FOXP3-Positive Regulatory T Cells and Kidney Allograft Tolerance

Abstract

Normal immune homeostasis is achieved by several mechanisms, and prominent among them is immunoregulation. While several types of regulatory lymphocyte populations have been described, CD4 T cells expressing the Foxp3 transcription factor (Foxp3+ Tregs) are the best understood. This population of cells is critical for maintaining self-tolerance throughout the life of the organism. Foxp3+ Tregs can develop within the thymus, but also, under selected circumstances, naïve peripheral T cells can be induced to express Foxp3 and become stable Tregs as well. Abundant evidence from animal systems, as well as limited evidence in humans, implicates Tregs in transplant tolerance, although whether these Tregs recognize alloantigens or self-antigens is not clear. New translational approaches to promote immunosuppression minimization and/or actual tolerance are being designed to exploit these observations. These include strategies to boost the generation, maintainence and stability of endogenous Tregs, as well as adoptive cellular therapy with exogenous Tregs.

Advances in the immunology of heart transplantation

“…Small-animal studies, using strategies of target cell depletion or adoptive transfer, have demonstrated that these cells downregulate effector T-cell responses, prevent transplant arteriopathy, and contribute to allograft tolerance. 5–8 Of note, recent data support the hypothesis that specific induction of Tregs by donor antigens plays a key role in tolerance induced by transient mixed chimerism in non-human primate recipients of kidney, lung and heart allografts (see later). 9 …”

“…3,4 Importantly, for transplantation, the potential for these cells to contribute to clinical immunosuppression minimization and/or tolerance induction has also now been recognized. 5 …”

“…Although more difficult to manufacture than non-specific Tregs, antigen-specific Tregs may be attractive as they are more potent in preventing rejection/inducing tolerance in experimental models and, theoretically, they should have less risk of non-specific immunosuppression. 5 In a pilot liver transplant study, antigen-specific Tregs were generated by culturing recipient peripheral-blood mononuclear cells with irradiated donor cells. Seven of 10 patients treated with antigen-specific Treg infusion were successfully weaned from immunosuppression, with 4 of the 7 patients off drugs for >2 years.…”

RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance

“…42 FOXP3 regulatory cells are commonly identified in allograft tolerance. 3 In a murine model of spontaneous allograft acceptance, depletion of FOXP 3 T cells causes acute rejection of renal allografts. 41 In humans with immunosuppression, renal allograft intragraft FOXP3 T cells predicted favorable outcomes in subjects with subclinical/borderline rejections.…”

“…Preclinical studies in the cynomolgus nonhuman primate (NHP) 1 using bone marrow transplantation (BMT) to induce mixed chimerism has led to promising phase 1 trials. 2 The immunologic mechanisms leading to peripheral tolerance are complex and likely involve, in part, regulatory T cells 3,4 and regulatory B cells. 5 Reliable identification of tolerance could benefit clinical trials and provide insights into the immunologic mechanisms.…”