Background: Belatacept is a costimulation blocker that has been increasingly used as maintenance immunosuppression to improve long term outcomes in kidney transplant recipients by avoiding the toxic effects of calcineurin inhibitors. Since acute rejection in patients on belatacept in the phase 3 trials have been noted to be more frequent and histologically more severe, identifying the select population of patients with Precision Medicine who will benefit from belatacept is important. We investigated pretransplant recipient immune profiles to determine which lymphocyte populations would be the best predictor in identifying patients who will be at lowest risk for costimulation blockade-resistant rejection.
Methods: We prospectively enrolled 20 kidney transplant recipients (8 deceased and 12 living donors) at our center to receive denovo belatacept from May 2016 to March 2017. PMBCs were collected prior to transplantation and at the time of cause and protocol biopsies. All patients received thymoglobulin 3mg/ kg divided into 2 doses for induction with belatacept 10mg/kg administered on POD 1, 4, 14, 28, 56, and 84. Monthly maintenance dose of 5mg/kg was given starting week 16. Patients were initially on mycophenolate but were converted to everolimus after 1 month, and all patients were maintained on prednisone 5mg daily. Protocol biopsies were performed at 6 months. Acute rejections included those noted on protocol or cause biopsies.
Results: On cause biopsies, 2 patients were noted to have ACR 1a (at 4 weeks; at 6 weeks), 1 with ACR 2b (at 2 months), and 1 with AMR (at 4 months). In addition, 6 patients were found to have borderline rejection on protocol biopsies. 9 patients did not have any inflammation on biopsies. 18 patients remained on belatacept and 2 patients were converted to tacrolimus. 3 of the 4 rejections occurred in patients who remained on MMF and not on everolimus. 4 of the 6 patients who had borderline rejection were on MMF. No correlation was found between rejection and percentage of CD4+CD57+ T cells in pre-transplant PBMC, a marker previously reported to be associated with rejection on belatacept-based regimen. Patients who had biopsy-proven rejection or borderline changes had significantly higher percentages of CD8+CD28- T cells in pre-transplant PBMC when compared to those who had normal biopsy. Patients with greater than 50% of CD8+CD28- T cells pre-transplant were more likely to experience rejection (odds ratio was 18.7, sensitivity 87.5% with false positive of 12.5%, p= 0.02). Moreover, rejection was associated with elevated ex-vivo donor antigen-stimulated TNFa, but not IFNg, production by CD8+CD28- T cells that was resistant to belatacept inhibition.
Conclusion: CD28-CD8+ T cells are associated with belatacept-resistant rejection. Pretransplant immunotyping and functional assessment of circulating lymphocytes may provide a useful tool for identification and selection of patients suitable for belatacept therapy