Belatacept-Based Maintenance Immunosuppression Controls the Post-Transplant Humoral Immune Response in Highly Sensitized Nonhuman Primates.
Robin SchmitzZachary W FitchMiriam ManookPaul M SchroderAshley Y ChoiDanae G OlasoJanghoon YoonYeeun BaeBrian I ShawMingqing SongMaragatha KuchibhatlaAlton Brad FarrisAllan KirkJean KwunStuart J KnechtlePublished in: Kidney360 (2022)
Preexisting donor-specific antibodies (DSA) to MHC antigens increase the risk of antibody-mediated rejection (AMR) in sensitized transplant recipients and reduces graft survival. Pretransplant desensitization with costimulation blockade and proteasome inhibition has facilitated transplantation in our preclinical nonhuman primate (NHP) model. However, long-term graft survival is limited by rebound of DSA after transplantation. In this study, we performed kidney transplants between highly sensitized, maximally MHC-mismatched NHPs ( n =14). At kidney transplantation, primates received T cell depletion with rhesus-specific anti-thymocyte globulin (rhATG; n =10) or monoclonal anti-CD4 and anti-CD8 antibodies ( n =4). Maintenance immunosuppression consisted of belatacept and tacrolimus ( n =5) or belatacept and rapamycin ( n =9) with steroids. Rebound of DSA post-kidney transplantation was significantly reduced compared with maintenance immunosuppression with tacrolimus, mycophenolate, and steroids. Protocol lymph node biopsy specimens showed a decrease in germinal center activity, with low frequencies of T follicular helper cells and class-switched B cells after kidney transplantation. Combined belatacept and rapamycin was superior in controlling viral reactivation, enabling weaning of ganciclovir prophylaxis. Tacrolimus was associated with increased morbidity that included cytomegalovirus and parvovirus viremia and post-transplant lymphoproliferative disorder. All primates in the tacrolimus/belatacept group failed discontinuation of antiviral therapy. Overall, belatacept-based immunosuppression increased AMR-free graft survival by controlling post-transplant humoral responses in highly sensitized NHP recipients and should be further investigated in a human clinical trial.
Keyphrases
- kidney transplantation
- immune response
- lymph node
- clinical trial
- dendritic cells
- cell therapy
- epstein barr virus
- endothelial cells
- randomized controlled trial
- induced apoptosis
- squamous cell carcinoma
- regulatory t cells
- toll like receptor
- open label
- cell cycle arrest
- stem cells
- early stage
- inflammatory response
- study protocol
- multiple myeloma
- oxidative stress
- mesenchymal stem cells
- mass spectrometry
- atomic force microscopy
- bone marrow
- acute respiratory distress syndrome
- endoplasmic reticulum stress
- double blind
- rectal cancer