Ocular immune privilege is maintained in part by the induction of systemic regulatory T cells mediated by events that are initiated after the introduction of antigen into the Anterior Chamber. This potent (ocular) response specifically preempts the systemic induction of tissue-damaging cell-mediated immunity, some complement fixing antibodies and atopic antibodies. Accordingly, we suggest that regulatory T cells induced by intracameral antigen could be used to selectively regulate systemic autoreactive T cells. Most investigations on the induction of regulatory T cells in autoimmunity do not discriminate between the regulation of the induction of an autoimmune response and the regulation of T cells that effect autoimmunity during on-going disease. Preliminary studies by our laboratories have demonstrated that the injection of myelin basic protein or myelin oligodendrocyte glycoprotein into an anterior chamber of mice immunized to these myelin proteins induces the production of antigen-specific regulatory T cells that suppress delayed- type hypersensitivity and/or experimental allergic encephalomyelitis (EAE) effected by an encephalitogenic T cell clone. Therefore we propose that the injection of myelin proteins into an anterior chamber of mice induces T cells that specifically regulate the induction of EAE by EAE effector T cells and may modulate on-going disease. We will test this hypothesis by raising antigen-specific splenic regulatory T cells by the injection of myelin oligodendrocyte glycoprotein into an anterior chamber and (1) Test the hypothesis that antigen-specific regulatory T cells that effect and/or induce the suppression of an encephalitogenic T cells are produced (but not necessarily activated) during an immune response to the autoantigen.
This Aim will also test the hypothesis that inactive regulatory T cells are produced during an immune response to autoantigen and how these cells may be activated in vivo to prevent autoimmunity and/or eliminate an on-going autoimmune response;(2) Determine the mechanism(s) of cell-mediated suppression of EAE induced by encephalitogenic effector T cells. We will test the hypothesis that the suppression of encephalitogenic effector T cells by antigen-specific, regulatory T cells is mediated by cytokines that induce the regulatory T cells or effect suppression. The results of this study could aid our understanding of the systemic basis for the ocular regulation of autoimmunity and develop procedures for the modulation of active autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017537-03
Application #
7676000
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2007-09-30
Project End
2010-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$296,000
Indirect Cost
Name
University of Connecticut
Department
Pathology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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
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
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
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; 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
Cone, Robert E; Chattopadhyay, Subhasis; O'Rourke, James (2008) Control of delayed-type hypersensitivity by ocular- induced CD8+ regulatory t cells. Chem Immunol Allergy 94:138-49