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L. Shen, A.W. Taylor, S. Barabino, R. Dana; The Effect of the Cornea and Aqueous Humor on Dendritic Cell Maturation Phenotype . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2808.
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Purpose: Prior work has shown that antigen–presenting cells (APCs) in central cornea exhibit a highly immature phenotype. Therefore, we hypothesized that this phenotype is actively maintained by local immunosuppressive mechanisms. Because the cornea and aqueous humor (AqH) have each been shown to be potent sources of various immunomodulatory molecules, we investigated the possible regulatory roles of the cornea and AqH in the maturation process of corneal APCs. Methods: Immature DCs were cultured from bone marrow precursors using GM–CSF. Mature DCs were obtained by TNF–α treatment of immature DCs. The immature and matured DCs were incubated with either AqH or corneal culture supernatant at various concentrations and compared to DCs cultured with medium only. The maturation levels of DCs in different cultures were measured by surface expression of MHC class II and co–stimulatory molecules using flow cytometry. To identify the causative factors for the suppressive effect, physiological concentrations of candidate immunosuppressive factors (TGFß2, α–MSH, etc) were added to the DC cultures. Alternatively, the factors in AqH or corneal culture supernatant were neutralized using specific antibodies before their addition to DC cultures. Results: Two days after exposure of immature and mature DCs to either AqH or corneal culture supernatant, flow analysis revealed delayed DC maturation by a decrease in the expression of class II antigen and costimulatory molecules (CD80, CD86) as compared to untreated immature DCs. For matured DCs, we detected downregulated MHC class II, CD80 and CD86 upon treatment with AqH or cornea culture supernatant. This suppression in immature and mature DCs was dose–dependent and was not seen with untreated cell cultures. Furthermore, pre–incubation of AqH with neutralizing antibody to TGFß2 did not abrogate the inhibitory effect of AqH on DC maturation. Moreover, addition of α–MSH but not TGF ß2 in DC cultures appears to have an inhibitory impact on DC maturation. Conclusions: Our results demonstrate that factors in AqH and cornea interfere with DC maturation by effectively blocking the maturation process of immature DCs and by actively downreguating the expression of class II antigen, CD80 and CD86 on matured DCs. We suggest by these mechanisms, the anterior segment of the eye retains corneal APCs in an immature phenotypic state, therefore impair their antigen–presenting capacity, and ultimately contribute to immune privilege of the site.
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