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T H Khanh Vu, Huihui Chen, Djoeke Doesburg, Kin-Sang Cho, Martine Jager, Dongfeng Feng Chen; CD4+T Cell Responses Contribute To Progressive Neurodegeneration In Ischemic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1894.
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Retinal ischemia is a common cause of dysfunction or death of retinal ganglion cells (RGCs) leading to progressive visual loss and blindness. In this study we aimed to have a better understanding of the pathophysiological processes and mechanisms underlying ischemic retinopathy and the progressive damage of RGCs. A mouse model of transient ischemic injury was thus used to assess the role of the adaptive immune response.
Retinal ischemia was induced in C56BL/6J (B6), Rag1-/- and TCR-/- mice, by raising the IOP to 110 mmHg for 60 minutes. Sham-operated mice underwent the same procedure but without elevated IOP. Mice were sacrificed at 3 days, and 1, 4, and 8 weeks post-injury or at 28 days after sham operation. RGC loss was assessed in retina whole-mounts that were immunostained with βIII-tubulin antibody. Ocular immune responses were evaluated by assessing CD11b+macrophage and CD4+T cell activation, and cytokine expression in the retina. Systemic immune responses were measured by detecting anti-Hsp responding T cells with IFN-γ ELISPOT assay. Additionally, adoptive transfer of CD4+T cells isolated from B6 mice after ischemia or sham operation was performed.
Transient ischemic injury induces progressive RGC degeneration, starting at as early as 3 days post-ischemia with continued loss detectable up to 8 weeks after injury. Increased numbers of macrophages and T cells and increased expression of IFN- γ were observed in ischemic eyes compared to sham-operated eyes. Concomitant with an increased induction of Hsp27 and Hsp60 expression in RGCs following ischemia, increased CD4+T cells against Hsp27 and Hsp60 were also detected in the splenocytes of ischemic mice compared to sham-operated mice. Rag1-/- and TCRβ-/- mice showed significantly less RGC loss than B6 wild-type mice after ischemic injury. Rag1-/- mice who received adoptive transfer of T cells from B6 mice with retinal ischemia showed significantly more RGC loss compared to Rag1-/- mice or Rag1-/- mice with T cells from sham-operated mice.
T cell deficiency improved RGC survival, while adoptive transfer of CD4+T cells isolated from ischemia-induced mice into Rag1-/- mice, which carry both T and B cell deficiencies, resumes the later phase RGC damage. Thus, the adaptive immune response, especially CD4+TH1 type cell responses directed against Hsp27 and Hsp60, has an essential role in retinal ischemia-induced RGC loss.
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