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Differential effects of Belatacept on virus-specific memory versus de novo allo-specific T cell responses of kidney transplant recipients and healthy donors.
Transpl. Immunol. 61:101291 (2020)
Belatacept, Nulojix (R), inhibits the interaction of CD28 on naive 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 Belataceptbased 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-naive 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 virusspecific memory T cell responses by Belatacept, as measured by IFN-gamma production. In contrast, calcineurin inhibitors suppressed IFN-gamma production of virus-specific memory CD8(+) T cells completely. These results experimentally confirm the concept that Belatacept blocks CD28-mediated costimulation in newly primed naive 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-gamma-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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Immunosuppression ; Kidney Transplantation ; Costimulation Blockade ; Belatacept ; Virus Like Particles ; Vaccination; Cd8(+) Cd28(-); Activation; Costimulation; Requirements; Antigen
ISSN (print) / ISBN
0966-3274
e-ISSN
1878-5492
Zeitschrift
Transplant Immunology
Quellenangaben
Band: 61,
Artikelnummer: 101291
Verlag
Elsevier
Verlagsort
Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Research Unit Gene Vector (AGV)