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J. Gao, K. F. Siemasko, C. Vu, R. Chen, S. C. Pflugfelder, J. Y. Niederkorn, V. L. Calder, M. Calonge, M. E. Stern; Immunogenic Role of Dry Eye Corneas in Lymphocyte Proliferation and Effect of TGF-ß1 and T Regulatory Cells in Dry Eye Cornea-Induced Lymphoproliferation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):190. doi: https://doi.org/.
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The role of T cells in mediating inflammatory pathogenesis of dry eye has been elucidated in T cell deficient nude mice after adoptive transfer of CD4+ T cells from mice exposed to a desiccating environmental stress (DS). These T cells were found to restrict in the Lacrimal Functional Unit (LFU, cornea, conjunctiva and lacrimal gland). Such disease transfer was not detected when wide type mice were used as recipients. This led us to hypothesize that immunogenic components may reside in LFU of DS mice and stimulate lymphocyte proliferation. Intrinsic immunosuppressive modulators such as T regulatory cells (Tregs) and/or TGF-ß1 may play essential roles in maintaining immune homeostasis of LFU.
A co-culture system was designed to evaluate lymphoproliferation in a mixed lymphocyte reaction, where corneas and lymphocytes were used as the stimulator and responder, respectively. They were isolated from BALB/c naïve mice and mice exposed to DS. To determine the role of Tregs, a subset of mice was pre-treated with spleen derived Tregs 3 days prior to exposed to DS (0.75 or 1.0 million Tregs/mouse, ip.), while another subset of mice was injected with anti-CD25 antibodies (250µg/mouse, ip, bid on Day-3 and 1). Lymphoproliferation was assessed using WST-based assay. TGF-ß1 effect on lymphoproliferation was evaluated by addition of recombinant TGF-ß1 (200, 2000pg/ml) in the co-culture. Corneal TGF-ß1 secretion was determined by Luminex.
Lymphocyte proliferation was induced by corneas of DS mice compared to corneas of control mice (a 46% increase, p<0.001). Such lymphoproliferation was further enhanced by anti-CD25 antibody (a 133% increase), but suppressed by Treg treatment (a 55% decrease). TGF-ß1 dose-dependently inhibited lymphoproliferation induced by DS corneas. DS corneas had a significantly decreased TGF-ß1 secretion than naïve corneas. The level of TGF-ß1 secreted by DS corneas was normalized when mice were treated with Tregs prior to expose to DS.
The enhanced lymphoproliferation by DS corneas indicates an immunogenic role of the pathogenic cornea in immune activation in dry eye. The decreased lymphoproliferation by TGF-ß1 or Treg treatment revealed an immunosuppressive function of TGF-ß1 and T Regulatory cells in modulating immune response in dry eye disease.
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