Blockade of TIM-1 on the donor graft ameliorates graft-versus-host disease following hematopoietic cell transplantation.

Abstract

Acute graft-versus-host disease (GVHD) is a leading cause of mortality after allogeneic hematopoietic cell transplantation (HCT) mediated by dysregulated T-cell immune reconstitution. Given the role of the T-cell immunoglobulin and mucin 1 (TIM-1) surface protein in many immune processes, including organ transplantation tolerance, we asked if TIM-1 might drive post-transplant inflammation and acute GVHD. TIM-1 binds to phosphatidylserine (PtdSer), and agonism of TIM1 on immune cells is proinflammatory. HCT conditioning results in a significant supply of PtdSer from apoptosis and cellular debris. Using murine models, treatment with an antagonistic anti-TIM-1 monoclonal antibody (mAb) protects against acute GVHD while maintaining graft-versus-tumor effects. In contrast, the addition of exogenous free PtdSer worsened GVHD in a TIM-1-dependent manner. Importantly, TIM-1 blockade did not alter the expansion of donor T cells in vitro or in vivo. Instead, TIM-1 blockade reduces proinflammatory cytokines and promotes anti-inflammatory factors like carbonic anhydrase 1 and serum amyloid A1 in the gut tissue. This is mediated by TIM-1 on donor cells, as HCT of wild-type (WT) bone marrow (BM) and conventional T (Tcon) cells into TIM-1-/- knockout (KO) recipient mice showed little survival advantage compared with WT recipients, whereas WT recipients of TIM-1-/- KO Tcon cells or TIM1-/- KO BM had improved survival, in part due to the expression of TIM-1 on donor invariant natural killer T cells, which drives inflammation. Finally, in a humanized mouse xenograft GVHD model, treatment with anti-human TIM-1 antagonist mAb reduced GVHD disease burden and mortality. This supports TIM-1 as important for GVHD pathogenesis and as a target for the prevention of GVHD.

• Authors: Bettina P Iliopoulou, Katie Hsu, Magdiel Pérez-Cruz, Sai-Wen Tang, Wendy W Pang, Tom Erkers, Neeraja Kambham, Gordon J Freeman, Rosemarie H Dekruyff, Everett H Meyer
• Journal: Blood advances (Blood Adv) Vol. 3 Issue 21 Pg. 3419-3431 (11 12 2019) ISSN: 2473-9537 [Electronic] United States
• PMID: 31714958 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Antibodies, Blocking
• Antibodies, Monoclonal
• Biomarkers
• HAVCR1 protein, human
• Hepatitis A Virus Cellular Receptor 1
• Inflammation Mediators

Topics

• Animals
• Antibodies, Blocking (therapeutic use)
• Antibodies, Monoclonal (therapeutic use)
• Biomarkers
• Disease Models, Animal
• Gene Expression
• Graft vs Host Disease (diagnosis, drug therapy, etiology, mortality)
• Hematopoietic Stem Cell Transplantation (adverse effects, methods)
• Hepatitis A Virus Cellular Receptor 1 (antagonists & inhibitors, genetics, metabolism)
• Humans
• Immune Reconstitution
• Immunohistochemistry
• Immunophenotyping
• Inflammation Mediators (metabolism)
• Lymphocyte Count
• Mice
• Mice, Knockout
• Severity of Illness Index
• Survival Rate
• T-Lymphocytes (immunology, metabolism)
• Transplantation, Homologous