Blockade of Costimulation Through B7/CD28 Inhibits Experimental Autoimmune Uveoretinitis, But Does Not Induce Long-Term Tolerance

Abstract

It has been reported that costimulation blockade can result in T cell anergy. We investigated the effects of blocking costimulatory molecules in vivo on the development of experimental autoimmune uveoretinitis (EAU), a model for autoimmune uveitis in humans that is induced in mice by immunization with the retinal Ag interphotoreceptor retinoid binding protein. B10.A mice immunized with a uveitogenic regimen of interphotoreceptor retinoid-binding protein were treated with Abs to B7.1 and B7.2 for 2 wk. Evaluation of EAU and immunological responses 1 wk later showed that disease had been abrogated, and cellular responses were suppressed. To determine whether the costimulation blockade resulted in tolerance, adult-thymectomized mice immunized for uveitis and treated with anti-B7 or anti-CD28 were rechallenged for uveitis induction 5 wk after the initial immunization. Although confirmed to be disease free after the initial immunization, both anti-B7- and anti-CD28-treated mice developed severe EAU and elevated cellular responses after the rechallenge, equivalent to those of control mice. We conclude that in this model costimulatory blockade in vivo prevents the development of autoimmune disease, but does not result in long-term tolerance. The data are compatible with the interpretation that B7/CD28 blockade prevents generation of effector, but not of memory, T cells.

The role of the ICOS/B7RP‐1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitis

“…The retinal antigen-specific Th1 cells then target the neural retina where the endogenous antigen is located and elicit an inflammatory response, resulting in progressive and irreversible destruction of the retinal photoreceptor cell layer. Some costimulatory molecules, such as CD28/B7 and CD40/CD154, appear to play important roles in the pathogenesis of EAU [8,9,28]. For example, the blockade of CD28/B7 pathway with anti-CD80/CD86 mAb inhibited the development of EAU [8,9] and CD28-deficient mice were highly resistant to EAU (Y. Usui and H. Akiba, unpublished observation).…”

“…Some costimulatory molecules, such as CD28/B7 and CD40/CD154, appear to play important roles in the pathogenesis of EAU [8,9,28]. For example, the blockade of CD28/B7 pathway with anti-CD80/CD86 mAb inhibited the development of EAU [8,9] and CD28-deficient mice were highly resistant to EAU (Y. Usui and H. Akiba, unpublished observation). In contrast to CD28, ICOS is not expressed constitutively but is up-regulated following T cell activation.…”

“…CD28 is expressed on naive T cells and plays a critical role in the initial activation of naive T cells. Blockade of CD28/B7 pathway has been shown to ameliorate experimental autoimmune diseases such as lupus, arthritis, experimental autoimmune encephalomyelitis (EAE), and experimental autoimmune uveoretinitis (EAU) [5][6][7][8][9].…”

Ocular transfer of retinal glial cells transduced ex vivo with adenovirus expressing viral IL-10 or CTLA4-Ig inhibits experimental autoimmune uveoretinitis

“…58,59 In EAU, the CD28 pathway of costimulation is necessary to induce EAU, as systemic administration of antibodies to B7-1 and B7-2 during antigen challenge prevents the development of the disease and inhibits immunological responses. 8 We thus investigated the possibility of delivering CTLA4 by injection of genetically manipulated cells to inhibit EAU. Local expression of CTLA4 after intravitreal administration of RMG-CTLA4 inhibited the disease, more effectively than RMG-vIL-10 injection compared to controls (39% protection in RMG-CTLA4 treated rats versus 29% in RMG-vIL-10-treated rats), suggesting the importance of costimulatory molecules in the effector stage of EAU.…”

“…Interestingly, immune privilege of the eye has been attributed to a number of factors including IL-10 production. In addition, systemic injections of IL-10 6 and systemic administration of antibodies to B7.1 and B7.2 8 limit expression of the experimental uveitis, but, due to a short half-life, daily injections of these regulatory molecules have been needed to obtain this protection.…”