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

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.

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.

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.

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.