The eye is protected from destructive innate and adaptive immune mechanisms by a local environment that is not conducive to immune-mediated reactions and by the ocular-induced regulation of systemic immunity. Active systemic regulation of destructive cell-mediated immunity is mediated by Anterior Chamber-Associated Immune Deviation (ACAID) imposed on the systemic immune system by complex cellular pathways in which circulating antigen presenting cells home to the thymus and to the spleen. In the thymus and spleen T lymphocytes that induce and effect the suppression of cell-mediated immunity are produced. Our laboratory has shown that after the intracameral injection of antigen (i) intracameral antigen but not intravenous antigen is found in the thymus;(ii) both iris monocytic cells and similar circulating monocytic cells activate immunoregulatory NK 1.1+ thymocytes that (i) enhance the production of lgG1 antibodies to the intracameral antigen and activate CD4+ and CD8+ splenic T cells that suppress cell-mediated immunity. To advance these studies we propose that the intracameral injection of antigen induces monocytic cells in the iris/ciliary body that activate thymic regulatory T cells and splenic immunoregulatory T cells that suppress systemic delayed-type hypersensitivity. To test this hypothesis we will (1) determine the mechanisms(s) by which intracameral antigen travels to the thymus and spleen, (2) determine the induction of regulatory thymocytes by monocytic cells derived from the iris. (3) Determine the mechanism(s) by which immunoregulatory thymocytes from donors receiving intracameral antigen activate splenic suppressor T cells. These studies are essential to a full definition of an oculo/thymic/splenic axis. This ocular-thymic link confirms an active role for the thymus and the eye in the regulation of systemic immunity that could impact on the management of inflammatory eye disease, corneal transplantation, ocular tumors and autoimmune disease. ? ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Shen, Grace L
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University of Connecticut
Schools of Medicine
United States
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Pais, Roshan; Bhowmick, Sourojit; Chattopadhyay, Subhasis et al. (2012) An intracameral injection of antigen induces in situ chemokines and cytokines required for the generation of circulating immunoregulatory monocytes. PLoS One 7:e43182
Sharafieh, Roshanak; Lemire, Yen; Powell, Sabrina et al. (2011) Immune amplification of murine CD8 suppressor T cells induced via an immune-privileged site: quantifying suppressor T cells functionally. PLoS One 6:e22496
Bhowmick, Sourojit; Clark, Robert B; Brocke, Stefan et al. (2011) Antigen-specific splenic CD4+ and CD8+ regulatory T cells generated via the eye, suppress experimental autoimmune encephalomyelitis either at the priming or at the effector phase. Int Immunol 23:119-28
Yadav, Rajwahrdhan; Bhowmick, Sourojit; Gorecki, Philip et al. (2010) Paradoxical effect of pertussis toxin on the delayed hypersensitivity response to autoantigens in mice. PLoS One 5:e11983
Cone, Robert E; Chattopadhyay, Subhasis; Pais, Roshan et al. (2010) The Induction of Circulating, ACAID-Inducing Monocytes Requires CCR2/CCL2-Dependent Migration of Circulating F4/80(+) Cells into the Anterior Chamber. Ophthalmol Eye Dis 2:57-68
Cone, Robert E; Chattopadhyay, Subhasis; Sharafieh, Roshanak et al. (2009) T cell sensitivity to TGF-beta is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber. Int Immunol 21:567-74
Cone, Robert E; Chattopadhyay, Subhasis; Sharafieh, Roshanak et al. (2009) The suppression of hypersensitivity by ocular-induced CD8(+) T cells requires compatibility in the Qa-1 haplotype. Immunol Cell Biol 87:241-8
Bhowmick, Sourojit; Singh, Anurag; Flavell, Richard A et al. (2009) The sympathetic nervous system modulates CD4(+)FoxP3(+) regulatory T cells via a TGF-beta-dependent mechanism. J Leukoc Biol 86:1275-83
Cone, Robert E; Pais, Roshan (2009) Anterior Chamber-Associated Immune Deviation (ACAID): An Acute Response to Ocular Insult Protects from Future Immune-Mediated Damage? Ophthalmol Eye Dis 1:33-40
Chattopadhyay, Subhasis; O'Rourke, James; Cone, Robert E (2008) Implication for the CD94/NKG2A-Qa-1 system in the generation and function of ocular-induced splenic CD8+ regulatory T cells. Int Immunol 20:509-16

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