Regulatory T Cell Therapy for Uveitis: A New Promising Challenge Arnaud Foussat, 1 Sylvie Gregoire, 2 Nathalie Clerget-Chossat, 1 Celine Terrada, 2,3 He ´ le ` ne Asnagli, 1 Franc ¸ ois M. Lemoine, 2 David Klatzmann, 4 Phuc LeHoang, 3,4 Miguel Forte, 1 and Bahram Bodaghi 3,4 Abstract Uveitis is a sight-threatening primary intraocular inflammation of various origins in mainly young and active patients. Due to the absence of biomarkers in most of the cases, the current treatment of noninfectious entities remains nonspecific, using corticosteroids, conventional immunosuppressors, and more recently biological agents. Identification of regulatory T cells in different models of autoimmune uveitis together with the eval- uation of this important subpopulation in different entities paved the way for new therapeutic strategies, in addition to exclusive pharmaceutical approaches. Upregulation of regulatory T cells induced by biological agents has been recently highlighted. Development of cell therapy in autoimmune diseases is at its stammering needing more experimental data and robust clinical trials to demonstrate safety and efficacy before larger developments. Specific or polyclonal Tregs may be used, but it is of utmost importance to determine the method of selection, the level of activation, and the route of administration. Mastering immune cell therapy remains a challenging goal in patients with autoimmune diseases, but it may significantly enlarge our therapeutic pos- sibilities in severe and refractory situations. Keywords: biological agents, blindness, experimental autoimmune uveoretinitis, immunosuppressors, regula- tory T cells, Treg, noninfectious uveitis Introduction C ell therapy and in particular the use of T cells for treating diseases has emerged as attractive target for new therapeutic strategies of translational medicine. The last 5 to 10 years have seen considerable efforts to understand generation, activation, and mechanisms of action of Tregs, leading to the development of tools and new promises of regenerative medicine, considered as breakthrough treat- ment modalities for the care of patients. This evolution forced the set-up of specific regulations from national Eu- ropean and FDA regulators to structure a framework for cell-based medicinal products. These combined elements have allowed faster development of new strategies using T cell-based immunotherapy. Most of T cell-based products in development aimed at fighting inflammation and cancer through the use of effector T cells isolated from the patient’s blood. These autologous T cells are either educated or engineered using molecular bi- ology tools to specifically recognize and kill a specific tumor or a cellular target infected by a specific pathogen. Recent clinical trials in oncology with effector T cells showed compelling results leading to bring the top pharmaceutical companies as well as worldwide investors to enter the field. Effector T cells represent one side of the immune system. On this side, T cell immunity can be viewed as an entity aimed at protecting the organism against pathogens, such as virus, bacteria, and against tumor development. This prop- erty is the basis of the development of T cell-based therapy in oncology and infectious diseases. However, a second side of T cell immunity coexists being directed to the estab- lishment of tolerance. This immune-mediated tolerance is part of the need to control the response of the body to our environment as external antigens that the organism has to classify as nonharmful constantly surrounding us. Immune Tolerance and Treg Cells Immune tolerance is mediated through multiple mecha- nisms. However, 1 T cell population emerged as leader: 1 Txcell SA, Valbonne, France. 2 Centre d’Immunologie et des Maladies Infectieuses (CIMI), Sorbonne Universite ´s, Paris, France. 3 Department of Ophthalmology, DHU ViewMaintain, Pitie ´-Salpe ˆtrie `re Hospital, Paris, France. 4 Laboratoire de Biologie et The ´rapeutique des Pathologies Immunitaires, UMR 7211 UPMC/CNRS, U972 INSERM, Paris, France. JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 33, Number 4, 2017 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2016.0165 278