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  • Title: Systemic application of sphingosine 1-phosphate receptor 1 immunomodulator inhibits corneal allograft rejection in mice.
    Author: Zhu J, Liu Y, Pi Y, Jia L, Wang L, Huang Y.
    Journal: Acta Ophthalmol; 2014 Feb; 92(1):e12-21. PubMed ID: 23910624.
    Abstract:
    PURPOSE: This study aims to investigate the effects of systemic application of sphingosine 1-phosphate receptor 1(S1P1) on allogeneic corneal transplantation in mice. METHODS: A total of 112 BALB/c mice received corneal grafts from C57BL/6 donors. Recipients were randomly divided into seven groups and treated with intraperitoneal injections of S1P1 (5 mg/kg/days), cyclosporine A (5 mg/kg/days), dexamethasone (1 mg/kg/days) and rapamycin (2 mg/kg/days). S1P1was combined with rapamycin or cyclosporine A, and saline served as negative control. Serum levels of IL-2, IL-10, TGF-β1 and IFN-γ were measured by Elisa. The numbers of CD4+ T and regulatory (Treg) cell phenotype were measured by flow cytometry. Cytokine mRNA expression was analysed by real-time quantitative PCR. CD4+ T cells and cytokines were histologically identified by immunofluorescence staining. RESULTS: Corneal graft survival was prolonged by intraperitoneal injections in S1P1 alone (mean survival time MST, 35.3 ± 5.6 days), S1P1 combined with rapamycin (MST, 38.7 ± 6.5 days) or S1P1 and cyclosporine A (MST, 32.7 ± 4.8 days) compared with the controls (MST, 14.6 ± 0.2 days; n = 5, p < 0.01). S1P1 alone increased CD4+ T (p < 0.01) and Treg cells (p < 0.01; n = 5) in the cervical and mesenteric lymph nodes compared with the controls and S1P1 + rapamycin (p < 0.05; n = 5). TGF-β1 and IL-10 mRNA transcriptions in corneal grafts following S1P1+ rapamycin increased (both p < 0.01; n = 3), and TGF-β1 and IL-10 in the serum level following S1P1 alone increased (both p < 0.01; n = 3). These results paralleled the findings obtained from immunofluorescence. CONCLUSION: S1P1 has significant effect in corneal allograft rejection inhibition. The combined treatment of S1P1 and rapamycin results in synergistic effect.
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