Cutting edge: Administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning

Transplantation tolerance, defined as allograft acceptance by an immunocomp etent recipient in the absence of long-term immunosuppression, has remained an elusive goal in clinical transplantation. Robust experimental tolerance induction strategies hale in common methods to induce mixed hemopoietic ch imerism, To date, however, chimerism induction across allogeneic barriers h as required recipient conditioning with irradiation or cytoablative agents. In this paper we show that B6 recipients of fully allogeneic BALB/c skin g rafts treated with repeated doses of donor bone marrow and anti-CD40 ligand (CD40L) develop durable (>300 days), readily detectable (6-12%) multilinea ge hemopoietic chimerism, indefinite allograft acceptance (>300 days), and donor-specific tolerance to secondary skin grafts. Analysis of the TCR repe rtoire of treated mice indicates that the underlying mechanisms of toleranc e are in part mediated by deletion of donor-reactive T cells. These data de monstrate that durable hemopoietic chimerism and robust transplantation tol erance can be achieved without cytotoxic conditioning using a potentially c linically applicable regimen.