In this study, we tested the efficiency of an intravitreal injection of tamoxifen, a non-steroidal estrogen receptor modulator, in retinal soluble antigen (S-Ag)-induced experimental autoimmune uveoretinitis (EAU). To increase the bioavailability of tamoxifen, we incorporated tamoxifen into polyethylene glycol (PEG)-coated nanoparticles (NP-PEG-TAM). The localization of the nanoparticles within the eye was investigated using fluorescent-labeled PEG-coated nanoparticles after injection into the vitreous cavity of rats with EAU. Some nanoparticles were distributed extracellularly throughout the ocular tissues, others were concentrated in resident ocular cells and in infiltrating macrophages. Whereas the injection of free tamoxifen did not alter the course of EAU, injection of NP-PEG-TAM performed 1-2 days before the expected onset of the disease in controls resulted in significant inhibition of EAU. NP-PEG-TAM injection significantly reduced EAU compared to injection of NP-PEG-TAM with 17b-estradiol (E2), suggesting that tamoxifen is acting as a partial antagonist to E2. Diminished infiltration by MHC class II + inflammatory cells and low expression of TNF-a, IL1b, and RANTES mRNA were noted in eyes of NP-PEG-TAM-treated rats. Intravitreal injection of NP-PEG-TAM decreased S-Ag lymphocyte proliferation, IFN-c production by inguinal lymph node cells, and specific delayed-type hypersensitivity indicative of a reduced Th1-type response. It increased the anti-S-Ag IgG1 isotype indicating an antibody class switch to Th2 response. These data suggest that NP-PEG-TAM inhibition of EAU could result from a form of immune deviation. Tamoxifen-loaded nanoparticles may represent a new option for the treatment of experimental uveitis.

Summary Pathological ocular manifestations result from a dysregulation in the balance between proinflammatory type 1 cytokines and regulatory type 2 cytokines. Interleukin‐10 (IL‐10) is an anti‐inflammatory cytokine with potent immunosuppressive effects. We have examined the efficiency of viral IL‐10 adenovirus (Ad‐vIL‐10)‐mediated gene transfer on experimental autoimmune uveoretinitis (EAU) induced in mice and rats by purified retinal autoantigens, respectively, interphotoreceptor binding protein (IRBP) and S‐antigen (S‐Ag). B10‐A mice that received a single unilateral injection of Ad‐vIL‐10 in the retro‐orbital sinus venosus performed 1 day before immunization with IRBP in the footpads showed high levels of circulating vIL‐10 in their sera and a significant reduction in pathological ocular manifestations. Lower levels of IFN‐γ and IL‐2 were found in cellular supernatants from IRBP‐stimulated splenic cells in these treated mice. The local effect on ocular disease of vIL‐10 was neutralized completely by injection of a monoclonal anti‐vIL‐10 antibody, demonstrating the specificity of the treatment. To determine whether the transfer of the vIL‐10 gene within the periocular tissues of the eye could prevent acute EAU, a subconjunctival injection of Ad‐vIL‐10 was performed in Lewis rats simultaneously with S‐­antigen in the footpads. This injection determined in situ vIL‐10 expression with very low circulating vIL‐10 and led to a significant reduction of EAU without affecting the systemic immune response. The present results suggest that Ad‐mediated gene transfer resulting in systemic and local expression of vIL‐10 provide a promising approach for the treatment of uveitis.

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The results suggest that T-cells from intraocular B-lymphomas are characterized by a Th1/Tc1-like profile that could be partially inhibited in vivo. These data raise the possibility of a T-cell immunostimulation to reactivate the Th1/Tc1-lymphocytes and improve intraocular antitumoral immunity.

Taken together, these results indicate that local immunomodulation was achieved and that no systemic adverse effects of TNF-alpha blockade observed after systemic injection of TNF-alpha inhibitors should be expected.