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.
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