Combined Administration Of A Mutant TGF-β1/Fc And Rapamycin Promotes Induction Of Regulatory T Cells And Islet Allograft Tolerance

Background:The critical roles of TGF-b in the reciprocal differentiation of tolerance-promoting CD4+Foxp3+regulatory T cells (Tregs) and proinflammatory Th17effector cells affect alloimmune reactivity and transplant outcome. We reasoned that a strategy to harness TGF-b and block proinflammatory cytokines would inhibit the differentiation of Th17cells and strengthen the cadre of Tregs to promote tolerance induction and long-term allograft survival.Methods:In this study, we report the development of a long-lasting autoactive human mutant TGF-b1/Fc fusion protein that acts in conjunction with rapamycin to inhibit T cell proliferation and induce the de novo generation of Foxp3+Treg in the periphery, while at the same time inhibiting IL-6-mediated Th17cell differentiation. Results:Short term combined treatment with TGF-b1/Fc and rapamycin achieved long-term pancreatic islet allograft survival and donor specific tolerance in a mouse model. This effect was accompanied by expansion of Foxp3+Tregs, enhanced alloantigen-specific Treg function, and modulation of transcript levels of Foxp3, IL-6, and IL-17.Conclusion:Our strategy of combined TGF-b1/Fc and rapamycin to target the IL-6-related Tregs and Th17signaling pathways provides a promising approach for inducing transplant tolerance and its clinical application.