CD40 signaling replaces CD4(+) lymphocytes and its blocking prevents chronic rejection of heart transplants

Chronic rejection remains the major obstacle to long term survival in heart transplant recipients, The cellular and molecular mechanisms that underlie chronic rejection are not known, and their discovery can form the basis of clinical intervention. Several investigators have suggested that the devel opment of chronic rejection in solid organ transplants is dependent on help mediated by CD4(+) lymphocytes, Importantly, the mechanism through which h elp is provided has not been fully delineated In transplant rejection. Usin g a murine heterotopic heart transplant model without immunosuppression, th is study defines the functional role of CD4(+) lymphocytes in chronic rejec tion. In an MHC class II-mismatched model, we demonstrate that chronic reje ction was absolutely contingent on the presence of CD4(+) lymphocytes. Impo rtantly, here we report that signaling through CD40 can replace the require ment of CD4(+) lymphocytes, demonstrated by the development of chronic reje ction In CD4 knockout recipients treated with a CD40-activating mAb (FGK45) , The return of rejection appears to be a CD8(+) lymphocyte dependent proce ss, noted by the absence of rejection in FGK45-treated recombinase-activate d gene knockout (CD4(+) and CD8(+) lymphocyte-deficient) recipients. The CD 40 signaling pathway works independently of B7-CD28 costimulation, as indic ated by the development of severe chronic rejection in CD28 knockout recipi ents. Importantly, this study provides evidence that CD40 ligand-targeted t herapies may prevent chronic rejection only in strain combinations where CD 4(+) lymphocyte help is absolutely required.