A short course of tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in the presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts

Marcos Iglesias, Saami Khalifian, Byoung C Oh, Yichuan Zhang, Devin Miller, Sarah Beck, Gerald Brandacher, Giorgio Raimondi, Marcos Iglesias, Saami Khalifian, Byoung C Oh, Yichuan Zhang, Devin Miller, Sarah Beck, Gerald Brandacher, Giorgio Raimondi

Abstract

Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.

Keywords: basic (laboratory) research / science; cytokines / cytokine receptors; immunobiology; immunosuppressant - fusion proteins and monoclonal antibodies: belatacept; immunosuppression / immune modulation; lymphocyte biology: activation; signaling / signaling pathways: JAK / STAT; tolerance: costimulation blockade.

© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.

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