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 xenografts. Depletion of murine CD4 cells by injecting anti-CD4 antibody prolongs 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(o/o), CD4 deficient mice (CD4(o/o)) and a novel type of CD4 cell deficient mice (designated GK). GK mice were rendered permanently and completely CD4 deficient by transgenic expression of anti-CD4 antibody, whereas both MHC II(o/o) and CD4(o/o) mice have a residual helper cell population. FPP grafts in wild type mice were rejected within a week, whereas FPP grafts survived up to 4 weeks in MHC II(o/o) and CD4(o/o) mice. Survival of grafts in GK mice was even longer (8 weeks). Differences in histology were also noted. Rejecting grafts in MHC II(o/o) and wild-type mice were infiltrated with both eosinophils and mononuclear cells, whereas the infiltrates in CD4(o/o) and GK mice were exclusively mononuclear cells. Immunohistochemistry showed that they were primarily CD8 cells. The immune response to FPP was clearly different in the three types of CD4 cell deficient mice. Splenocytes of MHC II(o/o) 3 weeks post-transplant with FPP produced substantial amounts of IFN-gamma and IL-5, whereas splenocytes of CD4(o/o) mice produced low levels of IFN-gamma but no detectable IL-5. At similar times, these cytokines were not detected in GK mice. Furthermore, CD4(o/o) mice were capable of mounting helper dependent, although reduced, IgG responses to FPP antigens, while GK mice were not. The 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 deficiency. Also, because there is eventual rejection of xenograft FPP in GK mice which lack detectable helper activity, we argue that these mice are a better model to investigate the involvement of CD4-independent rejection mechanisms.
Zhan
Y
Y
Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Corbett
A J
AJ
Brady
J L
JL
Sutherland
R M
RM
Lew
A M
AM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D016332:Fetal Tissue Transplantation / Q000276:immunology*; D005802:Genes, MHC Class II; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D016035:Pancreas Transplantation / Q000276:immunology*; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
D000906:Antibodies; D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II