Pharmacologic Targeting of Regulatory T Cells for Solid Organ Transplantation: Current and Future Prospects

Abstract

The last three decades have witnessed significant advances in the development of immunosuppressive medications used in kidney transplantation leading to a remarkable gain in short-term graft function and outcomes. Despite these major breakthroughs, improvements in long-term outcomes lag behind due to a stalemate between drug-related nephrotoxicity and chronic rejection typically due to donor-specific antibodies. Regulatory T cells (Tregs) have been shown to modulate the alloimmune response and can exert suppressive activity preventing allograft rejection in kidney transplantation. Currently available immunosuppressive agents impact Tregs in the alloimmune milieu with some of these interactions being deleterious to the allograft while others may be beneficial. Variable effects are seen with common antibody induction agents such that basiliximab, an IL-2 receptor blocker, decreases Tregs while lymphocyte depleting agents such as antithymocyte globulin increase Tregs. Calcineurin inhibitors, a mainstay of maintenance immunosuppression since the mid-1980s, seem to suppress Tregs while mammalian targets of rapamycin (less commonly used in maintenance regimens) expand Tregs. The purpose of this review is to provide an overview of Treg biology in transplantation, identify in more detail the interactions between commonly used immunosuppressive agents and Tregs in kidney transplantation and lastly describe future directions in the use of Tregs themselves as therapy for tolerance induction.

Complement component 3 deficiency prolongs MHC-II disparate skin allograft survival by increasing the CD4+ CD25+ regulatory T cells population

“…CD4 + CD25 + Foxp3 + Treg cells play a critical role in graft tolerance induction 22 23 24 . C3 deficiency could promote CD4 + CD25 + Treg cell differentiation in STZ-induced diabetic mice 29 .…”

“…Several studies have revealed that C3 deficiency is associated with attenuated Th1/Th17 responses 14 20 21 . CD4 + CD25 + Foxp3 + regulatory T (Treg) cells are thought to be critical for promoting peripheral tolerance, limiting chronic inflammatory disease and relieving autoimmune disease 22 23 24 . Strikingly, the absence of C3aR and C5aR signalling in CD4 + T cells has recently been confirmed to favour Treg expansion and survival 25 26 .…”

Severe type 1 upgrading leprosy reaction in a renal transplant recipient: a paradoxical manifestation associated with deficiency of antigen-specific regulatory T-cells?

“…The immunosuppressors have markedly different effects on Tregs. Calcineurin inhibitors block the expansion/function of Tregs, while mTor agents such as everolimus do not, favoring expansion and functional preservation of these cells [25]. The effect of mycophenolate on Tregs is less clear, but recent data show that at therapeutic concentrations, it potently blocks allospecific Treg function/expansion [26].…”

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“…Currently available immunosuppressive agents impact regulatory T cells in the alloimmune milieu with some of these interactions being deleterious to the allograft while others may be beneficial. 31 Variable effects are seen with common antibody induction agents such that basiliximab, an IL-2 receptor blocker, which decreases regulatory T cells, while lymphocyte-depleting agents such as antithymocyte globulin increases regulatory T cells. Calcineurin inhibitors, a mainstay of maintenance immunosuppression since the mid-1980s, seem to suppress regulatory T cells while mammalian targets of rapamycin (less commonly used in maintenance regimens) expand them.…”

“…The mechanisms of regulatory T cell suppression still remain elusive. In vitro studies have demonstrated that the immunosuppressive qualities native to regulatory T cells manifest through a variety of mechanisms, namely, modulation of antigen-presenting cell maturation and function, 32 anti-inflammatory cytokine production, 33 induction of apoptosis in target cells, 30,31 up-regulation of granzyme-B expression, 34 and disruption of metabolic pathways. 35 The general consensus throughout these studies concluded that donor antigen-specific regulatory T cells are more effective compared with polyclonal regulatory T cells.…”