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J. Gao, K.F. Siemasko, C. Vu, J.Y. Niederkorn, S.C. Pflugfelder, M. Calonge, V.L. Calder, M.E. Stern; The Effect of Corneas From Dry Eye Mice on Peripheral Lymphocyte Proliferation . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4363.
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Experimentally induced dry eye stimulates inflammatory cytokine production and activates MAPK pathways in the cornea and conjunctiva of dry eye mice (Luo, 2004; Nagelhout, 2005). These findings lead us to hypothesize that mediators produced by ocular surface resident cells may be immunogenic and function to attract / stimulate inflammatory cell proliferation and activation.
A co–culture system was designed to evaluate lymphocytic proliferation in a mixed lymphocyte reaction, where corneal epithelium, epithelial proteins or the entire cornea was co–cultured with lymphocytes from cervical lymph nodes of normal BALB/c or dry eye (DE) mice (Dursun, 2002). To enhance immune response, regulatory T cell effect was suppressed by administrating anti–CD25 antibody on days –3 and 1 (250µg /mouse, bid.). Lymphocyte proliferation was assessed on day 5 of the co–culture using WST–based assay. Pro–inflammatory mediators in the cornea were measured by Luminex.
1) When the corneal epithelium (sheets or protein extracts) was used as the stimulator, there was no difference on lymphocyte proliferation between control and DE mice. 2) When the whole cornea of DE mice was used as the stimulator, a significantly higher level of lymphocyte proliferation was detected in the lymphocytes of DE (a 46% increase, p<0.00002) and control (to a lesser extent, a 26% increase, p<0.02) mice when compared with the whole cornea of control mice used as the stimulator. 3) Anti–CD25 antibody treatment resulted in further increases in lymphocyte proliferation when the whole DE corneas were used as the stimulator in DE (133%) and control (58%) mice. 4) TNF–α levels of the DE mice cornea were greater than that of the controls (a 202% increase, p<0.004).
Cornea components of DE mice exhibited immunogenic activity, resulting in lymphocyte proliferation. Corneal epithelium may be one of the main sources for inflammatory/immunogenic activity. Physical contact among corneal cells may be required to provide antigenic signals to trigger lymphocyte response. These findings provide direct evidence that the cornea is an active stimulator of immune response in ocular inflammation.
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