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• W3190917259 abstract "While the ocular microenvironment normally expresses within its tissue microenvironment potent suppressors of inflammation, it is still susceptible, albeit rare, to autoimmune disease. Uveitis is a general term for intraocular inflammation that includes idiopathic inflammation assumed to be autoimmune in nature. The incidence rate of uveitis is 17–115 cases per 100,000 persons [[1]Gritz DC Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study.Ophthalmology. 2004; 111 (discussion PubMed PMID: 15019324): 491-500Summary Full Text Full Text PDF PubMed Scopus (573) Google Scholar,[2]Wakefield D Chang JH. Epidemiology of uveitis.Int Ophthalmol Clin. 2005; 45 (PubMed PMID: 15791154): 1-13Crossref PubMed Scopus (154) Google Scholar]. This makes it the third leading cause of blindness in the United States, and the standard therapy, like for most inflammatory diseases, is corticosteroids. This treatment is effective for many; however, as much as 60% of treated patients will have a recurrence of uveitis within 5 years and almost 18% of the patients become unresponsive to corticosteroid treatment to suffer chronic uveitis [[3]Teoh SC Dick AD. Diagnostic techniques for inflammatory eye disease: past, present and future: a review.BMC ophthalmology. 2013; 13 (PubMed PMID: 23926885. PMCID: PMC3750647. Epub 2013/08/10): 41Crossref PubMed Scopus (5) Google Scholar]. Therapeutic alternatives like biologics rely mostly on a trial-and-error approach to find an effective dose that balances between suppressing uveitis and susceptibility to infections and side effects [[4]Pasadhika S Rosenbaum JT. Update on the use of systemic biologic agents in the treatment of noninfectious uveitis.Biologics. 2014; 8 (PubMed PMID: 24600203. PMCID: PMC3933243): 67-81PubMed Google Scholar]. Each time an attempt fails vision is further degraded by the uveitis. Therefore, therapies that focus on the autoimmune activity targeting the eye with minimal side-effects would improve the health and quality of life for patients with chronic uveitis. The most common used animal model for uveitis is Experimental Autoimmune Uveitis (EAU) in mice. Many research groups have used EAU to not only understand the immunobiology of uveitis, but also evaluate the effects of therapeutic approaches to suppress uveitis. This model differs from human uveitis in that it is not spontaneous. Also, it resolves without intervention; however, there is substantial damage to the retina. This self-resolution of EAU is mediated by emergence of Treg cells with retinal-antigen specificity [[5]Silver PB Horai R Chen J Jittayasothorn Y Chan CC Villasmil R et al.Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis.J Immunol. 2015; 194 (PubMed PMID: 25716996. PMCID: PMC4459505. Epub 2015/02/27): 3011-3019Crossref PubMed Scopus (51) Google Scholar,[6]Lee DJ Taylor AW. Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice.J Immunol. 2013; 191 (PubMed PMID: 24043903. PMCID: PMC3796047. Epub 2013/09/18): 4103-4111Crossref PubMed Scopus (41) Google Scholar]. This has suggested that an approach that can augment Treg cell activity during uveitis can promote resolution, provide long term resistance to recurrence, and hopefully preserve vision. In the manuscript by Chen et al. [[7]Chen Z. Zhang T. Kam H. et al.Induction of antigen-specific Treg cells in treating autoimmune uveitis via bystander suppressive pathways without compromising anti-tumor immunity.EBioMedicine. 2021; 70103496Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar] they demonstrated an approach to expanding retinal-antigen specific Treg cells during EAU using anti-CD4-antibody (αCD4 Ab) therapy along with injecting retinal antigens. This generated antigen-specific Treg cells that suppress EAU. The approach to use αCD4 Ab is based on the idea that a systemic depletion of CD4 T cells would stop severe autoimmune disease with augmentation of Treg cells, which are refractory to αCD4 Ab-depletion [[8]Wofsy D Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4.J Exp Med. 1985; 161 (PubMed PMID: 3919141. PMCID: PMC2187572. Epub 1985/02/01): 378-391Crossref PubMed Scopus (398) Google Scholar,[9]Nagahama K Fehervari Z Oida T Yamaguchi T Ogawa O Sakaguchi S. Differential control of allo-antigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance.Int Immunol. 2009; 21 (PubMed PMID: 19228878. Epub 2009/02/21): 379-391Crossref PubMed Scopus (22) Google Scholar]. The depletion of CD4 T cells raises concerns about losing resistance to infection and tumor growth. As others have shown, Chen et al. showed that their approach did not diminish resistance to tumor growth; however, they did not test the possibility of impaired defense from infection. While the αCD4 Ab-therapy had induced a generic Treg cell response, which was effective in suppressing EAU, only when antibody-therapy was combined with retinal antigen injections was there seen substantial suppression of EAU and IL-17 production by effector T cells. This approach demonstrates the potential to drive in vivo an antigen-specific Treg cell. To explain the outcome of the therapy, Chen et al. propose that the antigen presenting cell (APC) uptake of apoptotic CD4 T cells along with the retinal antigen makes the APC present antigen in a manner to induce antigen-specific Treg cells. While their results support this possibility there are some interesting parallels with their findings and what is found when the mice self-resolve EAU [[5]Silver PB Horai R Chen J Jittayasothorn Y Chan CC Villasmil R et al.Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis.J Immunol. 2015; 194 (PubMed PMID: 25716996. PMCID: PMC4459505. Epub 2015/02/27): 3011-3019Crossref PubMed Scopus (51) Google Scholar,[6]Lee DJ Taylor AW. Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice.J Immunol. 2013; 191 (PubMed PMID: 24043903. PMCID: PMC3796047. Epub 2013/09/18): 4103-4111Crossref PubMed Scopus (41) Google Scholar]. Chen et al. show an antigen-specific accumulation of Treg cells in the eye. The accumulation of Treg cells within the eye is important for the self-resolution of EAU [[5]Silver PB Horai R Chen J Jittayasothorn Y Chan CC Villasmil R et al.Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis.J Immunol. 2015; 194 (PubMed PMID: 25716996. PMCID: PMC4459505. Epub 2015/02/27): 3011-3019Crossref PubMed Scopus (51) Google Scholar]. Also, there is in the spleens of self-resolving mice an APC that induces retinal-antigen specific Treg cells. Chen et al. found a Treg cell-inducing APC in the spleen; however, this induction of Treg cells is TGF-β-dependent, whereas in self-resolving EAU mice it is melanocortin and adenosine-dependent induction of Treg cells by the APC [[6]Lee DJ Taylor AW. Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice.J Immunol. 2013; 191 (PubMed PMID: 24043903. PMCID: PMC3796047. Epub 2013/09/18): 4103-4111Crossref PubMed Scopus (41) Google Scholar]. Interestingly, there is a known TGF-β-dependent pathway in the eye that induces an APC to mediate systemic tolerance to foreign antigen placed into the eye [[10]Taylor AW Ng TF. Negative regulators that mediate ocular immune privilege.J Leukoc Biol. 2018; 103 (PubMed PMID: 29431864. PMCID: PMC6240388. Epub 2018/02/13): 1179-1187Crossref Scopus (31) Google Scholar]. Whether the αCD4 Ab-treatment induces a similar APC is to be seen, but the ocular microenvironment is effective in inducing apoptosis in immune cells and could be the same apoptotic-inducing mechanism between αCD4 Ab treatment and injecting antigen into the eye. Since, the αCD4 Ab-therapy depletes the effector T cells this may be enough to enhance the self-resolving mechanisms with antigen specificity. While there remain many questions whether this can be translated into a safe and effective therapy for uveitis in humans, the approach does demonstrate the strength of looking at autoimmune disease therapy in a new way. Instead of applying general immunosuppressive or anti-inflammatory drugs with the hope that suppressing the inflammation will accord the tissue site and the immune system time to revert to normal, the work of Chen et al. promotes an approach that directly manipulates the behavior of immune cells from mediating an autoimmune disease to the ultimate desired mediators of antigen-specific tolerance. The work was solely written by AWT. AWT is a scientific consultant and recipient of a sponsored research agreement from Palatin Technologies, NJ, USA AWT is supported in part by a grant from the National Institutes of Health EY025961. Induction of antigen-specific Treg cells in treating autoimmune uveitis via bystander suppressive pathways without compromising anti-tumor immunityWe successfully addressed a specific immunotherapy of EAU by in vivo induction of autoantigen-specific Treg cells without compromising host overall T cell immunity, which should have potential implication for patients with autoimmune uveitis. Full-Text PDF Open Access" @default.
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• W3190917259 title "Tailoring immune cell behavior to stop autoimmune disease" @default.
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