Immune deviation induced by ocular antigen presenting cells involves a protective peripheral immune response that prevents inflammation. Such anti-inflammatory immune response plays a significant role in avoiding potentially blinding effects of ocular inflammation. The unique ability of ocular APCs to induce such a protective response is attributed to their exposure to TGF-2 in their local microenvironment. Studies described in this proposal seek to elucidate molecular mechanisms utilized by such TGF-2-exposed APCs in inducing a regulatory immune response. The first specific aim seeks to determine the significance of thrombospondin-1 (TSP-1) in the induction of a peripheral population of regulatory T cells. Since we demonstrated earlier that TSP-1 is essential for ocular immune privilege, experiments in this aim will allow us to determine the effect of TSP-1 on peripheral immune effectors.
The second aim seeks to investigate the specific contribution of the interactions of TSP-1 with its receptors on the effectors, which subsequently suppress inflammatory immune response. Considering the multidomain structure of a large molecule like TSP-1 with multiple cell type specific biological effects, these investigations will clarify mechanisms by which TSP-1 contributes to immune deviation.
The final aim addresses the relevance of TSP-1 dependent mechanisms in regulation of autoimmune ocular inflammatory conditions as seen in experimental autoimmune uveitis (EAU) and Sjogren's syndrome associated ocular surface disease dry eye. Since TSP-1 is known to be important in maintaining immune privilege these studies will allow us to evaluate if application of any of the TSP-1 dependent mechanisms can help resolve chronic ocular inflammatory diseases. Together these studies can build further on the existing knowledge of ocular immune responses and provide insights into novel therapeutic strategies.

Public Health Relevance

Immune privilege of the eye is an evolutionary phenomenon that protects the eye from potential vision-compromising inflammatory immune response. Understanding immunologic mechanisms underlying this phenomenon can help improve current therapeutic approaches used to treat ocular inflammation. The long-term goal of these investigations is to develop novel anti-inflammatory therapeutic strategies to counter inflammatory conditions such as autoimmune diseases and transplant rejections.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015472-11
Application #
8531938
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2013-04-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
11
Fiscal Year
2013
Total Cost
$422,945
Indirect Cost
$164,579
Name
Boston University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Contreras-Ruiz, Laura; Mir, Fayaz A; Turpie, Bruce et al. (2016) Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090. Exp Eye Res 143:1-8
Shatos, Marie A; Hodges, Robin R; Morinaga, Masahiro et al. (2016) Alteration in cellular turnover and progenitor cell population in lacrimal glands from thrombospondin 1(-/-) mice, a model of dry eye. Exp Eye Res 153:27-41
Terzulli, Marielle; Contreras-Ruiz, Laura; Ruiz, Laura Contreras et al. (2015) TSP-1 Deficiency Alters Ocular Microbiota: Implications for Sjögren's Syndrome Pathogenesis. J Ocul Pharmacol Ther 31:413-8
Regenfuß, Birgit; Dreisow, Marie-Luise; Hos, Deniz et al. (2015) The Naïve Murine Cornea as a Model System to Identify Novel Endogenous Regulators of Lymphangiogenesis: TRAIL and rtPA. Lymphat Res Biol 13:76-84
Mir, Fayaz Ahmad; Contreras-Ruiz, Laura; Masli, Sharmila (2015) Thrombospondin-1-dependent immune regulation by transforming growth factor-β2-exposed antigen-presenting cells. Immunology 146:547-56
Masli, Sharmila (2015) Matricellular Proteins in Ocular Diseases. J Ocul Pharmacol Ther 31:365
Nair, K Saidas; Barbay, Jessica; Smith, Richard S et al. (2014) Determining immune components necessary for progression of pigment dispersing disease to glaucoma in DBA/2J mice. BMC Genet 15:42
Dartt, Darlene A; Masli, Sharmila (2014) Conjunctival epithelial and goblet cell function in chronic inflammation and ocular allergic inflammation. Curr Opin Allergy Clin Immunol 14:464-70
Contreras-Ruiz, Laura; Ryan, Denise S; Sia, Rose K et al. (2014) Polymorphism in THBS1 gene is associated with post-refractive surgery chronic ocular surface inflammation. Ophthalmology 121:1389-97
Contreras-Ruiz, Laura; Regenfuss, Birgit; Mir, Fayaz Ahmad et al. (2013) Conjunctival inflammation in thrombospondin-1 deficient mouse model of Sjögren's syndrome. PLoS One 8:e75937

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