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Susmit Suvas, Subhash Gaddipati, Kathleen Estrada, Pushpa Rao; IL-2/anti-IL-2 Complex Treatment Inhibits the Development but not the Progression of Herpetic Stromal Keratitis (HSK). Invest. Ophthalmol. Vis. Sci. 2014;55(13):1690.
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To determine if IL-2/anti-IL-2 complex (IL-2 complex) treatment given prior to or late after ocular herpes simplex virus-1 (HSV-1) infection affect the development of corneal opacity and angiogenesis.
C57BL/6 mice received intra-peritoneal injection of freshly prepared IL-2 complex either prior to or late after ocular HSV-1 infection. IL-2 complex induced increased pool of naturally occurring CD4+Foxp3+ regulatory T cells (nTreg) were determined by flow cytometery. The development of the corneal opacity and angiogenesis was determined in different groups by slit lamp microscopy. Plaque assay was used to determine the viral load in infected corneas of PBS and IL-2 complex treated groups. Frequencies and absolute numbers of cytokine secreting CD4 T cells in the corneas, lymph nodes and spleens of mice from different groups were determined by intra-cellular cytokine assay.
In vivo administration of IL-2 complex is known to expand nTreg in uninfected mice. Our results showed that IL-2 complex treatment given three days prior to or four days after ocular HSV-1 infection optimally expand nTreg pool in secondary lymphoid tissues on day 2 or day 9 post- infection, respectively. Interestingly, treatment-induced increased pool of nTreg at the time of T cell priming (Day 2 post-infection) significantly reduced the corneal opacity and angiogenesis. To determine the underlying mechanism, our results showed that increase in nTreg numbers at the time of priming lead to decrease in viral load in the corneas on day 2 but not day 4 post-infection when compared with control group. Lesser virus on day 2 post-infection was correlated with an increased influx of NK cells in infected corneas. Moreover, increased nTreg pool at the time of priming also resulted into decreased influx of CD4 T cells in infected corneas as determined on day 7 post-infection. There was also a significant reduction in the frequency of IFN-γ, IL-2 and TNF-α producing CD4 T cells in lymph nodes and spleen tissue of IL-2 complex treated than control groups of mice. On the other hand, increasing nTreg pool during contraction phase of T cell response or late after infection did not decrease the severity of HSK lesions.
We conclude that IL-2 complex induced increase in nTreg pool early but not late after HSV-1 infection is effective in reducing HSV-1 induced corneal opacity and angiogenesis.
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