Program Manager Cleveland Clinic Foundation Cleveland, Ohio, United States
Introduction/Rationale: Acute and chronic antibody mediated rejection (ABMR) decreases clinical kidney graft function and survival. High titer donor-specific antibody (DSA) responses are induced in B6.CCR5-/- recipients of complete MHC-mismatched A/J kidney allografts that mediate acute injury and graft failure. The role of neutrophil function during acute ABMR is poorly understood.
Methods: We tested development of A/J kidney allograft reactive antibodies and ABMR in CCR5-deficient recipients with a deletion of the neutrophil-specific serine protease cathepsin G.
Results: Whereas B6.CCR5-/- recipients rejected kidney allografts by day 25, 70% of allografts survived beyond day 60 in B6.CCR5-/-cG-/- recipients. DSA titers in B6.CCR5-/-cG-/- recipients were 24-fold higher than those in wild-type C57BL/6 recipients on day 15 post-transplant. Trichrome stained allografts from B6.CCR5-/-cG-/- recipients on days 45 and 60 had typical characteristics of chronic graft injury including interstitial collagen deposition and peri-glomerular fibrosis that was associated with a fibrogenic transcript signature and late post-transplant serum autoantibodies to many structural proteins. Depletion of B cells at the time DSA peak titers were achieved on day 14 post-transplant did not alter the high DSA titers but decreased serum autoantibody levels at day 60 post-transplant, inhibited the fibrogenic transcript signature, and decreased chronic kidney allograft injury despite maintenance of the high DSA titers.
Conclusion: The results indicate a critical role for neutrophil cathepsin G during acute ABMR of kidney allografts. In the absence of recipient cathepsin G and acute ABMR, the DSA promotes the late appearance of autoantibodies that mediate chronic kidney allograft injury.
