Antibody-Mediated Rejection of Single Class I MHC-Disparate Cardiac Allografts

Murine CCR5^−/− recipients produce high titers of antibody to complete MHC-mismatched heart and renal allografts. To study mechanisms of class I MHC antibody-mediated allograft injury, we tested the rejection of heart allografts transgenically expressing a single class I MHC disparity in wild-type C57BL/6 (H-2^b) and B6.CCR5^−/− recipients. Donor-specific antibody titers in CCR5^−/− recipients were 30-fold higher than in wild-type recipients. B6.K^d allografts survived longer than 60 days in wild-type recipients whereas CCR5^−/− recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils and macrophages, and C4d deposition in the graft capillaries. B6.K^d allografts were rejected by CD8^−/−/CCR5^−/−, but not μMT^−/−/CCR5^−/−, recipients indicating the need for antibody but not CD8 T cells. Grafts recovered at day 10 from CCR5^−/− and CD8^−/−/CCR5^−/− recipients and from RAG-1^−/− allograft recipients injected with anti-K^d antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of antidonor class I MHC antibody can mediate allograft rejection, that donor-reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity (read more). Print this post