ABSTRACT
So far, clinical benefit of hematopoietic stem cell induced donor-specific tolerance across major histocompatibility complex (MHC) barriers was hampered by either graft rejection or graft-versus-host disease. An alternative approach focuses on the use of donor-derived cells that bear an inherent mechanism to circumvent allospecific rejection upon injection into non-immunosuppressed hosts. Using a myeloablative conditioning model in the rat, full donor chimeric recipients were generated and their potential to induce long-term cardiac allograft survival was compared with the fate of grafts transferred to non-immunosuppressed host rats pretreated with donor-macrophages derived from the peritoneal cavity in the LEW to DA inbred strain combination. The induction of full multilineage long-term donor-chimerism (> 150 days) after initial host conditioning using two doses of cyclophosphamide and one shot of busulphan prevented acute graft rejection, whereas non-chimeric animals experienced acute and complete rejection. Conversely, vigorous T-cell depletion is required to protect conditioned animals from lethal graft-versus-host disease. Instead, the use of donor intraperitoneal macrophages achieved a state of transient chimerism and subsequent long-term graft survival in fully immunocompetent rats without the need of lethal conditioning regimens. In conclusion, the complex immunologic interactions, observed after allogeneic bone marrow transplantation as a means to induce donor chimerism, and subsequent long-term graft acceptance can be avoided if appropriate cell populations can be identified that, by themselves, induce a transient state of donor chimerism prevailing long enough to deviate allospecific immune responses, as outlined in this study.
