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In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients
Published on: August 12, 2017
Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys
Agnes M Azimzadeh1, Tianshu Zhang, Guosheng Wu
11 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD. 2 Department of Surgery, Fourth Military Medical University, Xi'an, People's Republic of China. 3 Division of Vascular Surgery, Department of Surgery, George Washington University, Washington, DC. 4 VA Maryland Health Care System, Baltimore, MD.
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:
αCD154 (IDEC-131)-treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (αCD20) alone or with rabbit antihuman thymocyte globulin.
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 > 90 days, n = 7, vs 28 days for αCD154 alone (IDEC-131), n = 21; P = 0.05). Addition of rabbit antihuman thymocyte globulin 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 antidonor 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 calcineurin inhibitors to the context of CD154 blockade.
Insights
Preemptive B cell depletion using anti-CD20 (rituximab) therapy significantly improved heart transplant outcomes in primates by reducing antidonor antibodies and cardiac allograft vasculopathy (CAV). This approach offers a promising strategy for modulating alloimmunity in transplantation.
Area of Science:
- Transplantation immunology
- Immunosuppression strategies
- Preclinical research models
Background:
- Anti-CD154 monotherapy in primate models is linked to antidonor antibody production, cardiac allograft vasculopathy (CAV), and graft failure.
- Preemptive B cell depletion, particularly with anti-CD20 agents, has shown potential in delaying these adverse outcomes within calcineurin inhibitor (CNI) regimens.
Purpose of the Study:
- To evaluate the efficacy of preemptive B cell depletion using anti-CD20 (rituximab) in combination with anti-CD154 therapy in a non-human primate heart transplant model.
- To assess the impact of this combined therapy on antidonor antibody production, CAV development, and allograft survival.
Main Methods:
- Cynomolgus monkeys received heart allografts and were treated with anti-CD154 (IDEC-131) therapy, with some also receiving peritransplant rituximab (anti-CD20) or rabbit antihuman thymocyte globulin.
- Graft survival, antidonor antibody levels, and CAV were monitored and compared to historical control groups.
Main Results:
- The combination of anti-CD154 and anti-CD20 significantly prolonged graft survival (median > 90 days vs. 28 days) and delayed antibody detection compared to anti-CD154 alone.
- Anti-CD20 therapy attenuated CAV within 3 months post-transplant.
- Addition of rabbit antihuman thymocyte globulin offered protection but was associated with significant morbidity, including infections.
Conclusions:
- Efficient preemptive CD20 B cell depletion effectively modulates pathogenic alloimmunity and attenuates CAV in this translational primate model.
- These findings extend the benefits of B cell depletion to the context of CD154 blockade, complementing previous results with calcineurin inhibitors.
