Mixed Bone Marrow Reconstitution Across MHC Barriers

Abstract

It has been known for some time that reconstitution of lethally irradiated mice with allogeneic bone marrow leads to chimerism and tolerance across major histocompatibility (MHC) barriers [1,2]. However, if mature T cells are not removed from the allogeneic bone marrow, this procedure leads also to graftversus-host disease (GVHD), which severely limits the applicability of this approach. If all mature T cells are first removed from the allogeneic bone marrow inoculum, a graft can still be achieved in mice, but in large animals, including humans [3] and miniature swine [4,5], such depletion produces major problems of failure of engraftment. The reason for this difference between rodents and large animals probably involves the much higher tolerance which mice exhibit to the toxic effects of total body irradiation (TBI) as compared to the larger species. Mice are routinely prepared for bone marrow transplantation by administration of 10 Gy TBI at 1.0 Gy/min, and the only target tissue damage which appears to be fatal is that of the lymphohematopoietic system. TBI administration at similar dose and dose rate to large animals, on the other hand, produces unacceptable levels of toxicity to other target organs, such as the gut and the lungs [6,7]. In order to develop approaches to achieving alloengraftment across MHC barriers, therefore, it is important to examine preclinical models in which T cells are not depleted from the allogeneic inoculum. We review here some of our own work with such models, including attempts to diminish the GVHD induced by allogeneic T cells without causing failure of engraftment.