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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Schepens Eye Research Institute
United States
Zip Code
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
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
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
Cursiefen, Claus; Maruyama, Kazuichi; Bock, Felix et al. (2011) Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med 208:1083-92
Masli, Sharmila; Turpie, Bruce (2009) Anti-inflammatory effects of tumour necrosis factor (TNF)-alpha are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-beta-treated antigen-presenting cells. Immunology 127:62-72
Ghafoori, Paiman; Yoshimura, Takeru; Turpie, Bruce et al. (2009) Increased IkappaB alpha expression is essential for the tolerogenic property of TGF-beta-exposed APCs. FASEB J 23:2226-34
Vega, Jose L; Keino, Hiroshi; Masli, Sharmila (2009) Surgical denervation of ocular sympathetic afferents decreases local transforming growth factor-beta and abolishes immune privilege. Am J Pathol 175:1218-25
Ng, Tat Fong; Turpie, Bruce; Masli, Sharmila (2009) Thrombospondin-1-mediated regulation of microglia activation after retinal injury. Invest Ophthalmol Vis Sci 50:5472-8
Turpie, Bruce; Yoshimura, Takeru; Gulati, Abha et al. (2009) Sjogren's syndrome-like ocular surface disease in thrombospondin-1 deficient mice. Am J Pathol 175:1136-47