TIM4 regulates the anti-islet Th2 alloimmune response

Andrea Vergani, FRancesca Gatti, Kang M. Lee, Francesca D’Addio, Sara Tezza, Melissa Chin, Roberto Bassi, Ze Tian, Erxi Wu, Paola Maffi, Moufida Ben Nasr, James I. Kim, Antonio Secchi, James F. Markmann, David M. Rothstein, Laurence A. Turka, Mohamed H. Sayegh, Paolo Fiorina

Research output: Contribution to journalArticlepeer-review

Abstract

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 islettransplanted 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.

Original languageEnglish
Pages (from-to)1599-1614
Number of pages16
JournalCell Transplantation
Volume24
Issue number8
DOIs
Publication statusPublished - Aug 19 2015

Keywords

  • Autoimmune diabetes
  • Costimulatory molecules
  • Islet transplantation
  • Regulatory cells

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation
  • Biomedical Engineering

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