Total lymphoid irradiation and transplantation tolerance

Abstract

Purpose of review The immunosuppressive effects of total lymphoid irradiation (TLI) for protection against graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) and induction of transplantation tolerance following solid organ allografts have been studied for years in animal models. In preclinical models of BMT, nonmyeloablative TLI conditioning protects against GVHD by skewing host T cell subsets to favor regulatory natural killer T cells that suppress GVHD by polarizing donor T cells toward secretion of noninflammatory cytokines such as interleukin-4. In preclinical models of organ transplantation, pre- or post-transplantation TLI conditioning induced long-term donor specific tolerance to organ allografts when combined with the infusion of donor bone marrow cells. These preclinical models were recently adapted to human transplantation. Recent findings Patients receiving allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies conditioned with TLI and depletive T cell antibodies exhibited sustained donor chimerism and reduced incidence of acute GVHD, but they retained antitumor activity. As in the preclinical models, nonmyeloablative TLI conditioning significantly alters residual host T cell subsets favoring natural killer T cells, and the low incidence of GVHD is associated with increased interleukin-4 secretion by chimeric donor T cells. The TLI regimen used in cancer patients was modified to determine conditions for stable mixed chimerism and tolerance induction following combined HCT and kidney transplantation. Summary This review summarizes the evolution of the preclinical TLI protocols and their recent translation to clinical trials, and discusses the mechanisms involved in protection from GVHD and the induction of tolerance following mixed chimerism.