INTRODUCTION: We have reported murine recipients lacking the chemokine receptor CCR5 reject renal allografts with marked C4d deposition in peritubular capillaries and high serum donor-reactive antibody titers, features consistent with antibody-mediated rejection (AMR). Anti-CD20 monoclonal antibody induces profound depletion of B-cells and has been used to treat AMR in a number of uncontrolled clinical studies. Given that plasma cells do not express CD20, the mechanism of action of anti-CD20 mAb in AMR remains unclear. The current studies were conducted to investigate the efficacy and the mechanism of anti-CD20 mAb in a murine model of AMR of renal allografts.

METHODS: CCR5−/− and human CD20 transgenic mice were crossed to generate the CCR5−/−/hCD20Tg C57BL/6 mice expressing human CD20 only on B cells. Complete MHC-mismatched A/J kidneys were transplanted into hCD20Tg/CCR5−/− C57BL/6 or wild-type C57BL/6 recipients. Some recipients were treated with 250 Μg of human anti-CD20 mAb on days 5 and 12.

RESULTS: While A/J renal allografts were accepted long-term in all wild-type C57BL/6 recipients, hCD20Tg/CCR5−/− recipients rejected the renal allografts by day 20 post-transplant with high titers of donor-reactive antibody and diffuse C4d deposition in the graft. Anti-CD20 mAb treatment resulted in rapid depletion of B cells from human CD20 transgenic mice and significantly prolonged renal allografts survival in hCD20Tg/CCR5−/− recipients (MST: anti-CD20 mAb treatment group, day 58 vs. non-treatment group, day 15) with decreased serum creatinine levels and serum antibody titers compared to non-treated recipients at day 12 post-transplant but the antibody titers returned to control titers by day 30 post-transplant. Histological analyses indicated that anti-CD20 mAb treatment decreased T cell and macrophage infiltration into the allografts at day 20 when compared to allografts in non-treated recipients. When analyzed at day 60 post-transplant, allografts from anti-CD20 mAb treated recipients had severe interstitial fibrosis and diffuse C4d deposition.

CONCLUSIONS: Our model using hCD20Tg/CCR5−/− recipients is useful for evaluating the efficacy of anti-CD20 mAb in murine kidney transplant with AMR. Although this treatment abrogated AMR and prolonged allograft survival, the anti-donor antibody titer did return and rather than acute rejection, mediated chronic injury of the allograft.

« Back to 2013 American Transplant Congress