In vivo Treg expansion under costimulation blockade targets early rejection and improves long-term outcome

Abstract

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Costimulation blockade and Tregs in solid organ transplantation

“…Next, we aimed at increasing Treg numbers through IL-2 complexes (IL-2 cplxs). Thereby, we could successfully increase the number of regulatory T cells but also showed a synergistic effect of IL-2 cplxs and CTLA4Ig in reducing the expression of B7 molecules on dendritic cells (34).…”

“…In addition to PD-1, Tregs also upregulated ICOS and CTLA4 upon stimulation with IL-2 complexes (52). Together with CTLA4Ig these in vivo expanded Tregs facilitated long-term survival of fully mismatched cardiac allografts in mice (34).…”

Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen

“…Our findings highlight again the potency of dual costimulation blockade, but also the need for further investigation of the mechanisms behind the “partial efficacy” and observed costimulation blockade resistant rejection. In this context, regulatory T-cells (Tregs) represent an attractive therapeutic target as their in-vivo expansion with IL-2 complexes (that allow for a more targeted delivery of IL-2 to Tregs than conventional IL-2) successfully prevented rejection under CTLA4-Ig in murine cardiac transplantation ( 32 ). The biggest advantage of combined costimulatory pathway blockade including CD40-CD40L is certainly the superior control over humoral allo-immunity, as CD40-CD40L is the main signaling pathway responsible for B cell activation and immunoglobulin class switch ( 33 ).…”

Impact of interleukin-6 on T cells in kidney transplant recipients

“…CTLA4‐Ig impairs Treg generation and survival through inhibition of signaling via CD28 and has been shown to abrogate Treg‐dependent graft acceptance in animal models 153,154 . Conversely, in vivo Treg expansion using IL‐2 prior to transplant reversed CTLA‐Ig‐mediated decline on Tregs and prolonged allograft survival 155 . Finally, treatment of IL‐6‐deficient mice with CTLA4‐Ig resulted in graft infiltration with Tregs and prolonged graft acceptance, 156 suggesting that IL‐6 inhibition can synergize with costimulation blockade, and potentially mitigate the early risk of acute T cell‐mediated rejection associated with belatacept‐based immunosuppression.…”

“…153,154 Conversely, in vivo Treg expansion using IL-2 prior to transplant reversed CTLA-Ig-mediated decline on Tregs and prolonged allograft survival. 155 Finally, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft infiltration with Tregs and prolonged graft acceptance, 156 suggesting that IL-6 inhibition can synergize with costimulation blockade, and potentially mitigate the early risk of acute T cell-mediated rejection associated with belatacept-based immunosuppression. This strategy is currently being tested in a pilot trial of living donor kidney transplant recipients who receive tocilizumab for 6 months, in combination with lulizumab for the first 3 months and belatacept for the next 3 months, following which patients are maintained on belatacept in combination with everolimus and prednisone (NCT04066114).…”