Anti-huCD20 Antibody Therapy for Antibody-Mediated Rejection of Renal Allografts in a Mouse Model

• DOI: 10.1111/ajt.13150
• Publication Date: 2015-03-02T19:17:31Z
• Authors: T. Abe; D. Ishii; V. Gorbacheva; N. Kohei; H. Tsuda; T. Tanaka; N. Dvorina; N. Nonomura; S. Takahara; A. Valujskikh; W.M. Baldwin; R.L. Fairchild
• Keywords: Graft Rejection; Male; Receptors, CCR5; Graft Survival; Mice, Transgenic; Allografts; Antigens, CD20; Flow Cytometry; Fibrosis; Immunohistochemistry; Kidney Transplantation; Antibodies; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Microscopy, Fluorescence; Creatinine; Antibody Formation; Animals; Humans

We have reported that B6.CCR5(-/-) mice reject renal allografts with high serum donor-specific antibody (DSA) titers and marked C4d deposition in grafts, features consistent with antibody-mediated rejection (AMR). B6.huCD20/CCR5(-/-) mice, where human CD20 expression is restricted to B cells, rejected A/J renal allografts by day 26 posttransplant with DSA first detected in serum on day 5 posttransplant and increased thereafter. Recipient treatment with anti-huCD20 mAb prior to the transplant and weekly up to 7 weeks posttransplant promoted long-term allograft survival (>100 days) with low DSA titers. To investigate the effect of B cell depletion at the time serum DSA was first detected, recipients were treated with anti-huCD20 mAb on days 5, 8, and 12 posttransplant. This regimen significantly reduced DSA titers and graft inflammation on day 15 posttransplant and prolonged allograft survival >60 days. However, DSA returned to the titers observed in control treated recipients by day 30 posttransplant and histological analyses on day 60 posttransplant indicated severe interstitial fibrosis. These results indicate that anti-huCD20 mAb had the greatest effect as a prophylactic treatment and that the distinct kinetics of DSA responses accounts for acute renal allograft failure versus the development of fibrosis.