TIM4 regulates the anti-islet Th2 alloimmune response

Details

• Alternative Title:
  Cell Transplant
• Personal Author:
  Vergani, Andrea ; Gatti, Francesca ; Lee, Kang M. ; D’Addio, Francesca ; Tezza, Sara ; Chin, Melissa ; Bassi, Roberto ; Tian, Ze ; Wu, Erxi ; Maffi, Paola ; Nasr, Moufida Ben ; Kim, James I. ; Secchi, Antonio ; Markmann, James F. ; Rothstein, David M. ; Turka, Laurence A. ; Sayegh, Mohamed H. ; Fiorina, Paolo
• Description:
  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.
• Subjects:
  Adult Animals Article Autoimmune Diabetes Autoimmunity B-Lymphocytes Cell Differentiation Costimulatory Molecules Cytokines Diabetes Mellitus, Experimental Diabetes Mellitus, Type 1 Female Graft Survival Humans Islets Of Langerhans Islets Of Langerhans Transplantation Islet Transplantation Male Membrane Proteins Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Inbred NOD Middle Aged Regulatory Cells Survival Rate Th1 Cells Th2 Cells Transcriptome Transplantation, Homologous

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• Source:
  Cell Transplant. 24(8):1599-1614.
• Pubmed ID:
  24612609
• Pubmed Central ID:
  PMC4280358
• Document Type:
  Journal Article
• Funding:
  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
• Volume:
  24
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:c3e0293bfbb725b78ea745e5ae84b03a2304d0a8854c2653a0ad931127a3f42a
• Download URL:
  https://stacks.cdc.gov/view/cdc/42009/cdc_42009_DS1.pdf
• File Type:
  [PDF - 1.64 MB ]