[Background] Sensitization is a growing problem on the kidney waiting list. Alloantibody can significantly deteriorate graft survival. Currently used desensitization strategies are time-consuming, expensive and moderately effective. Preliminary data showed that combining the proteasome inhibitor Bortezomib and costimulation blockade with Belatacept and anti-CD40 monoclonal antibody, will reduce donor specific antibody (DSA) and bone marrow-antibody-producing cells in sensitized non-human primates (NHP). We tested efficacy of this treatment pre kidney transplantation (TX) into sensitized NHP mimicking clinically used immunosuppression.

[Methods] Fully mismatched rhesus macaques were sensitized with skin TX. Immunologic responses were monitored by T- and B-cell flow crossmatches (FXM). 3 animals (DES-group) underwent 4 weeks of desensitization therapy with Btz (1.33mg/m2), Belatacept (20mg/kg) and anti-CD40 Ab (2c10; 20mg/kg), all twice weekly. Six control animals (CON-group) did not receive desensitization. Animals underwent native nephrectomy and kidney TX from their skin donors. Immunosuppression included induction with anti-rhesus CD4 and CD8 antibodies, maintenance therapy using Tacrolimus and Mycophenolate mofetil and tapered methylprednisolone. Assessment included laboratory testing, FXM (DSA), urine output and clinical status. After sacrifice kidney grafts were submitted to pathology for H&E, PAS and C4d staining. Following Banff-criteria we calculated a score for antibody mediated rejection (AMR) using the formula g+ptc+C4d (maximal score 9).

[Results] T- and B-cell FXM at TX were comparable between groups. Mean survival was not different in the two groups. 6/6 (100%) CON-animals succumbed to kidney failure post transplant. One had hyperacute rejection; in 4 acute AMR was culpable; one had mixed rejection after suboptimal depletion. In the DES-group one graft (33%) failed due to AMR, 2 animals had to be sacrificed for weight loss and refractory anemia with functioning grafts at days 16 and 41 respectively. AMR scores at necropsy were 6+/-0.8 (CON) vs. 3+/-2.6 (DES) (t-test p=0.023).

[Conclusion] These results show that combining costimulation blockade with proteasome inhibition may prevent early AMR, but toxicity is high and further refinement of the therapy is needed.

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