Acute Humoral Rejection of Renal Allografts in CCR5–/– Recipients

Abstract

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 lmol/L). All CCR5 -/-recipients rejected renal allografts within 21 days posttransplant (mean 13.3 ± 4 days) with elevated creatinine (90 ± 31 lmol/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, lMT -/-/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.

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

“…Comparable results have been published by our group for cardiac and carotid artery allografts [12] and by Abdi et al for islet allografts [14]. By contrast, Gao et al and Amano et al described for Ccr5-deficient recipients a reduced infiltration of cardiac allografts with F4/80 1 cells, whereas Bickerstaff et al reported an increased infiltration of renal allografts with these cells [13,16,17].…”

“…In these experiments, Ccr5 deficiency of the recipient had a beneficial effect on the transplant and led to modest prolongation of graft survival. In contrast, a recent study by Bickerstaff et al reported an accelerated rejection of renal allografts in Ccr5 À/À mice, leading to a marked shortening of graft survival in comparison to WT mice [17]. The authors related this to acute humoral rejection occurring in Ccr5 À/À mice.…”

“…The authors related this to acute humoral rejection occurring in Ccr5 À/À mice. This conclusion was supported by the deposition of C3d in the grafts and markedly elevated donorspecific antibody titers in the serum of Ccr5 À/À recipients [17]. We used a comparable murine renal transplant model, which results in long-term graft survival, though with evidence of chronic graft nephropathy.…”

“…Two recent publications demonstrated that Ccr5 deficiency in allograft recipients leads to increased humoral rejection [16,17]. We therefore measured the levels of alloreactive antibodies in plasma samples from C57BL/6 WT and Ccr5 À/À mice, which had either been immunized with BALB/c splenocytes or which had received a BALB/c renal allograft 42 days ago.…”

“…Phenotypic alterations in these mice have been analyzed in different transplant models including experimental cardiac, carotid artery, islet, and renal allografts [12][13][14][15][16][17][18]. Kidney transplantation represents the most frequent organ replacement therapy in humans, but despite major advances in the treatment of acute rejection, long-term graft survival has not markedly improved.…”