Contribution of CD4+ and CD8+ T cells to graft-versus-host disease and graft-versus-leukemia reactivity after transplantation of MHC-compatible bone marrow.

Abstract

A murine model of allogeneic bone marrow (BM) transplantation was used to determine the relative importance of CD4+ and CD8+ T cells in establishing donor T cell chimerism and in the development of graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity. Mature donor T cells were essential for complete chimerism when host mice (AKR, H-2k) were conditioned with suboptimal irradiation (9 Gy = LD50). Transplantation of donor BM (B10.BR, H-2k) resulted in mixed chimerism, whereas mice given BM containing additional T cells developed into complete and stable chimeras. Depletion of T cell subsets was associated with an increase in the frequency of mixed chimerism. The incidence of lethal GVHD was dependent on the number of T cells added to the BM inoculum. Ex vivo depletion of CD4+ T cells eliminated GVH-associated mortality. Removal of CD8+ T cells had no effect on overall survival. In contrast to the GVH results, removal of either CD4+ or CD8+ T cells compromised GVL reactivity, indicating that an optimal GVL response required both CD4+ and CD8+ T cells. T cell-subset depletion did not interfere with the induction of donor-host tolerance in these chimeras and may have facilitated its development. The loss of GVH/GVL effector cells as a result of T cell depletion and the development of donor-host tolerance may act synergistically to prevent or suppress GVH and GVL reactivity.