Our laboratory has studied the role of CD40 ligand (CD40L, CD154) in the primate immune response to allogenic and infectious challenges. We find that intensive early blockade of CD40L reliably attenuates acute rejection of primate cardiac allografts. Monotherapy fails to prevent late graft loss, which often occurs in association with rising antidonor antibody titers and allograft vasculopathy, despite continuing anti-CD40L therapy. In contrast, the primary humoral response to T helper dependent influenza viral antigen is inhibited during anti-CD40L therapy, and responses to subsequent immunization are blunted after discontinuation of therapy. These results are encouraging with regard to the tolerogenic potential of costimulatory blockade for specific T helper dependent antigens. However, these findings also indicate that pathogenic allograft responses in primates are probably not entirely CD40L-dependent. As such, additional immunomodulatory strategies are needed to facilitate tolerance to a transplanted organ.