Adaptive and innate regulation of immune privilege.

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DESCRIPTION: Systemic immunity to anterior chamber derived antigens is deviant: certain immune effectors (delayed hypersensitivity, complement fixing antibodies) are deleted/suppressed, whereas others (cytotoxic T cells, non-complement fixing antibodies) are promoted. Anterior Chamber Associated Immune Deviation (ACAID) is an important expression of ocular immune privilege. During the past years our ACAID studies have (i) identified the genes that confer ACAID -inducing properties on APCs (ii) documented ACAID-APCs capable of generating T regulatory (Tregs) cells; (iii) defined a novel lymphocyte traffic pattern for these APCs ;(iv) and showed that the ACAID APC interacted with novel cells (NKT cells, marginal zone B cells) as well as T cells in the marginal zone of the spleen. Based on these results we now propose a new experimental plan for five years to test three related postulates concerning the T regulatory cell that effects peripheral tolerance in ACAID: (i) We propose that the profile of the genes upregulated in the ACAID CD4+ and CD8+ Treg cell will be distinct from the gene profile in immune T cells or na¿ve. (ii) We propose that the ACAID CD4+ Treg are not natural CD4 CD25 Tregs or dependent on them for their differentiation and that the unique genes that are up regulated in ACAID CD4+ Treg are critical for their function in the ACAID process, (iii) CD8+ regulatory T cells of ACAID use unique gene products to effect suppression of induction and expression of immunogenic inflammation. Absence of certain genes critical for T cell regulation leads to a breech in immune privilege and appearance ocular inflammation. To test these hypotheses we describe two specific aims: 1. To analyze the quality and mechanism of CD4+ T regulatory function in ACAID; 2: To explore the mechanisms of induction and expression of CD8+ Tregs in ACAID. Our long term goal is to push our understanding of ACAID and ocular immune privilege to the molecular level, and then to devise treatment strategies of very limited (or no) toxicity with which to prevent or suppress ocular inflammatory diseases (uveitis), (ii) to promote survival of orthotopic cornea and retinal grafts, and perhaps (iii) to alleviate multifactorial eye diseases.