Tolerance induction for solid organ grafts with donor-derived hematopoietic reconstitution

Abstract

Tolerance of transplanted tissue has been a focus of immunologists for decades. Indeed, to some the birth of immunology and the search for tolerance of the non-self are synonymous. One of the most powerful and reproducible methods of tolerance induction to allogeneic tissue has involved infusion of donor-specific hematopoietic cells. Under certain conditions, such infusion can result in hematopoietic reconstitution that can be experimentally accomplished at a variety of different time-points in the life of an organism from the in utero period through adulthood, reconstitution at each time-point involving consideration of a different set of immunological and physiological parameters. When high levels of donor-derived hematopoietic reconstitution are achieved, tolerance induction to donor-specific antigens is reproducible and long-lasting. Unfortunately, however, clinical efforts to achieve such high levels of hematopoietic reconstitution have historically been unsuccessful or fraught with complications. Transplantation efforts have been plagued by failure of engraftment, graft-vs-host disease (GVHD), or severe immunoincompetence of the recipient. Laboratory and clinical efforts during the last decade have resulted in a variety of developments that may overcome these barriers: (1) methods have been devised in which cells that cause GVHD can be depleted from the hematopoietic graft while hematopoietic reconstitution potential is preserved, (2) methods of harvesting large numbers of cells with multilineage reconstitution potential have been devised (an accomplishment that seems to allow the immunological barrier to be overwhelmed), and (3) capitalizing on the above two principles, minimally toxic preconditioning regimens have been designed that allow allogeneic engraftment. This review will focus on some of the experimental and clinical data of the past and the experimental and clinical issues that loom ahead.