DO DONOR CELLS FUNCTION AS VETO CELLS IN THE INDUCTION AND MAINTENANCE OF TOLERANCE ACROSS AN MHC DISPARITY IN MIXED LYMPHOID RADIATION CHIMERAS

Mixed lymphoid chimeras can be established across H-2b --> H-2d by injection of C57BL/6J (B-6) donor bone marrow cells into BALB/c hosts conditioned by sublethal irradiation, 235 cGy x3. These chimeras are specifically tolerant to both donor and host alloantigens. Tolerance cannot be broken even by injection of 4 x 10(8) normal BALB/c spleen cells (SC), suggesting a suppressor mechanism. In contrast to conventional suppression, however, in which suppressors are syngeneic to the cells they suppress, tolerance can be transferred only by cells of the allogeneic donor allotype (1, 2). Thy 1+ cell depletion eliminates the capacity of the donor population to transfer tolerance and markedly reduces the capacity of B-6 BMC to induce tolerance (3). In the present studies spleen cells from tolerant chimeras (CSC), when coinjected in a 1:1 ratio, reduced the high GVHD mortality induced in irradiated H-2d/b F1 hybrids by injection of 2 X 10(7) normal BALB/c SC alone (P<.01). When coinjected at a 5:1 ratio) CSC eliminated the GVHD mortality and weight loss induced by 5 X 10(6) BALB/c SC (P<.01). Depletion of B-6 cells from CSC removed their capacity to inhibit the GVHD induced by normal BALB/c SC. In contrast to conventional suppression, which requires the continued presence of suppressor cells, the BALB/c cells isolated from CSC, although unable to inhibit the GVHD of normal BALB/c SC, remained nonreactive against the H-2 b allotype for a prolonged period following depletion of the B-6 cells. This prolonged response reduction dependent upon some interaction with allogeneic donor cells-which, in turn, are specifically nonreactive to host antigens-is compatible with a veto mechanism.