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
- free survival
- randomized controlled trial
- endothelial cells
- sars cov
- induced apoptosis
- study protocol
- cell cycle arrest
- squamous cell carcinoma
- neoadjuvant chemotherapy
- intensive care unit
- radiation therapy
- open label
- inflammatory response
- fine needle aspiration
- cell proliferation
- acute respiratory distress syndrome
- ultrasound guided
- high resolution
- diffuse large b cell lymphoma
- phase ii
- oxidative stress
- endoplasmic reticulum stress
- pi k akt
- smoking cessation
- antimicrobial resistance