期刊
CELL TRANSPLANTATION
卷 24, 期 8, 页码 1599-1614出版社
COGNIZANT COMMUNICATION CORP
DOI: 10.3727/096368914X678571
关键词
Islet transplantation; Autoimmune diabetes; Costimulatory molecules; Regulatory cells
资金
- JDRF Career Development Award
- ASN Career Development Award
- ADA Mentor-based Fellowship grant
- Translational Research Program (TRP) grant from Boston Children's Hospital
- Harvard Stem Cell Institute grant (Diabetes Program) [DP-0123-12-00]
- Italian Ministry of Health grant [RF-2010-2303119, RF-FSR-2008-1213704]
- NIH-Research Training grant [T32DK007726-28]
- AMD-SID Pasquale di Coste Scolarship
- Italian Scientists and Scholars of North America Foundation (ISSNAF)-Fondazione Marche Fellowship
- AST Genentech Clinical Science Fellowship [R01 AI-037691]
The role of the novel costimulatory molecule TIM4 in anti-islet response is unknown. We explored TIM4 expression and targeting in Th1 (BALB/c islets into C57BL/6 mice) and Th2 (BALB/c islets into Tbet(-/-)C57BL/6 mice) models of anti-islet alloimmune response and in a model of anti-islet autoimmune response (diabetes onset in NOD mice). The targeting of TIM4, using the monoclonal antibody RMT4-53, promotes islet graft survival in a Th1 model, with 30% of the graft surviving in the long term; islet graft protection appears to be mediated by a nil to Th2 skewing of the immune response. Differently, in the Th2 model, TIM4 targeting precipitates graft rejection by further enhancing the Th2 response. The effect of anti-TIM4 treatment in preventing autoimmune diabetes was marginal with only minor Th1 to Th2 skewing. B-Cell depletion abolished the effect of TIM4 targeting. TIM4 is expressed on human B-cells and is upregulated in diabetic and islet-transplanted patients. Our data suggest a model in which TIM4 targeting promotes Th2 response over Th1 via B-cells. The targeting of TIM4 could become a component of an immunoregulatory protocol in clinical islet transplantation, aiming at redirecting the immune system toward a Th2 response.
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