Dry eye is the most common cause of ocular morbidity in developed countries. This important vision health problem increases with age and .affects a significant proportion of the female population, presumedly as the result of hormonal influences. Clinical manifestations of dry eye range from mild to vision-threatening corneal damage and can result from immune-related and non-immune related causes of lacrimal insufficiency. These disorders share the common feature of immune cell infiltration of the lacrimal gland, suggesting that autoimmune events play a role. In an in vivo model of autoimmune dacryoadenitis, lymphocytes from a mature female rabbit proliferate in a mixed cell reaction with autologous acinar cells purified from one surgically excised lacrimal gland. These proliferating lymphocytes, when injected into the rabbit's contralateral gland, induce intense focal lymphocytic infiltration, thus creating an in vivo model for autoimmune dacryoadenitis. By introducing anti- inflammatory cytokine genes into acinar cells in vitro and in vivo, we will investigate mechanisms of immunoregulation, pathogenesis and autoimmunity.
Specific Aims i nclude the following: l) To evaluate the timing and distribution of transgene expression in the lacrimal gland; 2) To introduce anti-inflammatory genes TGF-beta and IL-10 into lacrimal gland cells in vitro and determine if transgene expression will inhibit lymphocyte proliferation in the autologous mixed cell reaction; and 3) To characterize the immunopathology of anti-inflammatory cytokine gene expression on immune cell infiltration. Lymphocyte proliferation will be studied in vitro by tritiated-thymidine uptake along with blocking experiments using antibodies against the specific anti-inflammatory cytokine and recombinant cytokine proteins as positive controls. Immune cells infiltrating the lacrimal gland will be identified by immunocytochemical staining, and severity of induced-autoimmune dacryoadenitis will be graded by computerized analysis of digitized images. This new model provides a novel opportunity to: a) investigate, at the molecular level, mechanisms associated with induction of autoimmune disease and, b) thwart influences of proinflammatory genes in induced-autoimmune dacryoadenitis with the transfer and expression of anti-inflammatory cytokine genes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY012689-01A1
Application #
6131771
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
2000-05-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$314,444
Indirect Cost
Name
Doheny Eye Institute
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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
Mircheff, A K; Wang, Y; Thomas, P B et al. (2011) Systematic variations in immune response-related gene transcript abundance suggest new questions about environmental influences on lacrimal gland immunoregulation. Curr Eye Res 36:285-94
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
Selvam, Shivaram; Chang, Wenji V; Nakamura, Tamako et al. (2009) Microporous poly(L-lactic acid) membranes fabricated by polyethylene glycol solvent-cast/particulate leaching technique. Tissue Eng Part C Methods 15:463-74

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