Long-term immunologic tolerance induction in chimeric mice after bone marrow transplantation across major histocompatibility barriers: persistent or redeveloping immunologic responsiveness after prolonged survival.

Employing allogeneic bone marrow chimeras [B6----C3H] (C3H/HeN mice lethally irradiated and then reconstituted with T cell-depleted C57BL/6J bone marrow), we investigated the kinetics of immunological reconstitution and the functional characteristics of the immune system at regular intervals following bone marrow transplantation (BMT). In chimeric mice, almost all spleen cells and peritoneal macrophages showed donor H-2 haplotype within 2 weeks after BMT. The differentiation and maturation of B lymphocytes and macrophages was largely complete by 2 weeks following BMT, whereas T cell functions such as Con A responsiveness and alloreactivity were not restored within 4 weeks. Newly developed T cells were found to be exclusively of donor origin but were tolerant of both donor type and host type major histocompatibility complex (MHC) determinants in assays of mixed lymphocyte reactions and capacity to generate cytotoxic T lymphocytes. Fully allogeneic chimeric mice survived up to one year after bone marrow transplantation without significant reactions or serious diseases. Neither graft-versus-host reaction (GVHR), host-versus-graft reaction (HVGR), nor the wasting diseases described. As compared to age-matched control mice, such fully allogeneic chimeras exhibited one year following BMT somewhat reduced but quite significant plaque forming cell responses to in vitro stimulation with a T-dependent antigen, SRBC. These findings suggest that BMT across MHC barriers may ultimately be useful in humans if all manifestations of GVHR are eliminated by completely removing all T cells from the bone marrow and if all hematopoietic resistance and all aspects of HVGR are eliminated by using sufficient immunosuppression and myeloablation.