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Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells
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TIM4 Regulates the Anti-Islet Th2 Alloimmune Response
Andrea Vergani1,2, Francesca Gatti1,3, Kang M Lee4
1Transplantation Research Center, Division of Nephrology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
Cell Transplantation
|March 12, 2014
Summary
Targeting TIM4 (T-cell immunoglobulin and mucin-domain containing-3) molecule shows promise for islet transplantation by promoting graft survival. This approach redirects the immune response, potentially benefiting patients with diabetes.
Area of Science:
- Immunology
- Transplantation Biology
- Autoimmunity
Background:
- The role of TIM4 in anti-islet immune responses remains unclear.
- TIM4 is a novel costimulatory molecule with potential implications in transplantation and autoimmunity.
Purpose of the Study:
- To investigate TIM4 expression and the effects of its targeting in models of anti-islet alloimmune and autoimmune responses.
- To determine if TIM4 targeting can modulate immune responses for improved islet graft survival and prevention of autoimmune diabetes.
Main Methods:
- Explored TIM4 expression and targeting using monoclonal antibody RMT4-53 in Th1 and Th2 alloimmune models and a non-obese diabetic (NOD) mouse model.
- Assessed islet graft survival, immune response skewing (Th1/Th2), and the impact of B-cell depletion.
- Analyzed TIM4 expression in human B-cells from diabetic and islet-transplanted patients.
Main Results:
- TIM4 targeting promoted long-term islet graft survival (30%) in a Th1 model, associated with a Th1 to Th2 immune response shift.
- In a Th2 model, TIM4 targeting exacerbated graft rejection by enhancing the Th2 response.
- Anti-TIM4 treatment showed marginal effects in preventing autoimmune diabetes, with minimal Th1 to Th2 skewing.
- B-cell depletion abrogated the effects of TIM4 targeting, indicating a crucial role for B-cells.
Conclusions:
- TIM4 targeting promotes a Th2-dominant immune response over Th1, mediated through B-cells.
- TIM4 is expressed on human B-cells and is upregulated in patients with diabetes and after islet transplantation.
- Targeting TIM4 could be a valuable immunoregulatory strategy in clinical islet transplantation to enhance graft survival by redirecting the immune system towards a Th2 response.
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