Tolerance, mixed chimerism and protection against graft-versus-host disease after total lymphoid irradiation

Total lymphoid irradiation (TLI), originally developed as a non-myeloablati ve treatment for Hodgkin's disease, has been adapted for the induction of i mmune tolerance to organ allografts in rodents, dogs and non-human primates . Moreover, pretransplantation TLI has been used in prospective studies to demonstrate the feasibility of the induction of tolerance to cadaveric kidn ey allografts in humans. Two types of tolerance, chimeric and non-chimeric, develop after TLI treatment of hosts depending on whether donor bone marro w cells are transplanted alone with the organ allograft. An advantageous fe ature of TLI for combined marrow and organ transplantation is the protectio n against graft-versus-host disease (GVHD:I and facilitation of chimerism a fforded by the predominance of CD4(+)NK1.1(+)-like T cells in the irradiate d host lymphoid tissues. Recently a completely post-transplantation TLI reg imen has been developed resulting in stable mixed chimerism and tolerance t hat is enhanced by a brief course of cyclosporine. The post-transplantation protocol is suitable for clinical cadaveric kidney transplantation. This r eview summarizes the evolution of TLI protocols for eventual application to human clinical transplantation and discusses the mechanisms involved in th e induction of mixed chimerism and protection from GVHD.