Increasing detection of acute humoral rejection (AHR) of renal allografts has generated the need for appropriate animal models to investigate underlying mechanisms. Murine recipients lacking the chemokine receptor CCR5 reject cardiac allografts with marked C3d deposition in the parenchymal capillaries and high serum donor-reactive antibody titers, features consistent with AHR. The rejection of MHC-mismatched renal allografts from A/J (H-2(a)) donors by B6.CCR5(-/-) (H-2(b)) recipients was investigated. A/J renal allografts survived longer than 100 days in wild-type C57BL/6 recipients with normal blood creatinine levels (28 +/- 7 micromol/L). All CCR5(-/-) recipients rejected renal allografts within 21 days posttransplant (mean 13.3 +/- 4 days) with elevated creatinine (90 +/- 31 micromol/L). The rejected allografts had neutrophil and macrophage margination and diffuse C3d deposition in peritubular capillaries, interstitial hemorrhage and edema, and glomerular fibrin deposition. Circulating donor-reactive antibody titers were 40-fold higher in B6.CCR5(-/-) versus wild-type recipients. Depletion of recipient CD8 T cells did not circumvent rejection of the renal allografts by CCR5-deficient recipients. In contrast, microMT(-/-)/CCR5(-/-) recipients, incapable of producing antibody, did not reject most renal allografts. Collectively, these results indicate the rapid rejection of renal allografts in CCR5(-/-) recipients with many histopathologic features observed during AHR of human renal allografts.