Bharati Matta1,2, Puran S Bora1, Adam J Neuhouser1, Nalini S Bora3. 1. Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 523, Little Rock, AR, 72205, USA. 2. The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA. 3. Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 523, Little Rock, AR, 72205, USA. NBora@UAMS.edu.
Abstract
PURPOSE: Experimental autoimmune anterior uveitis (EAAU) is a clinically relevant animal model for human idiopathic anterior uveitis (IAU). The role of the immunomodulator transforming growth factor β2 (TGF-β2) in EAAU pathology is unknown. In this study, we investigated the regulatory role of TGF-β2 in EAAU. METHODS: EAAU was induced in male Lewis rats by footpad injection of melanin-associated antigen (MAA). TGF-β2 was administered intravenously (iv) in MAA-sensitized rats during the induction of EAAU, or after the clinical onset of uveitis. MAA-sensitized rats injected similarly with an equal volume of PBS served as control. Animals were examined daily between days 7 and 30 post-injection for the clinical signs of uveitis using slit lamp biomicroscopy. Animals were sacrificed at various time points and eyes were harvested for histological analysis to assess the course and severity of inflammation. For histopathological analysis, paraffin sections of harvested eyes were stained with hematoxylin and eosin. Popliteal lymph nodes (LNs) were used for CD4+CD25+FoxP3+ T regulatory (Tregs) population analysis and for CD4+ T cell proliferation assay. RESULTS: Administration of recombinant TGF-β2 during the early stages of EAAU prevented the induction of uveitis. Compared to PBS, the presence of TGF-β2 in the cell culture significantly (p < 0.05) inhibited the proliferation of CD4+ T cells in response to MAA. In MAA-sensitized Lewis rats, iv treatment with recombinant TGF-β2 resulted in significantly (p < 0.05) increased percentage of Tregs compared to animals treated similarly with PBS. Thus, TGF-β2 inhibited the induction of EAAU by inhibiting CD4+ T cell proliferation and increasing the number of Tregs. Injection of TGF-β2 in rats with active EAAU resulted in diminished disease activity. Unfortunately, this treatment did not lead to the early resolution of EAAU. CONCLUSIONS: TGF-β2 plays a critical role in regulation of intraocular inflammation in EAAU. Findings reported in this study improve our understanding of immunopathology of IAU and suggest that recombinant TGF-β2 may be a promising therapeutic agent for human IAU.
PURPOSE: Experimental autoimmune anterior uveitis (EAAU) is a clinically relevant animal model for humanidiopathic anterior uveitis (IAU). The role of the immunomodulator transforming growth factor β2 (TGF-β2) in EAAU pathology is unknown. In this study, we investigated the regulatory role of TGF-β2 in EAAU. METHODS: EAAU was induced in male Lewis rats by footpad injection of melanin-associated antigen (MAA). TGF-β2 was administered intravenously (iv) in MAA-sensitized rats during the induction of EAAU, or after the clinical onset of uveitis. MAA-sensitized rats injected similarly with an equal volume of PBS served as control. Animals were examined daily between days 7 and 30 post-injection for the clinical signs of uveitis using slit lamp biomicroscopy. Animals were sacrificed at various time points and eyes were harvested for histological analysis to assess the course and severity of inflammation. For histopathological analysis, paraffin sections of harvested eyes were stained with hematoxylin and eosin. Popliteal lymph nodes (LNs) were used for CD4+CD25+FoxP3+ T regulatory (Tregs) population analysis and for CD4+ T cell proliferation assay. RESULTS: Administration of recombinant TGF-β2 during the early stages of EAAU prevented the induction of uveitis. Compared to PBS, the presence of TGF-β2 in the cell culture significantly (p < 0.05) inhibited the proliferation of CD4+ T cells in response to MAA. In MAA-sensitized Lewis rats, iv treatment with recombinant TGF-β2 resulted in significantly (p < 0.05) increased percentage of Tregs compared to animals treated similarly with PBS. Thus, TGF-β2 inhibited the induction of EAAU by inhibiting CD4+ T cell proliferation and increasing the number of Tregs. Injection of TGF-β2 in rats with active EAAU resulted in diminished disease activity. Unfortunately, this treatment did not lead to the early resolution of EAAU. CONCLUSIONS: TGF-β2 plays a critical role in regulation of intraocular inflammation in EAAU. Findings reported in this study improve our understanding of immunopathology of IAU and suggest that recombinant TGF-β2 may be a promising therapeutic agent for human IAU.
Entities:
Keywords:
Anterior uveitis; CD4+ T cells; Experimental autoimmune anterior uveitis; Inflammation; T regulatory cells; Transforming growth factor β2
Authors: N S Bora; M C Kim; N H Kabeer; S C Simpson; M T Tandhasetti; T P Cirrito; A D Kaplan; H J Kaplan Journal: Invest Ophthalmol Vis Sci Date: 1995-05 Impact factor: 4.799