Tolerance in Organ Transplantation: Evolution of Strategies

Shrestha BM
2016 International Journal of Stem Cell Research and Transplantation  
The primary objectives of prolonging survival of transplanted organs and their recipients are compromised by cell-mediated and antibody-mediated rejections, infections, side-effects of immunosuppressive agents, malignancies and no-adherence [1] . Strategies to eliminate the need of long-term immunosuppressive agents and induction of tolerance have been the goal of research for 60 years. Transplantation tolerance is defined as induced modification of the host immune system which leads to
more » ... te, drugfree, transplant survival with maintenance of full incompetence [2]. Peter Medawar et al., pioneered in inducing tolerance in experimental animals 60 years ago. They demonstrated that prenatal or neonatal mice inoculated with allogeneic splenocytes were tolerant as adults to skin grafts from same donor strains resulting in drug-free indefinite graft survival, devoid of complications, including chronic rejection [3] . Since then several strategies of tolerance including heart, liver, kidney, bone marrow transplants have been developed in laboratory rodent models [4]. In 1999, Spitzer et al., demonstrated successful induction of tolerance in human renal transplant recipients through development of mixed lymphohaemopoietic chimerism and observed sustained allograft tolerance [5]. Tolerance of one's own tissues and elimination of autoimmunity are achieved by central and peripheral mechanisms. Central tolerance is generated within the thymus where immature autoreactive T cells with a high affinity for self-major histocompatibility complex molecules are subjected to apoptosis, a process referred to as negative selection or deletional tolerance [6] . The peripheral tolerance involves extrathymic mechanisms, whereby the activated T cells, which have escaped negative selection and emigrated from thymus, are suppressed by specialised T cells, termed as regulatory T cells (Tregs) [7] . Combination of both central and peripheral mechanisms are essential for the elimination of autoreactive cells and induction of self-tolerance. Thymic-derived, regulatory Treg cells represent a subset of CD4 + T cells (Foxp3 + CD4 + CD25 + regulatory T cells), which suppress unwanted responses against self-antigens and prevent autoimmunity. Tregs can suppress a whole range of immune cells including B cells, NK cells, CD4+ or CD8+ T cells, and both monocytes and dendritic cells. Emerging evidence suggest that the presence of regulatory B cells (Breg) in the spleen and blood of patients that spontaneously develop graft tolerance, bearing the phenotype CD24 int CD38 + CD27 + IgD -IgM +/low , can transfer donor-specific tolerance via IL-10 and TGF-beta1-dependent mechanisms and to suppress in vitro TNF-alpha secretion [8, 9] . Based upon the experience of animal models and human studies, in transplant recipients, central deletional tolerance provides the most robust and long-lasting state of unresponsiveness. Mixed haemopoietic chimerism and donor thymic transplantation are two strategies aimed at harnessing the potential of central tolerance in humans. Co-stimulation blockade using cytotoxic T cell lymphocyte associated antigen-4 immunoglobulin (CTLA4Ig) which blocks the CD28:CD80/86 costimulatory pathway has been used to develop peripheral tolerance. Mixed haemopoietic chimerism strategy involves a bone marrow or stem cell transplant in addition to the organ transplant. Historically, the experimental transplant recipients were subjected to whole body irradiation to eliminate mature alloreactive T cells. This was followed by transfusion of donor haemopoietic stem cells. The donor alloreactive T cells in the recipient were subsequently eliminated by the thymus leaving behind the newly developed T-cell repertoire of mixed chimeras tolerant toward the donor organs [10]. Subsequently, a T-cell depleting and non-myeloablative conditioning regimens were introduced for induction of mixed chimerism, which included limited body irradiation, splenectomy, antithymocyte globulin, donor bone marrow cell infusion and course of cyclosporine [11] . To avoid the risk of non-myeloablative irradiation, less toxic protocols of co-stimulation blockade led to mixed chimerism animals. The most frequently used co-stimula- International Journal of Stem Cell Research and Transplantation (IJST)
doi:10.19070/2328-3548-160009e fatcat:tddwexyqrrf3visbxcdwtjhl6e