mTOR Inhibitor Therapy Diminishes Circulating CD8+ CD28- Effector Memory T Cells and Improves Allograft Inflammation in Belatacept-refractory Renal Allograft Rejection.Castro-Rojas, C. M., et al.
Transplantation 2020; 104(5): 1058-1069.
This is a secondary analysis of the Belatacept-based Early Steroid Withdrawal (BEST) Trial, a randomized controlled trial comparing two belatacept-based early steroid withdrawal (ESW) regimens versus a TAC (tacrolimus)-based ESW regimen. The aim of this study was to examine the kidney transplant patients that experienced rejection under the belatacept-based ESW following T-cell–depleting induction, in order to establish the mechanisms of rejection and treatment.
Participants were randomly assigned to one of the three groups: the alemtu-zumab/belatacept group, the rabbit antithymocyte globulin (rATG)/belatacept group, or the rATG/tacrolimus group.
4 kidney transplant recipients enrolled in the BEST Trial.
The outcomes of interest were the resistance of belatacept-refractory rejection (BRR) to standard-of-care immunosuppression, analysis of peripheral mononuclear cells (PBMCs) for lymphocyte activation and proliferation markers, and the regulation of phosphorylated ribosomal protein S6 (p-RPS6) in effector memory CD8+ T cells (TEM) emerging under belatacept.
This manuscript reports a secondary analysis from the BEST trial, an RCT investigating belatacept alongside CNI avoidance and early steroid withdrawal. It focuses on patients with acute rejection refractory to therapy with steroids or rATG. Patients with such belatacept refractory rejection (BRR) did not respond to standard rejection protocols, and the T-cell signature demonstrated high levels of CD8+/CD28- effector cells with activation of the mTOR pathway. Everolimus was found to be effective in reducing the numbers of these cells and reversing rejection. The main concern with use of belatacept-based immunosuppression, particularly in the context of steroid minimization, is the high incidence of acute rejection. These findings suggest that standard rejection therapy may be ineffective, and salvage with mTORi may be more effective. These data come from a small subset of patients and require further exploration in prospective trials
ClinicalTrials.gov - NCT01729494