Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 21, Issue 8, Pages 2675-2687Publisher
WILEY
DOI: 10.1111/ajt.16456
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
Categories
Funding
- NIH [1R21HL127355]
- United States Army Medical Research Acquisition Activity [W81XWH-18-1-0789]
- Plastic & Reconstructive Surgery
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Research shows that the combination of JAK/STAT inhibitor Tofacitinib and CTLA4-Ig can enhance the regulatory effect on transplant recipients, offering a promising strategy for improved management of transplanted patients.
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.
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