Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.

BACKGROUND: Anti-CD154 monotherapy is associated with anti-donor alloantibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin inhibition (CNI), these pathogenic phenomena are delayed by preemptive “induction” B-cell depletion. METHODS: IDEC-131(αCD154)-treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (αCD20) alone or with rabbit anti-human thymocyte globulin (rATG). RESULTS: Relative to previously reported reference groups, αCD20 significantly prolonged survival, delayed Ab detection, and attenuated CAV within 3 months in αCD154-treated recipients (αCD154+αCD20 graft median survival time (MST) >90d, n=7, vs 28d for αCD154 alone (IDEC-131), n=21; p=0.05). Addition of rATG to αCD154 (n=6) or αCD154+αCD20 (n=10) improved graft protection from graft rejection and failure during treatment, but was associated with significant morbidity in 8 of 16 recipients (6 infections, 2 drug-related complications). In αCD20-treated animals, detection of anti-donor Ab and relatively severe CAV were anticipated by appearance of CD20(+) cells (>1% of lymphocytes) in peripheral blood, and were associated with low αCD154 trough levels (below 100 µg/ml). CONCLUSIONS: These observations support the hypothesis that efficient preemptive ‘induction’ CD20(+) B-cell depletion consistently modulates pathogenic alloimmunity and attenuates CAV in this translational model, extending our prior findings with CNIs to the context of CD154 blockade

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

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