Owing to the adverse effects of immunosuppression and an inability to prevent chronic rejection, there is a pressing need for alternative strategies to control alloimmunity. In three decades, regulatory T cells (Tregs) have evolved from a hypothetical mediator of adoptively transferred tolerance to a well-defined population that can be expanded ex vivo and returned safely to patients in clinical trials. Herein, we review the historical developments that have permitted these advances and the current status of clinical trials examining Tregs as a cellular therapy in transplantation. We conclude by discussing the critical unanswered questions that face this field in the coming years.
Regulatory T cells (Tregs) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring Tregs, an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen presenting cells under conditions that lead to the generation or expansion of donor-reactive, adaptive Tregs. Here we demonstrate that stimulation of mouse CD4 + T cells by immature allogeneic dendritic cells (DCs) combined with pharmacological inhibition of phosphodiesterase 3 (PDEi) results in a functional enrichment of Foxp3 + T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4 + effectors or donor-reactive CD8 + TCR transgenic T cells and inhibited both effector cell proliferation and T cell priming for IFN-γ production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3 + CD4 + T cells driven by allogeneic APC. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and importantly, attenuated the development of vasculopathy mediated by autologous PBMC in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graftreactive, functional mouse and human Tregs that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for Treg-based therapies
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