The unique nature of ocular immunity is characterized by anterior chamber associated immune deviation (ACAID), an unusual immune response that is eye characterized by suppressed DH induced to antigens introduced in the anterior chamber. Such an immune response is systemic in nature. Indigenous ocular antigen presenting cells are known to induce a unique type of antigen-specific regulatory cell population in the spleen which is believed to be responsible for suppressed DH responses in ACAID. While it is known that various factors in the ocular environment influence antigen presenting cells to modify their function such that these cells acquire the ability to induce ACAID, the exact mechanisms by which these APCs acquire and express this unique ability is not dearly understood. A cytokine found in abundance in the ocular environment, TGFP, has been demonstrated to play a significant role in functional modification of APCs thereby conferring upon them the ability to induce ACAID. We propose to study molecular mechanisms underlying ACAID induction by examining changes induced within these cells at genetic levels, by TGF[3, changes which in turn lead to functional alterations of an APC. Taking advantage of the latest advances in molecular biology techniques we have successfully compared the transcriptional program of conventional APCs with that of ACAID-inducing APCs. Applying differential display analysis (using RAP-PCR) we have identified genes uniquely expressed by the APCs that functionally resemble eye- derived APCs. Furthermore, we have recently employed DNA microarray technology to accomplish a more comprehensive analysis of expression profiles of these APCs. We now propose to first determine which of the differentially expresssed genes are reasonable candidates for ACAID induction based on our current knowledge of the immune response in ACAID and the available literature. We then adopt a systematic approach, employing various strategies (such as antisense inhibition, antibody or antagonist mediated inhibition, use of transgenic mice selectively deficient in certain genes, induction by chemical or pharmacological . agents or gene transfection) to study the functional relevance to ACAID of the selected candidate genes. Such an approach to examine involvement of specific gene products in conferring unique functional capabilities on eye-derived APCs will not only enhance our understanding of carefully regulated ocular immune responses but give rise to suggested therapies by which the ocular microenvironment can be selectively manipulated.
| Masli, Sharmila; Turpie, Bruce; Streilein, J Wayne (2006) Thrombospondin orchestrates the tolerance-promoting properties of TGFbeta-treated antigen-presenting cells. Int Immunol 18:689-99 |
| Streilein, J Wayne; Masli, Sharmila; Takeuchi, Masaru et al. (2002) The eye's view of antigen presentation. Hum Immunol 63:435-43 |
