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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY005912-09A2
Application #
2405215
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1986-08-01
Project End
2002-06-30
Budget Start
1997-07-07
Budget End
1998-06-30
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Jabs, Douglas A; Prendergast, Robert A; Campbell, Adam L et al. (2007) Autoimmune Th2-mediated dacryoadenitis in MRL/MpJ mice becomes Th1-mediated in IL-4 deficient MRL/MpJ mice. Invest Ophthalmol Vis Sci 48:5624-9
Jabs, D A; Kuppers, R C; Saboori, A M et al. (1994) Effects of early and late treatment with anti-CD4 monoclonal antibody on autoimmune disease in MRL/MP-lpr/lpr mice. Cell Immunol 154:66-76
Jabs, D A; Prendergast, R A (1994) Murine models of Sjogren's syndrome. Adv Exp Med Biol 350:623-30
Jabs, D A; Burek, C L; Hu, Q et al. (1992) Anti-CD4 monoclonal antibody therapy suppresses autoimmune disease in MRL/Mp-lpr/lpr mice. Cell Immunol 141:496-507
Jabs, D A; Prendergast, R A (1991) Autoimmune ocular disease in MRL/Mp-lpr/lpr mice is suppressed by anti-CD4 antibody. Invest Ophthalmol Vis Sci 32:2718-22
Jabs, D A; Enger, C; Prendergast, R A (1991) Murine models of Sjogren's syndrome. Evolution of the lacrimal gland inflammatory lesions. Invest Ophthalmol Vis Sci 32:371-80
Jabs, D A; Prendergast, R A (1991) Ocular inflammation in MRL/Mp-lpr/lpr mice. Invest Ophthalmol Vis Sci 32:1944-7
Jabs, D A; Prendergast, R A (1988) Murine models of Sjogren's syndrome. Immunohistologic analysis of different strains. Invest Ophthalmol Vis Sci 29:1437-43
Jabs, D A; Prendergast, R A (1987) Reactive lymphocytes in lacrimal gland and vasculitic renal lesions of autoimmune MRL/lpr mice express L3T4. J Exp Med 166:1198-203