Critical Role of Proinflammatory Cytokine IL-6 in Allograft Rejection and Tolerance

Authors

  • X. Zhao,

    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
    2. Department of Urology, Nanjing Drum Tower Hospital, Nanjing, Jiangsu Province, P. R. China
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    • X.Z. and O.B. contributed equally to this work.

  • O. Boenisch,

    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
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    • X.Z. and O.B. contributed equally to this work.

  • M. Yeung,

    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
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  • B. Mfarrej,

    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
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  • Sunmi Yang,

    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
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  • L. A. Turka,

    1. Transplant Institute and Division of Transplant Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • M. H. Sayegh,

    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
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  • J. Iacomini,

    Corresponding author
    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
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  • X. Yuan

    Corresponding author
    1. Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA
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    • Presently at Beijing University Wujieping Urology Center and Beijing University Shougang Hospital, Beijing University, Beijing, China.


Xueli Yuan, yuanxueli@wjpumc.cn or John Iacomini, PhD, jiacomini@rics.bwh.harvard.edu

Abstract

The proinflammatory cytokine IL-6 plays an important role in controlling T-cell differentiation, especially the development of Th17 and regulatory T cells. To determine the function of IL-6 in regulating allograft rejection and tolerance, BALB/c cardiac grafts were transplanted into wild-type or IL-6-deficient C57BL/6 mice. We observed that production of IL-6 and IFN-γ was upregulated during allograft rejection in untreated wild-type mice. In IL-6-deficient mice, IFN-γ production was greater than that observed in wild-type controls, suggesting that IL-6 production affects Th1/Th2 balance during allograft rejection. CD28-B7 blockade by CTLA4-Ig inhibited IFN-γ production in C57BL/6 recipients, but had no effect on the production of IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart transplants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance. Allograft acceptance appeared to result from the combined effect of costimulatory molecule blockade and IL-6-deficiency, which limited the differentiation of effector cells and promoted the migration of regulatory T cells into the grafts. These data suggest that the blockade of IL-6, or its signaling pathway, when combined with strategies that inhibit Th1 responses, has a synergistic effect on the promotion of allograft acceptance. Thus, targeting the effects of IL-6 production may represent an important part of costimulation blockade-based strategies to promote allograft acceptance and tolerance.

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