Mixed Chimerism and Transplantation Tolerance
Reconstitution of lethally irradiated mice with MHC mismatched allogeneic bone marrow leads to allogeneic reconstitution and specific tolerance. Such reconstitution does not, however, provide a workable approach to achieving transplant tolerance for two reasons: 1) if mature T cells are not removed from the allogeneic inoculum, graft-versus-host disease (GVHD) ensues, and can be lethal; and 2) if mature T cells are removed from the allogeneic bone marrow inoculum the animals engraft allogeneically but are relatively immunoincompetent when examined late after reconstitution (Zinkernagel 1980). This immunoincompetence is presumably due to a failure of the newly maturing T cells in such animals to find appropriate presenting cells capable of presenting foreign antigens in the context of thymic MHC products. The new T cells develop in a host thymus, but the presenting cells, like the T cells, are derived from the allogeneic donor. Singer and colleagues (1981) have shown that mature T cells from such animals are in fact competent in vitro if allowed to react with antigen-presenting cells of appropriate host MHC type. Consistent with this finding, they showed, and we have confirmed (Ildstad 1985), that the reconstitution of such animals with a mixture of T-cell-depleted host and donor bone marrow cells leads to survival of both lymphohematopoietic lineages, and spleen cells from such animals are immunocompetent (Fig. 1) and specifically unresponsive in vitro to both donor and host MHC.
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