Background Anti-CD154 monotherapy is associated with antidonor allo-antibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin… Click to show full abstract
Background Anti-CD154 monotherapy is associated with antidonor allo-antibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin inhibitors (CNI), these pathogenic phenomena are delayed by preemptive “induction” B cell depletion. Methods &agr;CD154 (IDEC-131)–treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (&agr;CD20) alone or with rabbit antihuman thymocyte globulin. Results Relative to previously reported reference groups, &agr;CD20 significantly prolonged survival, delayed Ab detection, and attenuated CAV within 3 months in &agr;CD154-treated recipients (&agr;CD154 + &agr;CD20 graft median survival time > 90 days, n = 7, vs 28 days for &agr;CD154 alone (IDEC-131), n = 21; P = 0.05). Addition of rabbit antihuman thymocyte globulin to &agr;CD154 (n = 6) or &agr;CD154 + &agr;CD20 (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 &agr;CD20-treated animals, detection of antidonor Ab and relatively severe CAV were anticipated by appearance of CD20+ cells (>1% of lymphocytes) in peripheral blood and were associated with low &agr;CD154 trough levels (below 100 &mgr;g/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 calcineurin inhibitors to the context of CD154 blockade.