TH17 Cells in Organ Transplantation Rejection and Tolerance

DOI: 10.1007/978-1-4419-9371-7_17 In book: TH17 Cells in Health and Disease, pp.319-339


The emergence of TH17 cells as a distinct subset of effector T cell has led to a revised model of the adaptive immune system. In experimental
and clinical transplantation, the TH17-producing cytokine, interleukin (IL)-17, is evident in allograft rejection. It is conceivable that TH17 cells could play a specific role in pathogenic process of allograft rejection. This chapter summarizes the current spectrum
of TH17 cells in transplant rejection. The tolerance and regulation of TH17 response in the allogeneic context is also discussed.

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    ABSTRACT: Th17, recently identified as a new subset of effector Th cells, has been shown to be involved in microbe infection and autoimmunity. However, the role of these cells in organ allograft rejection remains largely unknown. In this study, we investigate whether Th17 cells participate in allogeneic corneal rejection in a mouse model. Donor cornea (C57BL/6) was transplanted into orthotopic graft bed of Balb/c recipients. At different time points after keratoplasty, the expression of Th17 and Th1- related cytokines in draining cervical lymph nodes (LN) and grafted cornea was examined by flow cytometry and quantitative RT- PCR, respectively. Furthermore, IL- 17(-/-) Balb/c mice were used to determine the effects of Th17 cells on allogeneic cornea survival. Finally, the profiles of Th1 and proinflammatory cytokines in IL- 17(-/-) recipients after transplantation were examined. Th17 expression was enhanced significantly in inflamed transplants and draining lymph nodes at the early stage of allocorneal rejection, while upregulation of Th1 producing IFN- gamma was seen in the late phase. Upon activation by allogeneic accessory cells, responder cells in draining LN from transplanted recipients secreted high levels of IL- 6, TGF- beta and IL- 21 compared to controls, which may drive naive T cells to differentiate into Th17 cells. Importantly, IL- 17 deficiency led to the delayed development of allogeneic rejection, but did not affect the overall survival time of transplants. This effect correlated with restrained Th1 polarization and decreased production of proinflammatory cytokines. Th17 cells play a disease-promoting role at the early stage of corneal allograft rejection.
    Transplant Immunology 05/2009; 21(3):155-61. DOI:10.1016/j.trim.2009.03.006 · 1.46 Impact Factor
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    ABSTRACT: Interleukin-23 (IL-23) and T helper 17 (Th17) cells have been cast as major players in autoimmunity, but their role in transplantation immunity remains to be specified. The aim of our study was to investigate the time course of serum levels of IL-23 and IL-17 during hepatic allograft rejection. Serum levels of IL-23 and IL-17 were determined in 20 healthy subjects and 50 hepatic transplant recipients. These patients were divided into 2 groups: group I was composed of 15 patients with acute rejection, and group II was composed of 35 patients without acute rejection. Samples were collected on days 1 and 7 after liver transplantation and on the day of liver biopsy. The concentrations of IL-23 were similar for the rejection group and nonrejection group at early postoperative times. We observed a significant increase in serum IL-23 levels in the rejection group when a diagnosis of acute rejection had been established. Similarly to IL-23, at the diagnosis of acute rejection, the concentration of IL-17 was significantly higher in the rejection group versus the nonrejection group. The whole transplant group, including those with stable graft function, had higher serum levels of IL-23 and IL-17 than the controls during the entire postoperative period. In conclusion, IL-23 and IL-17 are up-regulated during acute hepatic rejection. These findings suggest a role for Th17 cells in human liver allograft rejection.
    Liver Transplantation 06/2009; 15(6):629-33. DOI:10.1002/lt.21724 · 4.24 Impact Factor
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    ABSTRACT: T helper (Th)1 cells were considered responsible for the induction of graft-versus-host disease (GVHD), but recently the concept has been challenged. Th17 cells play a critical role in mediating autoimmune diseases, but their role in the pathogenesis of GVHD remains unclear. Herein we compare the ability of in vitro generated Th1 and Th17 cells from C57BL/6 mice to induce GVHD in lethally irradiated BALB/c recipients. Allogeneic Th17 cells had superior expansion and infiltration capabilities in GVHD target organs, which correlated with their increased pathogenicity when compared with naïve or Th1 controls. Th17 cells caused no pathology in the syngeneic recipients, indicating that antigen-activation was required for their pathogenicity. Polarized Th17 cells could not maintain their phenotype in vivo as they produced a significant amount of interferon (IFN)-gamma after being transplanted into allogeneic recipients; however, IFN-gamma was not required for Th17 cell-induced GVHD. Further, we evaluated the pathogenesis of Th17 cells in GVHD by using polyclonal nonprimed CD4T cells in a clinically relevant allogeneic bone marrow transplantation (BMT) setting. We found that disruption of Th17-differentiation alone by targeting RORgammat (Th17-specific transcription factor) had no significant effect on GVHD development. We conclude that Th17 cells are sufficient but not necessary to induce GVHD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2009; 16(2):170-8. DOI:10.1016/j.bbmt.2009.09.023 · 3.40 Impact Factor
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