Immunotolerance and prevention of ocular autoimmune disease

Abstract

Immunotherapeutic approaches to autoimmune disease have a common goal of inducing antigen-specific, long-lasting tolerance to autoantigens, without otherwise compromising the immune response. Here we review some of the most interesting experimental advances in this area. We discuss the use of T cell targeting drugs that have been reported to induce long lasting tolerance to ocular antigens. Strategies involving the targeting of idiotypic and clonotypic determinants associated with ocular autoimmunity, such as idiotypic network manipulation and T cell vaccination, are reviewed. The use of cytokines to promote perturbation of the Th1/Th2 balance with its possible implications for treatment of uveitis, is analysed. Finally, we review tolerogenic strategies based on acquisition of tolerance following presentation of antigen through alternative routes, such as injection of antigen into the anterior chamber, intravenous infusion of antigen, and oral administration of retinal antigens. Special emphasis is placed on the last strategy, since there are ongoing clinical trials using oral tolerance as an immunotherapeutic approach to treat autoimmune diseases, among them uveitis.

Intranasal Administration of Retinal Antigens Induces Transient T cell Activation and Apoptosis within Drainage Lymph Nodes but not Spleen

“…The results presented here are consistent with other descriptions of mechanisms of low dose tolerance induction via either the oral or nasal routes which suppress models of autoimmune disease [14,51]. However, this present work furthers these observations by documenting that in this model tolerance can be transferred via splenic derived T cells but not drainage lymph nodes.…”

Interphotoreceptor retinoid binding protein is a potent tolerogen in Lewis rat: suppression of experimental autoimmune uveoretinitis is retinal antigen specific

“…Recently Rizzo et al  22 have proposed, using a murine model of autoimmunity, that the mechanisms of oral tolerance with IRBP, be it T cell anergy or active cytokine driven suppression, depend on dose of antigen fed and concomitant IL-2 levels. Oral tolerance has been described with other models,8-12 where in general it has been described that low dose feeding of antigen gives rise to TGF-β secreting CD8 + T cell suppression or cytokine driven suppression (for example, IL-4) and high dose antigen feeding results in clonal anergy (for review see Rizzo and Caspi23). In the light of other data, this perhaps is an oversimplistic explanation of what is happening in vivo, which shows a fine balance between exacerbation or suppression of the immune response.…”

Experimental Autoimmune Uveoretinitis in the Rat and Mouse

“…Success of a given modality in down-regulating EAU in animals has served as a good predictor of its clinical usefulness. Basic questions that are being addressed using these models include the genetic control of susceptibility versus resistance to ocular autoimmunity, the cellular and molecular mechanisms that contribute to maintenance or breakdown of tolerance to organ-specific antigens, and the immunological events that constitute the autoimmune amplification cascade that culminates in the expression of disease (Caspi and Nussenblatt, 1994;Gery and Streilein, 1994;Rizzo and Caspi, 1995;reviewed in Caspi, 1993). Thus, EAU is useful as a tool for clinical as well as for basic studies of ocular and organ-specific autoimmunity.…”