Tregs and Mixed Chimerism as Approaches for Tolerance Induction in Islet Transplantation

Abstract

Pancreatic islet transplantation is a promising method for the treatment of type 1 and type 3 diabetes whereby replacement of islets may be curative. However, long-term treatment with immunosuppressive drugs (ISDs) remains essential for islet graft survival. Current ISD regimens carry significant side-effects for transplant recipients, and are also toxic to the transplanted islets. Pre-clinical efforts to induce immune tolerance to islet allografts identify ways in which the recipient immune system may be reeducated to induce a sustained transplant tolerance and even overcome autoimmune islet destruction. The goal of these efforts is to induce tolerance to transplanted islets with minimal to no long-term immunosuppression. Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (T_regs) and donor and recipient hematopoietic mixed chimerism. Here, we review preclinical studies which utilize T_regs for tolerance induction in islet transplantation. We also review myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT) strategies in preclinical and clinical studies to induce sustained mixed chimerism and allograft tolerance, in particular in islet transplantation. Since T_regs play a critical role in the establishment of mixed chimerism, it follows that the combination of T_reg and HSCT may be synergistic. Since the success of the Edmonton protocol, the feasibility of clinical islet transplantation has been established and nascent clinical trials testing immune tolerance strategies using T_regs and/or hematopoietic mixed chimerism are underway or being formulated.

Keywords: Tregs; hematopoietic stem cells; islet transplantation; mixed chimerism; transplant tolerance.

Figure 1

T_reg and hematopoietic mixed chimerism as clinical strategies for tolerance induction. The left half of the figure shows direct effect of T_regs in inducing peripheral tolerance by regulating different immune cells such as dendritic cells and T cells to suppress alloreactivity. The adoptive transfer of different types of T_regs that been used in preclinical studies to support mechanisms of peripheral islet tolerance including polyclonal T_regs, antigen-specific T_regs, and engineered T_regs. These studies suggest T_regs might be used to reduce or eliminate systemic immunosuppression. The right half shows establishment of mixed hematopoietic chimerism through combined donor islet and hematopoietic stem cell transplantation. This is a state of coexistence of donor and recipient hematopoietic cell precursors with evidence to indicate that both mechanisms of central deletion of alloreactive responses and peripheral tolerance pathways regulate allograft tolerance. The administration of exogenous T_regs have been used to promote mixed hematopoietic chimerism and tolerance in preclinical studies. T_reg are necessary for sustained chimerism and tolerance in these models and human clinical studies have shown T_reg exert allo-antigen specific regulation in the setting of mixed chimerism. Ag, antigen; BMT, bone marrow transplantation; CTL, cytotoxic T lymphocytes; DC, dendritic cell; dTregs, donor-derived regulatory T cells; rTregs, recipient-derived regulatory T cells; T, T cell; Teff, effector T cell.