TY - JOUR

T1 - Differential effects of Belatacept on virus-specific memory versus de novo allo-specific T cell responses of kidney transplant recipients and healthy donors

AU - Kühne, Jenny Franziska

AU - Neudörfl, Christine

AU - Beushausen, Kerstin

AU - Keil, Jana

AU - Malysheva, Svitlana

AU - Wandrer, Franziska

AU - Haller, Hermann

AU - Messerle, Martin

AU - Blume, Cornelia

AU - Neuenhahn, Michael

AU - Schlott, Fabian

AU - Hammerschmidt, Wolfgang

AU - Zeidler, Reinhard

AU - Falk, Christine S.

N1 - Funding Information: This work was supported by the German Research Foundation (DFG), SFB738, B3 (C.S.F.), FOR2830, P07 (M.M., C.S.F.), IFB-Tx of the German Ministry of Education and Research BMBF ( BMBF 01EO1302 ) (C.S.F.) and DZIF (German Center for Infection Research) TTU-IICH (M.M., M.N., C.S.F.).

PY - 2020/8

Y1 - 2020/8

N2 - 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.

AB - 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.

KW - Belatacept

KW - Costimulation blockade

KW - Immunosuppression

KW - Kidney transplantation

KW - Vaccination

KW - Virus like particles

UR - http://www.scopus.com/inward/record.url?scp=85084862331&partnerID=8YFLogxK

U2 - 10.1016/j.trim.2020.101291

DO - 10.1016/j.trim.2020.101291

M3 - Article

C2 - 32330566

AN - SCOPUS:85084862331

VL - 61

JO - Transplant immunology

JF - Transplant immunology

SN - 0966-3274

M1 - 101291

ER -