Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

Shahrooz S. Kelishadi, Agnes M. Azimzadeh, Tianshu Zhang, Tiffany Stoddard, Emily Welty, Christopher Avon, Mitch Higuchi, Amal Laaris, Xiang Fei Cheng, Christine McMahon, Richard N. Pierson

Research output: Contribution to journalArticle

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Abstract

Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B cells have recently been shown to play a pivotal role in the induction of alloimmunity and are being targeted in other transplant contexts, the efficacy of preemptive B cell depletion to modulate alloimmunity or attenuate cardiac allograft vasculopathy (CAV) (classic chronic rejection lesions found in transplanted hearts) in a translational model has not previously been described. We report here that the CD20-specific antibody (αCD20) rituximab depleted CD20+ B cells in peripheral blood, secondary lymphoid organs, and the graft in cynomolgus monkey recipients of heterotopic cardiac allografts. Furthermore, CD20+ B cell depletion therapy combined with the calcineurin inhibitor cyclosporine A (CsA) prolonged median primary graft survival relative to treatment with αCD20 or CsA alone. In animals treated with both αCD20 and CsA that achieved efficient B cell depletion, alloantibody production was substantially inhibited and the CAV severity score was markedly reduced. We conclude therefore that efficient preemptive depletion of CD20+ B cells is effective in a preclinical model to modulate pathogenic alloimmunity and to attenuate chronic rejection when used in conjunction with a conventional clinical immunosuppressant. This study suggests that use of this treatment combination may improve the efficacy of transplantation in the clinic.

Original languageEnglish (US)
Pages (from-to)1275-1284
Number of pages10
JournalJournal of Clinical Investigation
Volume120
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

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Cyclosporine
Haplorhini
Allografts
B-Lymphocytes
Transplantation
Transplants
Isoantibodies
Macaca fascicularis
Graft Survival
Immunosuppressive Agents
Cell- and Tissue-Based Therapy
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kelishadi, S. S., Azimzadeh, A. M., Zhang, T., Stoddard, T., Welty, E., Avon, C., ... Pierson, R. N. (2010). Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. Journal of Clinical Investigation, 120(4), 1275-1284. https://doi.org/10.1172/JCI41861

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. / Kelishadi, Shahrooz S.; Azimzadeh, Agnes M.; Zhang, Tianshu; Stoddard, Tiffany; Welty, Emily; Avon, Christopher; Higuchi, Mitch; Laaris, Amal; Cheng, Xiang Fei; McMahon, Christine; Pierson, Richard N.

In: Journal of Clinical Investigation, Vol. 120, No. 4, 01.04.2010, p. 1275-1284.

Research output: Contribution to journalArticle

Kelishadi, SS, Azimzadeh, AM, Zhang, T, Stoddard, T, Welty, E, Avon, C, Higuchi, M, Laaris, A, Cheng, XF, McMahon, C & Pierson, RN 2010, 'Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys', Journal of Clinical Investigation, vol. 120, no. 4, pp. 1275-1284. https://doi.org/10.1172/JCI41861
Kelishadi, Shahrooz S. ; Azimzadeh, Agnes M. ; Zhang, Tianshu ; Stoddard, Tiffany ; Welty, Emily ; Avon, Christopher ; Higuchi, Mitch ; Laaris, Amal ; Cheng, Xiang Fei ; McMahon, Christine ; Pierson, Richard N. / Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 4. pp. 1275-1284.
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AU - Higuchi, Mitch

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