Allogeneic versus semiallogeneic F1 bone marrow transplantation into sublethally irradiated MHC-disparate hosts. Effects on mixed lymphoid chimerism, skin graft tolerance, host survival, and alloreactivity

Abstract

In models of tolerance associated with mixed lymphoid chimerism, depletion of Thy 1+ cells from the allogeneic donor inoculum may decrease the level of chimerism achieved and the capacity of donor cells to induce tolerance. To determine whether the apparent role of Thy 1+ cells in the facilitation of bone marrow engraftment and induction of skin graft tolerance is related to alloaggression, the capacity of fully allogeneic C57BL/6J, H-2b BM cells to establish mixed lymphoid chimerism and skin graft tolerance in sublethally irradiated (2.5 Gy x 3) BALB/c, H-2d hosts was compared with that of semi-allogeneic BALB/c x C57BL/6J F1 H-2d/b BM cells which genetically lack the potential for graft-versus-host reactivity against parental recipients. The levels of mixed chimerism observed with allogeneic and semi-allogeneic F1 BM cells were nearly identical: 21.0 +/- 9.7% of spleen cells in H-2b BM-injected and 18.6 +/- 8.8% of spleen cells in H-2d/b BM-injected H-2d hosts were of donor allotype. There was no difference in the fraction of hosts rendered tolerant to C57BL/6J, H-2b skin grafts by H-2b vs. H-2d/b BM at either excess (94% vs. 92% tolerant) or threshold (37% vs. 40% tolerant) numbers of donor cells. Spleen cells from both types of mixed chimeras failed to respond to donor antigens in MLR. Both H-2b and H-2d/b BM-injected H-2d hosts rejected third party C3H/HeJ, H-2k skin grafts and responded to third party stimulators in MLR. Although these nonspecific allo-immune responses were not as strong as the responses of normal animals, they were suppressed to an equivalent degree in both types of chimeras. Graft-versus-host disease, if present in irradiated H-2b BM-injected hosts, did not significantly affect survival compared with survival of irradiated H-2d/b BM-injected animals. These results suggest that the tolerizing capacity of allogeneic BM does not depend upon GVHD and that allogeneic and semi-allogeneic BM establish mixed lymphoid chimerism and induce skin graft tolerance by similar mechanisms across a complete MHC disparity in sublethally irradiated adult hosts.