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The visual axis of the eye focuses light images precisely on the retina. The retina is intolerant of distortion that might be induced by innate or immune inflammation. In addition, the corneal endothelium and the neurosensory retina are unable to regenerate if injured by trauma or inflammation. Within the environment of this visual organ a phenomenon called ocular immune privilege provides the eye with the necessary immune protection against infectious agents by allowing the expression of the least deleterious immune effector mechanisms. Moreover, the mechanisms of immune privilege are multiple, overlapping, and include both active and passive suppression of innate and immune inflammation. At the very basis of an effective immune response are cellular interactions and their cross talk. Central to the ability of cells to communicate are the intercellular channels that are established to isolate signals and movement of proteins between cells. Within this secure nano-environment, cells signal each other and even exchange proteins. Studies reviewed here are centered on knowledge and exploration of the tolerogenic synapse rather than the immunogenic synapse. The unique cells (invariant natural killer T cells, F4/80+ antigen-presenting cells, and T and B lymphocytes) that cluster within the marginal zone following injection of antigen in the anterior chamber (AC) express a phenotype of cell surface molecules that that seem to be uniquely critical for the development of AC-associated immune deviation. How these cell surface molecules behave during the cellular interactions that result in the development of regulatory T cells and peripheral tolerance induced through the eye is discussed.

Anterior chamber (AC)-associated immune deviation (ACAID) is a form of ocularderived peripheral tolerance that helps to maintain the immune privilege of the eye by suppressing both the priming and elicitation of adaptive immune responses. ACAID is known to facilitate the survival of corneal grafts and suppression autoimmune uveitis in the eye. Intravenous inoculation of in vitro generated ACAID tolerance-inducing antigen presenting cells (APCs) treated with transforming growth factor-Beta2 (tolerogenic APCs) generates the kind of T regulatory cells found in in vivo ACAID when antigen is inoculated into the AC of the eye. Here, we review the application of peripheral tolerance induction by ACAID with either AC inoculation or in vitro generated tolerogenic ACAID-APCs in suppressing ongoing Th1- and Th2-mediated immune pathogenesis in naive and presensitized hosts. Transfer of tolerogenic APCs has suppressed antigen-specific immune inflammation in animal models of experimental autoimmune encephalomyelitis, hapten immune pulmonary interstitial fibrosis, and ovalbumin-induced allergic pulmonary inflammation. The possibility of immune therapy by in vitro generated ACAID-like tolerogenic APCs in humans is discussed.