Anti-huCD20 antibody therapy for antibody-mediated rejection of renal allografts in a mouse model

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1192-1204
Number of pages13
JournalAmerican Journal of Transplantation
Volume15
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

Keywords

  • alloantibody
  • B cell specific
  • chronic
  • fusion proteins and monoclonal antibodies
  • immunosuppressant
  • kidney disease: immune/inflammatory
  • rejection
  • rejection: antibody-mediated (ABMR)

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

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  • Cite this

    Abe, T., Ishii, D., Gorbacheva, V., Kohei, N., Tsuda, H., Tanaka, T., Dvorina, N., Nonomura, N., Takahara, S., Valujskikh, A., Baldwin, W. M., & Fairchild, R. L. (2015). Anti-huCD20 antibody therapy for antibody-mediated rejection of renal allografts in a mouse model. American Journal of Transplantation, 15(5), 1192-1204. https://doi.org/10.1111/ajt.13150