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B. Bodaghi, C. Terrada, S. Gregoire, Y. de Kozak, D. Klatzmann, P. LeHoang, B. Salomon; Contamination of Regulatory T Cells With 20% Polyclonal Effector T Cells Does Not Impair Suppression of Experimental Autoimmune Uveoretinitis After Intravitreal Administration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):825.
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© ARVO (1962-2015); The Authors (2016-present)
Administration of regulatory T cells (Tregs) in auto-immune diseases is a promising therapeutic strategy. Intra-vitreal injection of in vitro pre-activated polyclonal Tregs has been previously evaluated in a murine model of uveoretinitis, achieving the regulation of intraocular inflammation. The aim of the present study is to evaluate the regulatory effect after contamination of Tregs by effector T cells and disemination of Tregs in lymph nodes after intravitreal injection.
In mice expressing hemagglutinin (HA) in the retina after subretinal injection of rAAV 2/5, uveitis was induced by intravenous administration of 2 x 106 activated HA-specific effector T cells. These cells were obtained from purified Thy-1.1 TCR-HA CD25- cells and stimulated by BALB/c dendritic cells and HA peptide for 4 days. Three days later, activated polyclonal BALB/c CD4+CD25+ T cells were injected intravitreally. Polyclonal Tregs were contaminated with 10%, 20% or 50% polyclonal effectors T cells during activation. Intraocular inflammation was clinically and histologically studied in all animals. T regs dissemination was studied in cervical and inguinal lymph nodes using FACS analysis.
CD4+CD25+ Polyclonal Tregs suppressed the disease after local injection even in cultures contaminated with 10 to 20% of CD4+CD25- effector T cells, similar to what we observed with a purified preparation of polyclonal Tregs. Furthermore, dissemination was limitated to 0.01% of T cells in cervical lymph nodes and undetectable in inguinal lymph nodes.
These results support the relevance of a therapeutic strategy based on polyclonal regulatory T cells in non infectious uveitis. The efficacy of this approach is correlated to the suppressive bystander effect of activated Tregs in the target tissue. Safety issues are respected and allow us to propose a clinical trial.
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