| Tolerance regimens using bone marrow transplantation (BMT) permit permanent donor allo- or xenograft acceptance without compromising the immune system's competence to protect the host from disease, but the use of BMT for tolerance induction in the clinic has not been realized due to the toxicity of the conditioning regimens. Recently, progress has been made in animal models to develop non-myeloablative protocols for inducing mixed chimerism that utilize costimulatory blocking reagents that obviate the need for extensive host pre-treatment. High levels of multilineage mixed hematopoietic chimerism and systemic T cell tolerance can be achieved in mice through the use of anti-CD40L and costimulatory blockade (CTLA4Ig) alone or with recipient CD8 depletion and allogeneic bone marrow transplantation. While the establishment of central deletional tolerance serves as the primary means for the maintenance of donor-specific tolerance, the mechanisms by which costimulatory blockade facilitate the engraftment of allogeneic hematopoietic cells and the rapid tolerization of peripheral CD4+ T cells have not been defined in this protocol.; In various other experimental models using costimulatory blockade, anergy, immune deviation, suppression, and apoptosis have all been implicated as playing a role in graft prolongation. Analysis of chimeras that received BMT with anti-CD40L with CD8 depletion demonstrated the rapid development of specific tolerance (within 1 week post-BMT) and did not require a signal to the T cell through CD40L, suggesting that anti-CD40L is needed only to simply block CD40/CD40L interactions in order to induce CD4 cell tolerance. Furthermore, whereas evidence for the involvement of regulation, linked suppression, or cytokine deviation could not be demonstrated, anergy and the early deletion of allo-specific CD4+ T cells was observed, suggesting a critical role for these mechanisms in the induction of tolerance. Additionally, it appears that CTLA-4 may provide an important negative signal to peripheral CD4+ T cells within the first two days post-BMT. Together, these data are consistent with a hypothesis whereby blockade of T cell-APC costimulation through the CD40/CD40L pathway prevents the full activation of donor-reactive CD4 + T cells, potentially through an early CTLA-4-mediated negative signal followed by anergy and apoptosis through passive cell death pathways. These data also confirm that while the mechanisms involved in CD4+ T cell tolerance in this model are similar in some respects to other models of costimulatory blockade, the powerful tolerance achieved with a combination of anti-CD40L and BMT involves mechanisms that are unique to this combination. |
