Treg Therapy for the Induction of Immune Tolerance in Transplantation—Not Lost in Translation?

Abstract

The clinical success of solid organ transplantation is still limited by the insufficiency of immunosuppressive regimens to control chronic rejection and late graft loss. Moreover, serious side effects caused by chronic immunosuppressive treatment increase morbidity and mortality in transplant patients. Regulatory T cells (Tregs) have proven to be efficient in the induction of allograft tolerance and prolongation of graft survival in numerous preclinical models, and treatment has now moved to the clinics. The results of the first Treg-based clinical trials seem promising, proving the feasibility and safety of Treg therapy in clinical organ transplantation. However, many questions regarding Treg phenotype, optimum dosage, antigen-specificity, adjunct immunosuppressants and efficacy remain open. This review summarizes the results of the first Treg-based clinical trials for tolerance induction in solid organ transplantation and recapitulates what we have learnt so far and which questions need to be resolved before Treg therapy can become part of daily clinical practice. In addition, we discuss new strategies being developed for induction of donor-specific tolerance in solid organ transplantation with the clinical aims of prolonged graft survival and minimization of immunosuppression.

Cellular strategies to induce immune tolerance after liver transplantation: Clinical perspectives

“…Treg is a specialized subset of CD4 T cells characterized by the high expression of FoxP3 and interleukin-2 (IL-2) receptor CD25, and low expression of IL-7 receptor CD127[ 19 ]. Based on developmental origins, CD4+ Tregs could be divided into thymic Tregs (tTregs) and peripheral Tregs (pTregs).…”

Opportunities for Treg cell therapy for the treatment of human disease

“…However, given the bystander properties of Tregs and the recognition that organ-specific Tregs play a critical role in controlling autoimmunity in the local tissue environment, it was hypothesized that Tregs with single-antigen specificities might have an increased specific activity and a greater safety profile. In fact, data in multiple autoimmune ( 43 ) and transplant settings ( 44 ) showed that Treg cells expressing a single T cell receptor (TCR) suppressed autoreactive, multi-specific Teff cells and led to long-term tolerance. In fact, preliminary data in humans suggest that alloantigen-specific Treg cells can be effective in the transplantation setting ( 45 ).…”

Immunogenicity of mesenchymal stromal/stem cells

“…Tregs are regulatory T cells capable of secreting cytokines such as IL‐4, IL‐10, and TGFβ, which play an important role in immune homeostasis and induction of immune tolerance 55 . HLA‐G is an important factor to prevent the fetus from being rejected by the mother's immune system.…”

“…Tregs are regulatory T cells capable of secreting cytokines such as IL-4, IL-10, and TGFβ, which play an important role in immune homeostasis and induction of immune tolerance. 55 HLA-G is an important factor to prevent the fetus from being rejected by the mother's immune system. MSCs participate in inducing the proliferation of Tregs by secreting HLA-G. 56 MSCs are also believed to control immune tolerance by secreting HLA-G-5 and -7 isotypes, thereby affecting allograft tolerance.…”