OCULAR IMMUNOPATHOLOGY IN AUTOIMMUNE MODELS

Johns Hopkins University, Baltimore MD

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Abstract

Dry eye syndromes are among the most common causes of ocular morbidity in the developed world. Sjogren's syndrome is an autoimmune disorder in which lacrimal gland damage results from a mononuclear inflammatory infiltrate. MRL/Mp-1pr/1pr (MRL/1pr) and MRL/Mp-+/+ (MRL/+) mice are congenic murine models of autoimmunity, develop lacrimal gland inflammatory lesions, and are a model for Sjogren's syndrome. The 1pr mutation produces defective Fas antigen, which results in defective lymphocytic apoptosis and accelerates the autoimmune disease. Although the target organ inflammatory lesions in MRL/1pr mice are composed primarily of CD4+ T cells, lymphocyte subset depletion experiments have demonstrated that the lacrimal gland disease can be mediated by either CD4+ T cells or CD8+ T cells. Our investigations will address the mechanisms by which autoimmune lacrimal gland damage occurs in these mice. We hypothesize that the autoimmune lacrimal gland disease in MR/1pr mice; and (4) to intervene therapeutically in vivo and MRL/+ mice is initially an IL-12 driven, Th1-mediated process, which evolves to an IL-2 independent, Th2-mediated process. We also hypothesize that although the lacrimal gland disease is intrinsic to the MRL/Mp strain, the accelerated lacrimal gland disease in MRL/1pr mice compared to MRL/+ mice is due to a failure of lymphocytic apoptosis in the lacrimal gland in MRL/1pr mice. The specific aims are: 1) to determine the cytokines present in the lacrimal gland lesions in MRL/1pr and MRL/+ mice and define whether the disease is primarily a Th1- or Th2-mediated disorder and whether there is a change over time; 2) to evaluate the role of the IL-2/IL-2R autocrine pathway in the lacrimal gland disease in MRL/1pr mice, particularly in regard to the time period when this pathway is critical in the establishment of disease; 3) to investigate the pathogenesis of the lacrimal gland disease in MRL/+ mice and the role played by the defective Fas antigen and apoptosis in the accelerated lacrimal gland disease in MRL/1pr mice; and 4) to intervene therapeutically in vivo with monoclonal antibodies to cytokines to define the pathways involved in disease production.