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 III
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 III
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Research Article

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

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.

Authors

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 III

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Figure 1

B cell depletion in blood after αCD20 therapy.

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B cell depletion in blood after αCD20 therapy. Cardiac transplant recipi...
Cardiac transplant recipients were treated with CsA alone or with additional αCD20 treatment (rituximab, 20 mg/kg; days –1, 7, 14, and 21). One animal (DJ3M5) exhibiting high T cell counts at day 14 in association with acute parvovirus infection was censored from this analysis. (A) Peripheral blood B cells are efficiently depleted for over 2 months after αCD20 treatment ends. Data include DJ4J7, in which recovery to 20%–40% was seen within 2 months (see Supplemental Figure 1). (B) T cell numbers in peripheral blood are not significantly affected by αCD20 treatment. Blood cell levels are expressed as percentage of baseline levels (mean ± SEM). *P < 0.05 for αCD20+CsA vs. CsA alone, noted only at time intervals after transplant when sufficient individual measurements were available to justify statistical analysis.