Belatacept Can Inhibit Allo-Specific T Cell Responses in a Donor-Dependent Manner But Preserves Virus-Specific Memory T Cell-Responses.

Abstract

Purpose: Belatacept (Bela) blocks T cell activation via inhibition of the interaction between CD28 and B7.1/2. It is known that patients under Bela medication have increased risk of early rejections after kidney transplantation (KTx). Reactivation with EBV in kidney recipients represents a huge problem. EBV-vaccination would be a solution, but there is no vaccine available. However, EBV-derived virus like particles (VLPs) could be a feasible strategy. Methods: IFNg-ELISpots with PBMCs of healthy donors (n=5) or KTx patients (n=5) in the presence of Bela, CTLA-4-Ig or CNI were performed. PBMCs were stimulated with a pool of CMV, EBV, Flu peptides (CEF), an allogeneic B cell line, EBV-specific VLPs or PHA as positive control. In parallel, supernatants were collected and cytokines were measured via multiplex analysis. Results: Bela was not able to reduce the CEF-peptide-specific IFNg production in contrast to CNI. Allo-specific IFNg responses were reduced by Bela and CTLA-4-Ig in some donors (healthy controls and KTx patients). Interestingly, the allo-specific IL-2 production was diminished significantly by Bela and CTLA-4-Ig while IL-10 secretion was unaffected. EBV-specific VLPs induced weak IFNg production in healthy donors whereas they failed in most KTx patients to induce a VLP-specific immune response. Conclusions: In contrast to CNI, the memory CD8+ T cell response to viruses was not impaired by costimulation blockade (Bela, CTLA-4-Ig). However, the allo-specifi c immune response was partially blocked by costimulation blockers which primarily affected the IL-2 production while all other cytokines remained unaffected. This difference may explain the increased number of rejections early after Tx. EBV-specific VLPs may represent one possibility to vaccinate immunosuppressed patients. Our studies indicate that sensitivity towards Bela varies among healthy donors and Tx recipients which implies that predisposition of the immune response may determine the susceptibility to Bela treatment.