A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy

Xueli Yuan, Jesus Paez-Cortez, Isabela Schmitt-Knosalla, Francesca D'Addio, Bechara Mfarrej, Michela Donnarumma, Antje Habicht, Michael R. Clarkson, John Iacomini, Laurie H. Glimcher, Mohamed H. Sayegh, M. Javeed Ansari

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226 Scopus citations

Abstract

T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in the development of allograft rejection in an established MHC class II-mismatched (bm12 into B6) model of chronic allograft vasculopathy (CAV). Intriguingly, and in contrast to IFN-γ -/- mice that are protected from CAV, T-bet -/- recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17-producing CD4 T cells. Concurrently, T-bet -/- mice exhibit a T helper type 1 (Thl)-deficient environment characterized by profound IFN-7 deficiency, a Th2 switch characterized by increased production of interleukin (IL) 4, IL-5, IL-10, and IL-13 cytokines, as well as increased production of the proinflammatory cytokines IL-6, IL-12p40, and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection and vasculopathy in T-bet -/- mice. Interestingly, CD4 but not CD8 T cell deficiency in T-bet -/- mice affords dramatic protection from vasculopathy and facilitates long-term graft acceptance. This is the first study establishing that in the absence of Th1-mediated alloimmune responses, CD4 Th17 cells mediate an aggressive proinflamma-tory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for the development of novel therapies to target this intractable problem in clinical solid organ transplantation.

Original languageEnglish (US)
Pages (from-to)3133-3144
Number of pages12
JournalJournal of Experimental Medicine
Volume205
Issue number13
DOIs
StatePublished - Dec 22 2008

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Yuan, X., Paez-Cortez, J., Schmitt-Knosalla, I., D'Addio, F., Mfarrej, B., Donnarumma, M., Habicht, A., Clarkson, M. R., Iacomini, J., Glimcher, L. H., Sayegh, M. H., & Javeed Ansari, M. (2008). A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. Journal of Experimental Medicine, 205(13), 3133-3144. https://doi.org/10.1084/jem.20081937