Prolonged allograft survival in anti-CD4 antibody transgenic mice - Lack of residual helper T cells compared with other CD4-deficient mice

Background. Investigations of the role of CD4 T lymphocytes in allograft re jection and tolerance have relied on the use of mouse models with a deficie ncy in CD4 cells. However, in mice treated with depleting monoclonal antibo dy (mAb) and in MHC class II knockout (RO) mice, there are residual populat ions of CD4 cells. CD4 KO mice had increased CD4(-) CD8(-) CD8(-) TCR alpha beta(+) helper T cells, and both strains of KO mice could reject skin allo grafts at the normal rate. In this study, transgenic mice with no periphera l CD4 cells were the recipients of skin and heart allografts, Results were compared with allograft survival in CD4 and MHC class II KO mice. Methods. GK5 (C57BL/6 bm1 mice transgenic for a chimeric anti-CD4 antibody) had no peripheral CD4 cells. These mice, and CD4 and class II KO mice, rec eived BALB/c or CBA skin or cardiac allografts. Some GK5 mice were treated with anti-CDS mAb to investigate the role of CD8 cells in rejection. CD4 an d CDS cells were assessed by FACS and immunohistochemistry. Results. BALB/c skin on GK5 mice had a mean survival time SD of 24+/-6 days , compared with 9+/-2 days in wild-type mice. Anti-CDS mAb prolonged this t o 66+/-7 days. BALB/c skin survived 10+/-2 days on class II RO and 14+/-2 d ays on CD4 KO, both significantly less than the survival seen on GK5 recipi ents (P<0.001). BALB/c hearts survived >100 days in GK5 recipients and in w ild-type recipients treated with anti-CD4 mAb at the time of grafting, in c ontrast to a mean survival time of 10+/-2 days in untreated wild-type mice. Immunohistochemistry revealed that long-term surviving heart allografts fr om the GK5 recipients had CD8 but no CD4 cellular infiltrate. These hearts showed evidence of transplant vasculopathy. Conclusions. The GK5 mice, with a complete absence of peripheral CD4 cells, provide the cleanest available model for investigating the role of CD4 lym phocytes in allograft rejection. Prolonged skin allograft survival in these mice compared with CD4 and MHC class II KO recipients was clearly the resu lt of improved CD4 depletion. Nevertheless, skin allograft rejection, heart allograft infiltration, and vascular disease, mediated by CD8 cells, devel oped in the absence of peripheral CD4 T cells.