Title: REVERSAL OF CHIMERA DONOR-TO-HOST TOLERANCE IN A TOLEROGEN-FREE ENVIRONMENT
Abstract: 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 radioresistant 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 testgrafts 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.