Inhibition of Noninfectious Uveitis Using Intravenous Administration of Collagen II-Specific Type 1 Regulatory T Cells.

Abstract

PURPOSE:

To evaluate the therapeutic potential of Col-Treg, a collagen II-specific type 1 regulatory T-cell immunotherapy for the treatment of noninfectious uveitis (NIU).

METHODS:

Col-Treg cells were produced from collagen II-specific T cell receptor (TCR) transgenic mice or peripheral blood of healthy donors. Phenotypic characterization was performed by flow cytometry, and cytokine secretion was evaluated with Flowcytomix or ELISA. In vitro functional characterization included ATP hydrolysis, cytotoxicity, and contact-independent T-cell suppression and plasticity assays. Col-Treg migration was assessed by quantitative PCR specific to Col-Treg TCR. Col-Treg cells were administered intravenously in mice displaying experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP) immunizations. Efficacy of Col-Treg was assessed by ophthalmology, histology, and immunohistochemistry.

RESULTS:

Mice Col-Treg cells displayed identity features of type 1 Treg cells with expression of CD25, FoxP3, low surface expression of CD127, and cytokine secretion profile (IL-10(high), IL-4(low), IFN-γ(int)). In vitro functional assays demonstrated Col-Treg suppressive capacity via soluble factor-dependent immunosuppression, cytotoxicity, and ATP hydrolysis. Col-Treg cells expressed granzyme B, CD39, and glucocorticoid-induced TNF-related protein (GITR). Administration of Col-Treg in EAU mice inhibited clinical and morphologic signs of uveitis and decreased ocular leukocyte infiltration. Col-Treg cells homed in the ocular tissues 24 hours after intravenous injection. Human Col-Treg cells were comparable to mice Col-Treg cells in identity and function and did not show the capacity to differentiate into Th17 cells in vitro.

CONCLUSIONS:

These results demonstrate the therapeutic potential of Col-Treg cells as a targeted approach for the treatment of NIU and the feasibility of translating this approach to the human clinical setting.

• Authors: Hélène Asnagli, Marie Jacquin, Nathalie Belmonte, Julie Gertner-Dardenne, Marie-Françoise Hubert, André Sales, Papa Babacar Fall, Clémence Ginet, Irène Marchetti, Frédérique Ménard, Grégory Lara, Nicole Bobak, Arnaud Foussat
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 56 Issue 11 Pg. 6456-66 (Oct 2015) ISSN: 1552-5783 [Electronic] United States
• PMID: 26447979 (Publication Type: Journal Article)

Chemical References

• Collagen Type II

Topics

• Animals
• Collagen Type II (administration & dosage, immunology)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Immunity, Cellular
• Immunotherapy (methods)
• Injections, Intravenous
• Mice
• Mice, Inbred DBA
• Mice, Transgenic
• T-Lymphocytes, Regulatory (immunology)
• Uveitis (immunology, pathology, therapy)