Systemic immune responses to anterior chamber antigens are deviant in that certain types of immune effectors (delayed hypersensitivity and complement-fixing antibodies) are selectively suppressed, whereas other effectors (cytotoxic T cells, non-complement fixing antibodies) are retained. This pattern of response has been termed Anterior Chamber Associated Immune Deviation (ACAID). The mechanisms of this phenomenon involve shaping of the initial response to ocular antigens by the ocular microenvironment, so that regulatory cells arise that dictate the type of response generated. If the eye is altered by inflammation, trauma or disease, its capacity to promote ACAID is abolished. The experimental plan proposed addresses 3 related hypotheses, while making use of ovalbumin T cell receptor (OVA TCR) transgenic mice: (i) that OVA-specific TCR transgenic T cells, activated in vitro by OVA-pulsed TGF-beta2-treated antigen presenting cells (APC), become regulatory T cells that suppress, respectively, the induction and expression of delayed hypersensitivity in vivo; (ii) that pigment epithelium inhibits activation of Th1-type cells and converts activated T cells into regulatory cells; and (iii) that immune privilege and ACAID are abolished acutely in ocular inflammation, but secondary mechanisms intervene to restore immune suppression and ACAID. These hypotheses give rise to 3 specific aims: (1) to characterize and describe mode of action of regulatory T cells of ACAID; (2) to describe mode of action of ocular factors that promote immune privilege and ACAID in normal eyes; and (3) to determine the consequences of inflammation and trauma on ocular immune privilege. The investigators contend that the experimental plan will provide key information concerning the molecular basis of ocular immune privilege and ACAID in the normal mouse, and will reveal molecular processes that abolish immune privilege and allow it to be restored. A secondary benefit will be a significant expansion of knowledge of genes that are differentially regulated in the cellular processes by which ACAID is induced and expressed. The anticipation is that new knowledge concerning key genes in ACAID and immune privilege will lead to therapeutic strategies directed at alleviating ocular inflammatory disease and promoting orthotopic graft acceptance.
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