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K. Morohoshi, D. Miyazaki, S. Yamagami, M. Haino, K. Matsushima, Y. Inoue; Corneal Allograft Rejection in CCR5– and/or CXCR3–Deficient Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1295.
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© ARVO (1962-2015); The Authors (2016-present)
CD4+ Th1 cells play a pivotal role in organ graft rejection. Recently, the importance of chemokine receptors on Th1 cells, CCR5 and CXCR3, has been reported in the Th1–related pathogenesis. The purpose of this study was to examine the role of CCR5 and CXCR3 in the immune rejection of corneal allograft.
Murine orthotopic penetrating keratoplasties were performed using BALB/c donor corneas and C57BL/6 wild–type (WT), CCR5–deficient (CCR5KO), CXCR3–deficient (CXCR3KO) or CCR5/CXCR3–double–deficient (DKO) recipients. RNase protection assay for cell surface molecules was performed in order to investigate the graft–infiltrating cell population, and intraocular expression of chemokines and chemokine receptors were analyzed by real–time quantitative PCR. Moreover, flow cytometry analysis and alloreactive T cell proliferation assay against MMC–treated BALB/c spleen cells were performed in cervical lymph node cells after transplantation.
Prolonged graft survival was observed in DKO by Kaplan–Meier analysis (P= 0.028), but not in CCR5KO or CXCR3KO. This survival was cancelled by the transfer of WT spleen cells. RNase protection assay revealed the reduction of TCR–alpha, TCR–delta, CD4, ICAM–1, and F4/80 in BALB/c–grafted DKO mice. Intraocular expression of chemokines, such as IP–10, MIG, RANTES, MCP–2, was down–regulated in BALB/c–grafted DKO mice compared with BALB/c–grafted WT, whereas that of other chemokine receptors, such as CCR1 and CCR7, were up–regulated in BALB/c–grafted DKO mice. CD4+ cells were reduced in cervical lymph nodes in BALB/c–grafted DKO compared with BALB/c–grafted WT, and the proliferative response of T cells against donor spleen cells was significantly suppressed in BALB/c–grafted DKO compared with BALB/c–grafted WT (P<0.01).
Corneal allograft rejection is suppressed in DKO, along with a reduction of donor–specific CD4+ T cell responses. It indicates the strategy to manipulate chemokine receptors is potential therapy for corneal allograft rejection.
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