Combined blockade of CD28/B7 and CD40/CD40L costimulatory pathways prevents the onset of chronic rejection.

SIGNALING through CD28/B7 and CD40/CD40L costimulatory pathways as a prerequisite for optimal T-cell activation has been well documented. t •2 Furthermore, unlike that through CD40/gp39. blockade of signaling through the CD28/B7 pathway by perioperative use of CTLA4-Ig fusion protein has been shown to enhance allograft survival and mitigate the development of chronic rejection (CR).3 In contrast, combined blockage of these two pathways has been shown to abrogate the development of posttransplant vasculopathy in a murine model of cardiac allotransplantation. l However, the utility of this latter model to study pathogenesis of CR is limited and, for its acceptance and mitigation of acute cellular rejection, the use of immunosuppressive drugs is required-agents themselves implicated in playing a role in the etiopathology of this lesion. It is for this purpose that we have developed an aortic allotransplantation (AOTx) model of CR in mice in which, for the acceptance of the graft, no immunosuppression is required and in which resultant changes established within 30 days posttransplantation are pathognomonic of CR.4 Reported herein is the role of blockade of costimulation and the evolution of CR.