Delayed rejection of fetal pig pancreas in CD4 cell deficient mice was correlated with residual helper activity

CD4 cells have been shown to play a dominant role in the rejection of xenog rafts. Depletion of murine CD4 cells by injecting anti-CD4 antibody prolong s the graft survival, but does not prevent its rejection. For a more stable phenotype, we used genetically modified mice. To test whether the delayed rejection is caused by incomplete depletion of CD4 cells, we evaluated the response to fetal pig pancreas (FPP) xenografts in three types of CD4 cell deficient mice. They are MHC class II deficient mice (MHC II degrees / degr ees), CD4 deficient mice (CD4 degrees / degrees) and a novel type of CD4 ce ll deficient mice (designated GK). GK mice were rendered permanently and co mpletely CD4 deficient by transgenic expression of anti-CD4 antibody, where as both MHC II degrees / degrees and CD4 degrees / degrees mice have a resi dual helper cell population. FPP grafts in wild type mice were rejected wit hin a week, whereas FPP grafts survived up to 4 weeks in MHC II degrees / d egrees and CD4 degrees / degrees mice. Survival of grafts in GK mice was ev en longer (8 weeks). Differences in histology were also noted. Rejecting gr afts in MHC II degrees / degrees and wild-type mice were infiltrated with b oth eosinophils and mononuclear cells, whereas the infiltrates in CD4 degre es / degrees and GK mice were exclusively mononuclear cells. Immunohistoche mistry showed that they were primarily CD8 cells. The immune response to FP P was clearly different in the three types of CD4 cell deficient mice. Sple nocytes of MHC II degrees / degrees 3 weeks post-transplant with FPP produc ed substantial amounts of IFN-gamma and IL-5, whereas splenocytes of CD4 de grees / degrees mice produced low levels of IFN-gamma but no detectable IL- 5. At similar times, these cytokines were not detected in GK mice. Furtherm ore, CD4 degrees / degrees mice were capable of mounting helper dependent, although reduced, IgG responses to FPP antigens, while GK mice were not. Th e above results indicate that residual helper activity in some types of CD4 cell deficient mice could still contribute to xenograft rejection. Caution needs to be exercised where such mice are used as models of CD4 cell defic iency. Also, because there is eventual rejection of xenograft FPP in GK mic e which lack detectable helper activity, we argue that these mice are a bet ter model to investigate the involvement of CD4-independent rejection mecha nisms.