Inhibition of De Novo Autoantibody Production Attenuates Chronic Antibody-Mediated Rejection of Kidney Allografts Despite Maintenance of High Donor-Specific Antibody Titers

Mitsui, Y.; Keslar, K. S.; Nicosia, M.; Kish, D. D.; Dvorina, N.; Zhu, C.; Olman, M.; Southern, B. D.; Baldwin, W. M.; Fairchild, R. L.

doi:10.1101/2025.06.11.659154

bioRxiv · 10.1101/2025.06.11.659154

Inhibition of De Novo Autoantibody Production Attenuates Chronic Antibody-Mediated Rejection of Kidney Allografts Despite Maintenance of High Donor-Specific Antibody Titers

Mitsui, Y.·Keslar, K. S.·Nicosia, M.·Kish, D. D.·Dvorina, N.·Zhu, C.·Olman, M.·Southern, B. D.·Baldwin, W. M.·Fairchild, R. L.

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Abstract

Acute and chronic antibody mediated rejection (ABMR) continues to decrease clinical kidney graft function and survival. Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5-/- recipients of complete MHC-mismatched A/J kidney allografts with NK cells playing a critical role in the acute ABMR. We tested the role of neutrophils in ABMR by transplanting A/J kidneys to CCR5-/- mice with a deletion in the neutrophil serine protease cathepsin G. Whereas B6.CCR5-/- recipients rejected all kidney allografts between days 18-25, 70% of allografts survived beyond day 60 in B6.CCR5-/-cG-/- recipients. At days 15-17 post-transplant DSA titers in B6.CCR5-/-cG-/- recipients were 24.3-fold higher than those in wild-type C57BL/6 allograft recipients. 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 accompanied by a fibrogenic transcript signature and late post-transplant production of autoantibodies to many targets, including structural proteins including collagen IV and fibronectin. Depletion of B cells at the time DSA peak titers were achieved on day 14 post-transplant decreased serum autoantibodies levels, the kidney allograft fibrogenic transcript signature, and the chronic kidney allograft injury, despite maintenance of the high DSA titers. These results indicate a critical role for neutrophil cathepsin G during acute ABMR of kidney allografts and in its absence, DSA induced late appearance of autoantibodies mediating development of chronic kidney allograft injury.

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Mitsui, Y., Keslar, K. S., Nicosia, M., Kish, D. D., Dvorina, N., Zhu, C., Olman, M., Southern, B. D., Baldwin, W. M., Fairchild, R. L.. 2025-06-17. Inhibition of De Novo Autoantibody Production Attenuates Chronic Antibody-Mediated Rejection of Kidney Allografts Despite Maintenance of High Donor-Specific Antibody Titers. https://doi.org/10.1101/2025.06.11.659154

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