Chapter

TH17 Cells in Organ Transplantation Rejection and Tolerance

DOI: 10.1007/978-1-4419-9371-7_17

ABSTRACT 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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    Journal of Experimental Medicine 01/2009; 205(13):3133-44. · 13.21 Impact Factor
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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. · 1.52 Impact Factor
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    ABSTRACT: T cell responses to MHC-mismatched transplants can be mediated via direct recognition of allogeneic MHC molecules on the cells of the transplant or via recognition of allogeneic peptides presented on the surface of recipient APCs in recipient MHC molecules - a process known as indirect recognition. As CD4(+)CD25(+) Tregs play an important role in regulating alloresponses, we investigated whether mouse Tregs specific for allogeneic MHC molecules could be generated in vitro and could promote transplantation tolerance in immunocompetent recipient mice. Tregs able to directly recognize allogeneic MHC class II molecules (dTregs) were obtained by stimulating CD4(+)CD25(+) cells from C57BL/6 mice (H-2(b)) with allogeneic DCs from BALB/c mice (H-2(d)). To generate Tregs that indirectly recognized allogeneic MHC class II molecules, dTregs were retrovirally transduced with TCR genes conferring specificity for H-2K(d) presented by H-2A(b) MHC class II molecules. The dual direct and indirect allospecificity of the TCR-transduced Tregs was confirmed in vitro. In mice, TCR-transduced Tregs, but not dTregs, induced long-term survival of partially MHC-mismatched heart grafts when combined with short-term adjunctive immunosuppression. Further, although dTregs were only slightly less effective than TCR-transduced Tregs at inducing long-term survival of fully MHC-mismatched heart grafts, histologic analysis of long-surviving hearts demonstrated marked superiority of the TCR-transduced Tregs. Thus, Tregs specific for allogeneic MHC class II molecules are effective in promoting transplantation tolerance in mice, which suggests that such cells have clinical potential.
    Journal of Clinical Investigation 11/2008; 118(11):3619-28. · 12.81 Impact Factor