TIM4 regulates the anti-islet Th2 alloimmune response ; Cell Transplant

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 Th1 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. ; R01 AI-037691/AI/NIAID NIH HHS/United States ; T32 AI007529/AI/NIAID NIH HHS/United States ; T32 DK007726/DK/NIDDK NIH HHS/United States ; T32DK007726-28/DK/NIDDK NIH HHS/United States ; R01 AI057851/AI/NIAID NIH HHS/United States ; U01 DP000123/DP/NCCDPHP CDC HHS/United States ; 2015-09-07T00:00:00Z ; 24612609 ; PMC4280358