Dry eye affects approximately 10 million Americans, most of whom are women. An estimated 2 million cases of Sjogren's syndrome exist in America. Our long-term goal is to elucidate the mechanism of immunopathogenesis of autoimmune dacryoadenitis and to determine the impact of vlL-10 and TNF-inhibitor gene expression on the disease. In an in vivo rabbit model of autoimmune dacryoadenitis, lymphocytes proliferate in a mixed cell reaction with purified autologous lacrimal gland epithelial cells and, when injected back into the rabbit's own contralateral gland, induce intense focal lymphocytic infiltration, thus creating a model for autoimmune dacryoadenitis. Tear production is reduced and tear stability is decreased in the dysfunctional lacrimal gland while rose bengal staining of the corneal surface is increased. CD4+ T cells and CD18+ cells increase significantly in the immune infiltrates in the gland, and the CD4+ to CD8+ T cell ratio increases as it does in Sjogren's syndrome.
Aim 1. Characterize the cells that proliferate in autologous mixed cell reactions. Hypothesis 1a. Autoreactive CD4+ T cells proliferate in the mixed cell reaction and secrete proinflammatory cytokines (e.g. IL-2, TNF b, and IFNy,). Hypothesis 1b. Lacrimal autoimmunity is a normal phenomenon and active functioning regulatory T cells ordinarily prevent normal autoimmunity from developing into clinical disease.
Aim 2. Identify the autoreactive T cell responsible for inducing autoimmune dacryoadenitis and monitor the progression of the disease. Hypothesis 2a. Purified lymphocyte population that proliferate in mixed cell reactions induce autoimmune dacryoadenitis. Hypothesis 2b. Autoimmune dacryoadenitis can be induced by the animal's own activated lymphocytes administered at sites other than the lacrimal gland (e.g. intravenous or subcutaneous), and this will result in systemic disease involving the salivary glands and kidneys.
Aim 3. Develop gene transfer therapeutic strategies using an AAV vector (AAV-tetON-vlL- 10) with an inducible promoter for treating autoimmune dacryoadenitis and explain the mechanism of action of vlL-10 on effector T cells. Hypothesis 3a. Long-term expression of vlL-10 gene in the lacrimal gland suppresses effector T cell (e.g. CD4+ cells) proliferation, but not suppressor T cell activity. Hypothesis 3b. vlL-10 suppresses CD4+ T cell proliferation by down regulating expression of Th 1 cytokines IL-2, TNF-b and interferon-y.
Aim 4. Elucidate the exit pathway of transgene product from the transduced acinar cell. Hypothesis 4a. Intracellular trafficking of vlL-10 results in the anti-inflammatory cytokine exiting the transduced lacrimal cells via both apical and basolateral membranes. The overall study will determine the effector cell phenotype, their secreted proinflammatory cytokines and the impact of over expression of vlL-10 on Th 1, Th2 and Th3 responses during progression and regression of the autoimune disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AED (01))
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Shen, Grace L
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Doheny Eye Institute
Los Angeles
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Zhou, Lei; Wei, Ruihua; Zhao, Ping et al. (2013) Proteomic analysis revealed the altered tear protein profile in a rabbit model of Sjögren's syndrome-associated dry eye. Proteomics 13:2469-81
Nandoskar, Prachi; Wang, Yanru; Wei, Ruihua et al. (2012) Changes of chloride channels in the lacrimal glands of a rabbit model of Sjogren syndrome. Cornea 31:273-9
Wei, Rui Hua; Thomas, Padmaja B; Samant, Deedar M et al. (2012) Autoimmune dacryoadenitis and sialadenitis induced in rabbits by intravenous injection of autologous lymphocytes activated ex vivo against lacrimal antigens. Cornea 31:693-701
Ding, Chuanqing; Nandoskar, Prachi; Lu, Michael et al. (2011) Changes of aquaporins in the lacrimal glands of a rabbit model of Sjogren's syndrome. Curr Eye Res 36:571-8
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Ding, Chuanqing; Lu, Michael; Huang, Jianyan (2011) Na(+)/K(+)-ATPase in the lacrimal glands of rabbits and its changes during induced autoimmune dacryoadenitis. Mol Vis 17:2368-79
Thomas, Padmaja B; Samant, Deedar M; Wang, Yanru et al. (2010) Distinct dacryoadenitides autoadoptively transferred to rabbits by different subpopulations of lymphocytes activated ex vivo. Cornea 29:1153-62
Schechter, Joel E; Warren, Dwight W; Mircheff, Austin K (2010) A lacrimal gland is a lacrimal gland, but rodent's and rabbit's are not human. Ocul Surf 8:111-34
Thomas, Padmaja B; Samant, Deedar M; Selvam, Shivaram et al. (2010) Adeno-associated virus-mediated IL-10 gene transfer suppresses lacrimal gland immunopathology in a rabbit model of autoimmune dacryoadenitis. Invest Ophthalmol Vis Sci 51:5137-44
Thomas, Padmaja B; Samant, Deedar M; Zhu, Zejin et al. (2009) Long-term topical cyclosporine treatment improves tear production and reduces keratoconjunctivitis in rabbits with induced autoimmune dacryoadenitis. J Ocul Pharmacol Ther 25:285-92

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