Allograft tolerance induced by intact active bone co-transplantation and anti-CD40L monoclonal antibody therapy1

BACKGROUND: One of the most promising approaches to achieving allograft tolerance involves the transient inhibition of co-stimulatory signals in T cells. There is, however, increasing evidence that this approach alone cannot universally elicit allograft tolerance and that adjunct therapies capable of synergizing with co-stimulation blockade may be necessary. METHODS: We developed a novel tolerance strategy involving co-transplantation of intact allogeneic bone fragments containing active bone marrow (intact active bone [IAB]) with heart allograft and transient anti-CD40L monoclonal antibody therapy. RESULTS: Mice treated with IAB and anti-CD40L were tolerant to major histocompatibility complex and minor antigen-mismatched cardiac and skin allografts. Heart allografts had normal histology up to 270 days posttransplantation, and the production of graft-reactive antibodies was inhibited. Microchimerism, but no macrochimerism, of donor cells was detected in the peripheral blood or lymphoid organs of tolerant mice receiving IAB and anti-CD40L. Lymphocytes from tolerant mice retained normal proliferative responsiveness to donor cells in vitro but demonstrated a donor-specific loss in the priming of interferon-gamma responses. The ability to produce interleukin-2 or -4 when stimulated with donor cells was normal. CONCLUSIONS: Contrary to previous reports of the ability of bone marrow cells to induce central deletional tolerance, our data suggest that the regimen involving co-transplantation of IAB on the day of heart allograft transplantation and transient anti-CD40L therapy induces a robust donor-specific peripheral tolerance.