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

authored by

Jenny Franziska Kühne, Christine Neudörfl, Kerstin Beushausen, Jana Keil, Svitlana Malysheva, Franziska Wandrer, Hermann Haller, Martin Messerle, Cornelia Blume, Michael Neuenhahn, Fabian Schlott, Wolfgang Hammerschmidt, Reinhard Zeidler, Christine S. Falk

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.

Organisation(s)

Institute of Technical Chemistry

External Organisation(s)

Hannover Medical School (MHH)
Technical University of Munich (TUM)
Helmholtz Zentrum München - German Research Center for Environmental Health
Ludwig-Maximilians-Universität München (LMU)
German Center for Infection Research (DZIF)

Type

Article

Journal

Transplant immunology

Volume

61

No. of pages

10

ISSN

0966-3274

Publication date

08.2020

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Immunology and Allergy, Immunology, Transplantation

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1016/j.trim.2020.101291 (Access: Open)