TIM4 regulates the anti-islet Th2 alloimmune response #MMPMID24612609
Vergani A; Gatti F; Lee KM; D?Addio F; Tezza S; Chin M; Bassi R; Tian Z; Wu E; Maffi P; Nasr MB; Kim JI; Secchi A; Markmann JF; Rothstein DM; Turka LA; Sayegh MH; Fiorina P
Cell Transplant 2015[]; 24 (8): 1599-614 PMID24612609show ga
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 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.
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Cell+Transplant 2015 ; 24 (8): 1599-614
