisory Board for HiFiBio. She has received funding from Kymab Limited, Magenta Therapeutics, BlueBird Bio, and Regeneron Pharmaceuticals. She reports consulting fees from Equillium; FortySeven, Inc.; Novartis, Inc.; EMD Serono; Gilead Sciences; and Takeda Pharmaceuticals. L.S.K. reports grants and personal fees from Bristol Myers Squibb and has a patent “Method to prevent relapse after transplant,” which is pending, and a patent “Method to prevent GVHD after transplant,” with royalties paid.
G.R.H. has received funding from Roche for a clinical study of tocilizumab in acute GVHD prophylaxis and consulted for Generon and NapaJen. B.C.B. reports pacritinib is supplied by CTI BioPharma for the conduct of clinical trial NCT 02891603 and a pending patent, WO2017058950A1, for methods of treating transplant rejection. B.C.B. holds patents related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD (WO2015120436A2); for the use of JAK inhibitors for rejection and GVHD prevention (WO2017058950A1); and for the use of CD83-targeted chimeric antigen receptor T cells in GVHD prevention, immune tolerance, autoimmunity, and acute myeloid leukemia therapy (WO2019165156). At this time, neither B.C.B. nor the University of Minnesota (or Moffitt Cancer Center) have received payment related to claims described in the patent. B.C.B. has received honoraria for participating in advisory board discussions for Incyte Corp and CTI BioPharma within the past 5 years.
This work was supported by research grants from the National Institutes of Health (NIH): National Heart, Lung, and Blood Institute grants R01 HL148164 (G.R.H.), 2R01 56067 and R01 HL11879 (B.R.B.), HL095791 (L.S.K.), and R01 HL133823 (B.C.B.); National Institute of Allergy and Infectious Diseases grants R37 AI 34495 and P01 AI 056299 (B.R.B.), U19 AI051731 (L.S.K.); National Cancer Institute grants P01 CA142106 and 2P01 065493 (B.R.B.) and U01 CA244291 (G.R.H); and NIH/FDA grant FD004099 (L.S.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. G.R.H. is an Andy Hill CARE Distinguished Researcher. V.T. received an American Society of Transplantation and Cellular Therapy New Investigator Award Grant and Be the Match Foundation Amy Strelzer Manasevit Research Program Grant.
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- graft-versus-host disease