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C. Terrada, B. Bodaghi, S. Fisson, P. Lehoang, D. Klatzmann, B. Salomon; Polyclonal CD4+CD25+ Regulatory T-Cells Modulate Intraocular Inflammation in Experimental Uveoretinitis: A Step forward to a Clinical Trial?. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1114.
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Natural Foxp3 regulatory T cells (Tregs) specific for a retinal antigen modulate uveoretinitis in mice. However, antigen specific Tregs can not be obtained so far in clinical grade condition. Thus, only polyclonal Tregs can be used in the clinics. In this study, we have compared the therapeutic effects of polyclonal versus antigen-specific Tregs, injected in the blood or in the vitreous.
In mice with stable expression of hemagglutinin (HA) in the retina, which was obtained after subretinal injection of an rAAV vector, uveitis was induced by intravenous administration of in vitro pre-activated 2 x 106 HA-specific T cells. Four days later, freshly purified or in-vitro pre-activated HA-specific or polyclonal Tregs were injected intravenously or intravitreally. Some mice received a second injection of pre-activated HA-specific T cells 21 days later to challenge their capacity to control a second wave of pathogenic cells. Intraocular inflammation was clinically and histologically studied in all animals.
Polyclonal Tregs can suppress uveitis but only when pre-activated and injected intravitreally whereas retinal-Ag-specific Tregs suppressed the disease after local or systemic injection. Furthermore retinal-Ag-specific Tregs, but not polyclonal Tregs, induced protection from a secondary challenge. Compared to intravenous injection, the effect observed after intravitreal injection was obtained with low number of cells and had the great advantage of inducing local immunosuppression in this confined organ without affecting the rest of the immune system.
Low number of polyclonal Tregs can be prepared in a clinical grade condition. Since low numbers of polyclonal Tregs regulate uveitis in our pre-clinical mouse model, a clinical trial of Treg cellular therapy may be envisaged in patients with severe uveitis who are refractory to conventional treatments.
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