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‐2b) and B6.CCR5−/− recipients. Donor‐specific antibody titers in CCR5−/− recipients were 30‐fold higher than in wild‐type recipients. B6.Kd 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.Kd 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‐Kd 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. Anti–class I antibodies induce graft expression of perforin, CCL5 and myeloperoxidase during antibody‐mediated rejection of single class I MHC‐disparate allografts in a mouse model.