REVERSAL OF CHIMERA DONOR-TO-HOST TOLERANCE IN A TOLEROGEN-FREE ENVIRONMENT

Clonal deletion of self-antigen-reactive T cells is known to be a dominant mechanism for tolerance induction in animals with a normal immune system. This phenomenon is mediated intrathymically by macrophages and dendritic cells. Some recent data have shown that tolerance to antigens expressed on radio-resistant thymic stromal cells results in clonal anergy. This report considers tolerance to host antigens in murine H-2-incompatible chimeras (H-2d-->H-2k) where thymic stromal cells remained of the host origin while virtually all lymphoid cells were replaced by donor H-2d cells. To assess the mechanism responsible for donor-to-host tolerance induction and the possible role of tolerogens in this process, we transferred (H-2d-->H-2k) chimeric lymphoid cells into lethally irradiated H-2d mice (a murine environment free of host H-2k antigens). Engrafted chimeric cells restored immunocompetence of secondary recipients without inducing a graft-versus-host reaction. H-2k skin test-grafts performed four weeks later were acutely rejected (median survival time = 9 days versus 11 days in controls). These results indicate that (A) donor-type lymphocytes reactive to host antigens in (H-2d-->H-2k) chimeras are not deleted during tolerance induction; (B) the continuous presence of the H-2k tolerogens appears to be necessary for the maintenance of nonreactivity to these tolerogens; (C) the anamnestic-like response to the H-2k skin grafts suggests that, during tolerance induction, anti-host (anti-H-2k) memory cells developed, an interpretation consistent with the concept that tolerance can result from a powerful immune response.