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

被引:5
|
作者
Iliopoulou, Bettina P. [1 ]
Hsu, Katie [1 ]
Perez-Cruz, Magdiel [1 ]
Tang, Sai-Wen [1 ]
Pang, Wendy W. [1 ]
Erkers, Tom [1 ]
Kambham, Neeraja [2 ]
Freeman, Gordon J. [3 ]
Dekruyff, Rosemarie H. [4 ]
Meyer, Everett H. [1 ]
机构
[1] Stanford Univ, Sch Med, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA
[2] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA
[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[4] Stanford Univ, Dept Med, Sean N Parker Ctr Allergy & Asthma Res, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
KILLER T-CELLS; APOPTOTIC CELLS; PHOSPHATIDYLSERINE; FAMILY; IMMUNOGLOBULIN; PREVENTION; TOLERANCE; IMMUNITY; RECEPTOR; ROLES;
D O I
10.1182/bloodadvances.2019000286
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 Al 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 (icon) 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 TIM-1 -/- 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.
引用
收藏
页码:3419 / 3431
页数:13
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