Mp. Fischbein et al., CD40 signaling replaces CD4(+) lymphocytes and its blocking prevents chronic rejection of heart transplants, J IMMUNOL, 165(12), 2000, pp. 7316-7322
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.