Differential effects of Belatacept on virus-specific memory versus de novo allo-specific T cell responses of kidney transplant recipients and healthy donors

Abstract

Belatacept, Nulojix®, inhibits the interaction of CD28 on naïve T cells with B7.1/B7.2 (CD80/86) on antigen presenting cells, leading to T cell hyporesponsiveness and anergy and is approved as immunosuppressive drug in kidney transplantation. Due to its specificity for B7.1/2 molecules, side effects are reduced compared to other immunosuppressive drugs like calcineurin- and mTOR-inhibitors. Kidney transplant recipients under Belatacept-based immunosuppression presented with superior renal function and similar graft survival seven years after transplantation compared to cyclosporine treatment. However, de novo Belatacept-based immunosuppression was associated with increased risk of early rejections and viral (EBV) infections in clinical trials, especially in EBV-naïve patients. Since there is no vaccination against EBV infection available, EBV-derived virus like particles (EBV-VLPs) are currently developed as vaccine strategy. Here, we investigated the immunosuppressive effects of Belatacept compared to calcineurin- and mTOR inhibitors on allo- versus virus-specific T cells and the potency of EBV-VLPs to induce virus-specific T cell responses in vitro. Using PBMC of kidney recipients and healthy donors, we could demonstrate selective inhibition of allo-specific de novo T cell responses but not virus-specific memory T cell responses by Belatacept, as measured by IFN-γ production. In contrast, calcineurin inhibitors suppressed IFN-γ production of virus-specific memory CD8⁺ T cells completely. These results experimentally confirm the concept that Belatacept blocks CD28-mediated costimulation in newly primed naïve T cells but does not interfere with memory T cell responses being already independent from CD28-mediated costimulation. Additionally, we could show that EBV-VLPs induce a significant though weak IFN-γ-mediated T cell response in vitro in both kidney recipients and healthy donors. In summary, we demonstrated that immunosuppression of kidney recipients by Belatacept may primarily suppress de novo allo-specific T cell responses sparing virus-specific memory T cells. Moreover, EBV-VLPs could represent a novel strategy for vaccination of immunocompromised renal transplant recipients to prevent EBV reactivation especially under Belatacept-based immunosuppression.

Keywords: Belatacept; Costimulation blockade; Immunosuppression; Kidney transplantation; Vaccination; Virus like particles.