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Autoimmune Uveitis (autoimmune + uveitis)
Selected AbstractsGene transfer of disease regulated promoters during experimental autoimmune uveitisACTA OPHTHALMOLOGICA, Issue 2009V ELMALEH Purpose Adeno-associated virus (AAV) vectors have been successfully used to transfer immunosuppressive genes into the retina to prevent experimental uveitis development. Transgene expression is classically regulated by constitutive or tetracycline inducible promoters. It might be more advantageous that the control of transgene expression depends on the pathological process itself. Inflammation activates transcription factors acting on promoters containing short responsive sequences, responding, for example to nuclear factor kappa B (NF,B-RE). These responsive elements can be used to generate disease regulated promoters. Methods An AAV vector with the GFP gene under the control of a NF-kB-RE containing promoter will be injected subretinally in C57Bl6 mice. Autoimmune uveitis will be induced by adoptive transfer of IRBP specific lymphocytes. Animals will be sacrificed at different time points. GFP expression will be analysed by immunofluorescence. VCAM1, MHC II and CD45 will be analysed by immunofluorescence and used to monitor the level of retinal inflammation. Results One week after disease induction, GFP expression was found in eyes injected with this new vector. Milder GFP expression was also found in mice who did not received adoptive transfer. This background was increased a J14. Conclusion Our preliminary results suggest that disease driven GFP expression can be obtained by the use of AAV vectors containing disease regulated promoters. We still need some more times to improve our model. In the future, we plan to replace the GFP gene by an immunosuppressive gene and test if the system can be use to treat experimental uveitis. [source] The role of the ICOS/B7RP-1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2006Yoshihiko Usui Abstract ICOS/B7RP-1 is a new member of the CD28/B7 family of costimulatory molecules and plays differential roles in autoimmune diseases. In this study, we examined the role of ICOS/B7RP-1 pathway in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU), an animal model of human autoimmune uveitis. ICOS expression was found on infiltrating CD4+ T cells in the region of the retina in EAU-induced mice. The anti-B7RP-1 monoclonal antibody (mAb)-treated or ICOS-deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP-1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Moreover, administration of anti-B7RP-1 mAb effectively ameliorated the disease induced by adoptive transfer of pathogenic T cells. The anti-B7RP-1 mAb treatment inhibited the expansion and/or effector function of pathogenic T cells, given that proliferative response and IFN-, production by lymph node cells were reduced upon restimulation with the antigen peptide in vitro. These results suggest that the ICOS/B7RP-1 interaction plays a critical role in the pathogenesis of uveitis. We also indicated that ICOS-mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Th1 disease induced in the same manner as EAU. [source] Lymphotoxin,, receptor-Ig fusion protein treatment blocks actively induced, but not adoptively transferred, uveitis in Lewis ratsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2003Hui Shao Abstract Previous studies have shown that treatment of rodents with a lymphotoxin (LT),, receptor-Ig fusion protein (LT,R-Ig), which binds to both LT and LIGHT, prevents the development of autoimmune diseases, but the mechanism involved is unclear. To explore the potential role of LT or LIGHT in the pathogenesis of autoimmune uveitis, uveitis was induced in Lewis rats either by immunization with an uveitogenic peptide, R16, derived from the interphotoreceptor retinoid-binding protein, or by adoptive transfer of R16-specific T,cells. Interestingly, LT,R-Ig treatment completely prevented actively induced uveitis, but not the adoptively transferred disease. We also show that LT,R-Ig-treated R16-injected rats had a significantly decreased T,cell response to R16 and that herpesvirus entry mediator (HVEM)-Ig, a fusion protein that blocks LIGHT, also inhibited disease development. Our results suggest that LT or LIGHT plays a critical role in the induction, rather than the effector, phase of the disease. [source] 4254: Infectious and non infectious triggers in non-infectious uveitisACTA OPHTHALMOLOGICA, Issue 2010G WILDNER Purpose The induction of autoimmune uveitis is difficult to explain with respect to the immune privileged status of the eye. The intact BRB can only be passed by already activated leukocytes, which should normally be ignorant to the sequestered intraocular antigens. Antigenic mimicry of retinal autoantigens by environmental proteins could explain extraocular activation of effector T cells. Methods We have previously demonstrated antigenic mimicry of a peptide from retinal S-Antigen and peptides from rotavirus (Rota) and bovine milk casein (Cas). Both, Rota and Cas, induce T cell lines cross-reactive with retinal S-Ag peptide as well as experimental autoimmune uveitis in rats. Patients with uveitis have increased antibody and T cell responses to the mimicry peptides as well as to the S-Ag peptide compared to healthy donors. Accordingly, Infection with rotavirus or any gastrointestinal pathogen with concomitant ingestion of bovine milk products could induce an immune response in the gastrointestinal tract that is cross-reactive with ocular autoantigens and lead to induction of autoimmunity in the eye. Results Uveitis as a well known adverse effect after BCG (Bacille Calmette Guerin) treatment might also be the result of antigenic mimicry. We have shown T cell responses to PPD from M. tuberculosis and the retinal autoantigens S-Ag, IRBP and CRALBP from a patient who had developed granulomatous uveitis after BCG application for bladder carcinoma. Data base searches revealed a number of amino acid sequence homologies between proteins from mycobacteria and retinal autoantigens, suggesting antigenic mimicry. These findings might as well be an explanation for the occurrence of uveitis in connection with M. tuberculosis infection, even when no mycobacteria are detectable in the eye. [source] 2262: Study of the role of P2Y receptors in the development of experimental autoimmune uveitisACTA OPHTHALMOLOGICA, Issue 20103Article first published online: 23 SEP 2010, L JUDICE DE MENEZES RELVAS Purpose During autoimmune uveitis (AU), retinal specific auto-reactive T lymphocytes (TL) are activated, alter blood retinal barrier(BRB) and penetrate the eye where they start an inflammatory reaction. Nucleotides, normally present at low concentration in extracellular media, can act as a danger signal, through P2 receptors activation and might be implicated in AU. In this work we would like to investigate if the expression of the nucleotide receptor P2Y2 has any role in experimental autoimmune uveitis (EAU). Methods EAU will be induced in WT and P2Y2 KO mice by IRBP peptide 1-20 injection. 12 days later, TL from spleen and lymph nodes will be purified and restimulated by IRBP. TL proliferation will be measured by thymidine incorporation and cytokines secretion by ELISA. TL from the 2 groups of mice will also be adoptively transfered in WT mice. Similarly, TL from WT mice will be adoptively transfered in WT and P2Y2 KO mice. EAU development will be graded by clinical and histological scores. Results TL generated in KO mice proliferate and produce less IFN, and IL-17, after IRBP restimulation than TL generated in WT mice. Accordingly, adoptive transfer of TL generated in KO mice induce significantly a lower grade of disease than those generated in WT mice. Finally, adoptive transfer of TL generated in WT mice induce disease of significantly lower grade in KO mice recipient than in WT mice recipient. Conclusion Our preliminary data shows that P2Y2 KO mice have a defective immune response after immunisation and develop lower intraocular inflammation following adoptive transfer with TL. Altogether this suggests that P2Y2, as danger receptor signals, play an important role in the development of uveitis. [source] 2263: Analysis of the utility of QuantiFERON-TB GoldTM in tube and measurement of IFN, release by peripheral mononuclear cells in response to different mycobacterium antigen in the work-up of patients with uveitisACTA OPHTHALMOLOGICA, Issue 2010D MAKHOUL Purpose Tuberculosis remains an important cause of infectious uveitis and immune reaction against mycobacteria may contribute to the development of certain forms of autoimmune uveitis. Moreover, many non-infectious uveitis patients are treated with immunomodulatory treatment. The evaluation of tuberculosis immunity is thus an important aspect in the work-up of patients with uveitis. In this work, we would like to investigate the usefulness of different methods of tuberculosis immunity testing in a series of patients with intraocular inflammation. Methods Patients with uveitis will undergo a standard diagnosis procedure, including a chest Xray. Quantiferon TB Gold in Tube (QFT) and tuberculin skin test (TST) will be performed. IFN, production by mononuclear cells in response to PPD and to HBHA will be measured by ELISA. Results Thirty-two patients have already been recruited. Sixteen had a negative QFT and a negative TST. In two of them, mononuclear cells produce IFN, in response to PPD (but not to HBHA) and in 1 in response to HBHA (but not to PPD). In 11 patients QFT and TST were positive. In this group, IFN, response to PPD was observed in 82% but only in 50% in response to HBHA. Discordant results between QFT and TST were observed in 5 patients. One had a positive QFT and a negative TST and 4 had a positive TST and a negative QFT. In this group IFN, response to PPD or HBHA was not observed. Conclusion Discordant results between QuantiFERON-TB Gold and TST were observed in 15 % of uveitis patients. Analysis of the IFN, production in response to PPD and to HBHA seems to add important information in both concordant and discordant group. [source] Regional Immunity of the EyeACTA OPHTHALMOLOGICA, Issue 3 2010Manabu Mochizuki Abstract. This article reviews molecular mechanism of intraocular inflammation in animal models and in humans, and the immunological defence system of the eye with particular attention to ocular pigment epithelium. In experimental autoimmune uveitis (EAU), T lymphocytes, particularly CD4+ T lymphocytes, play a central role in its immunopathogenic mechanisms. In humans, activated CD4+ T cells also play a central role in the immunopathogenic mechanisms. This notion is demonstrated in two human diseases: one is Vogt,Koyanagi,Harada disease, and the other is human T-cell leukemia virus type 1 (HTLV-1) uveitis. Activated CD4+ T cells infiltrating the eye are harmful to vision-related cells and tissues in the eye and cause sight-threatening conditions. However, the eye has regional defence systems to protect itself from these harmful activated T cells. We focus on ocular pigment epithelium (PE) and demonstrate immunoregulatory activity of iris PE and retinal PE. Iris PE suppresses activated CD4+ T cells by cell-to-cell contact with a crucial role played by B7-2 molecule on iris PE and CTLA4 on T cells. The actual immunosuppressive factor being membrane bound TGF-,. In contrast, retinal PE suppresses activated CD4+ T cells by soluble factors, such as soluble TGF-, and thrombospondin 1. In addition to the direct T-cell suppression by ocular PE, ocular PE has the capacity to promote activated T cells to regulatory T cells and use them as a tool to amplify the immune down regulation in the eye. The molecular mechanisms of generation of T regulatory cells by iris PE and retinal PE is also discussed. [source] In vivo imaging of retinal inflammation in experimental autoimmune uveoretinitisACTA OPHTHALMOLOGICA, Issue 2009Purpose Experimental animal models are essential for us to understand the pathogenesis of human diseases. Posterior uveoretinitis can be modelled in mice with IRBP immunization (i.e. experimental autoimmune uveitis, EAU), whereas a number of mouse models are also available for age-related macular degeneration (AMD). With the advancement in new technologies, it is now possible to image inflammatory retinal changes in experimental mice in vivo none invasively. The aim of the study is to clinical revisit the traditional retinal inflammation animal models with modern imaging techniques. Methods EAU was induced in C57B/6 mice with IRBP peptide 1-20. Aged CCL2 knockout mice were used as an AMD model. Retinal inflammatory changes were imaged in vivo non-invasively using topical endoscopic fundus imaging system and the scanning laser ophthalmoscopy (SLO) system. Results Inflammatory retinal changes in the early stages of EAU were characterised as retinal oedema, vascular sheathing, multiple small retinal infiltrates or large linear retinal infiltrates. "Snow-ball"-like vitreous infiltrates were observed in the inferior part of the fundus at the peak stage of EAU. Using SLO autofluorescent (AF)-macrophages were detected at the peak stages of EAU and were located predominately around inflamed retinal venules. At the late stages of EAU, retinal scars and intraretinal neovascular membranes were observed. In the retina aged CCL2 KO mice, regional retinal atrophy and dursen-like multiple lesions were observed. Dursen-like changes were autofluorescent in SLO examination. Ex vivo confocal microscopy indicated that they were not dursen but subretinal lipofuscin-loaded microglial cells. Conclusion EAU mimics many aspects of human posterior uveoretinitis including retinal vasculitis, multifocal choroiditis. Late stage EAU could be a good model for inflammation induced retinal neovascularisation. CCL2 KO mouse is a model of dry-AMD. [source] Gene transfer of disease regulated promoters during experimental autoimmune uveitisACTA OPHTHALMOLOGICA, Issue 2009V ELMALEH Purpose Adeno-associated virus (AAV) vectors have been successfully used to transfer immunosuppressive genes into the retina to prevent experimental uveitis development. Transgene expression is classically regulated by constitutive or tetracycline inducible promoters. It might be more advantageous that the control of transgene expression depends on the pathological process itself. Inflammation activates transcription factors acting on promoters containing short responsive sequences, responding, for example to nuclear factor kappa B (NF,B-RE). These responsive elements can be used to generate disease regulated promoters. Methods An AAV vector with the GFP gene under the control of a NF-kB-RE containing promoter will be injected subretinally in C57Bl6 mice. Autoimmune uveitis will be induced by adoptive transfer of IRBP specific lymphocytes. Animals will be sacrificed at different time points. GFP expression will be analysed by immunofluorescence. VCAM1, MHC II and CD45 will be analysed by immunofluorescence and used to monitor the level of retinal inflammation. Results One week after disease induction, GFP expression was found in eyes injected with this new vector. Milder GFP expression was also found in mice who did not received adoptive transfer. This background was increased a J14. Conclusion Our preliminary results suggest that disease driven GFP expression can be obtained by the use of AAV vectors containing disease regulated promoters. We still need some more times to improve our model. In the future, we plan to replace the GFP gene by an immunosuppressive gene and test if the system can be use to treat experimental uveitis. [source] Role of ocular pigment epithelial cells in regional ocular immunityACTA OPHTHALMOLOGICA, Issue 2008S SUGITA Purpose To whether soluble factors by retinal pigment epithelial cells (RPE) promote the generation of T regulatory cells in vitro. Methods Primary cultured RPE cells were established from normal C57BL/6 mice. T cells were co-cultured with RPE, x-irradiated, and used as regulators (RPE Treg cells). Target bystander T cells were established from normal splenic T cells with anti-CD3 antibodies. T-cell activation was assessed for proliferation by [3H],thymidine incorporation. Expression of cytotoxic T lymphocyte antigen-2, (CTLA-2,) and cathepsin L on RPE and T cells was evaluated with oligonucleotide microarray, RT-PCR, immune staining, western blots and flow cytometry. Recombinant mouse CTLA-2, and anti-mouse CTLA-2, abs were used for the assay. For induction of experimental autoimmune uveitis (EAU), mice were immunized with interphotoreceptor retinoid-binding protein peptide emulsified in complete Freund's adjuvant. Results RPE converted CD4+ T cells into Treg cells by producing and secreting CTLA-2,, a cathepsin L inhibitor. CTLA-2, secreted by RPE cells selectively inhibited cathepsin L in the T cells and the cathepsin L-lacking T cells exhibited Treg phenotype, i.e. expression of Foxp3 and production of transforming growth factor beta (TGF,). CTLA-2, enhanced their production of active forms of TGF,. In addition, CD4+ T cells from EAU-induced cathepsin L knockout (KO) donors contained high population of Foxp3+ T cells and EAU in cathepsin L KO mice was significantly less than those in wild type mice. Furthermore, treatment with recombinant CTLA-2, significantly suppressed EAU. Conclusion These results indicate that immunosuppressive factors derived from RPE participate in the establishment of immune regulation in the posterior segment of the eye. [source] | ||||||||||