[Background] Chronic rejection of organ transplants remains an unsolved problem in the field of transplantation. Humoral immunity, typically manifesting as alloantibody, is increasingly recognized as detrimental during chronic rejection. Belatacept is a fusion protein that mediates CD28-B7 costimulation blockade and in a recent multicenter clinical trial demonstrated a minimal (1%) incidence of alloantibody. We and others have reported, in preclinical models, the efficacy of blocking CD28 pathways in the inhibition of alloantibody, however the mechanisms of this effective suppression and the effects on chronic humoral alloimmunity are poorly understood. In the current study we studied the effect of CD28-B7 blockade on alloantibody production in a recently described murine model of antibody mediated chronic rejection.

[Methods] We transplanted C56BL/6 hearts to human CD52 transgenic CBA mice. For T cell depletion induction therapy, Alemtuzumab (10Μg/dose) was given on day -2, -1, +2, and +4 of transplantation with or without CTLA-4 Ig. CTLA-4 Ig (250Μg/dose) was treated on day 0, +2, +4, and +6 of transplantation. De novo donor specific antibodies (DSA) and alloreactive B cells were measured with flow cytometry at 100 days post-transplantation.

[Results] There was no difference in graft survival between two groups, alemtuzumab alone in which undergo antibody-mediated chronic rejection and alemtuzumab/CTLA-4 Ig. Interestingly, decreased number of allo-specific B cells was observed compared with alemtuzumab alone (% of CD19+H-2Kb/Db+IgD-, 1.145±0.07 vs. 3.31±0.51; p<0.01) in the spleens in the spleens. Also, the trend of decreased DSA in alemtuzumab/CTLA-4 Ig treated group was observed compared with alemtuzumab alone at 100 days after transplantation (Fold increase, 3.31±0.51 vs. 2.50±0.46; p=0.26). Combined treatment with CTLA-4 Ig showed decreased allo-specific B cells resulted in the trend of decreased DSA production compared to alemtuzumab alone.

[Conclusion] This study showed that CD28/B7 blockade suppresses alloreactive B cell differentiation and alloantibody production during antibody mediated chronic rejection. These data support the efficacy of CD28/B7 blockade in the prevention of anti-donor antibody pretransplant and suggests the possibly of using this therapy postransplant.

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