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Abstract Number: 52

Interferon-Alpha Protects Against Pain and Joint Damages in Experimental Arthritis and Is Associated with Expansion of Highly Suppressive Regulatory T Lymphocytes in Protected Mice and in Tocilizumab-Treated Rheumatoid Arthritis Patients

Matthieu Ribon1, Roxane Hervé2, Delphine Lemeiter2, Katarzyna Matyja1, François Santinon1, Darragh Duffy3, Ken Tsumiyama4, Shunichi Shiozawa5, Marie-Christophe Boissier6, Natacha Bessis2 and Patrice Decker1, 1Inserm UMR 1125, Li2P, University of Paris 13, Sorbonne Paris Cité, Bobigny, France, 2Li2P, University of Paris 13, Sorbonne Paris Cité, Bobigny, France, 3Institut Pasteur, Paris, Paris, France, 4Department of Medicine, Rheumatic Diseases Unit, Kyushu University Beppu Hospital, Beppu, Japan, 5Institute for Rheumatic Diseases, Nagahama, Japan, 6Rheumatology Department, AP-HP, Avicenne Hospital, Bobigny, France

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Animal models, interferons, rheumatoid arthritis (RA) and therapeutic targeting, T-Regulatory Cells

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Session Information

Date: Sunday, October 21, 2018

Title: Rheumatoid Arthritis – Animal Models Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Type I interferons (IFN-I) can be both anti- and pro-inflammatory. Among them, IFN-α inhibits normal Th17 differentiation, whereas it is pathogenic in lupus. The role of IFN-I is controversial in rheumatoid arthritis (RA) and experimental models. An IFN-I signature has been reported in RA patients, the signification of which is unclear. In mice, IFN-I enhance or inhibit arthritis development according to IFN subtype, arthritis model and kinetics. We aimed to evaluate the therapeutic effect of IFN-α in collagen-induced arthritis (CIA) and its relation with regulatory T lymphocytes (Treg) in RA patients, where Treg are functionally deficient.

Methods: CIA was induced by 2 immunizations with collagen/CFA. Disease development was studied in conditional transgenic mice over-expressing mouse IFN-α1 and non-transgenic littermates after cessation of doxycyclin administration (Tet-off system). Arthritis was followed by clinical evaluation. Inflammation/bone destruction were estimated by histology. Pain was followed by Von Frey tests. Plasma cytokines/anti-collagen antibodies were measured by Luminex/ELISA. Leukocytes sub-populations and Th polarization were analyzed by flow cytometry. Osteoclasts were prepared from the bone marrow (BM) after culture with M-CSF/RANKL. CD4+CD25+ Treg and CD4+CD25– effector T cells (Teff) were purified by magnetic sorting. ATPase activity was determined in vitro. Treg inhibition of Teff activation was measured by flow cytometry/ELISA. The in vivo therapeutic capacity of purified Treg was estimated by adoptive transfer. Blood Treg (CD4+FoxP3+CD25+CD127low) and suppressive phenotype (CD39 expression) were analyzed by flow cytometry in RA patients before and 3 months after anti-IL-6-receptor therapy. Plasma IFN-α concentrations were measured by digital ELISA.

Results: IFN-α1 induction by doxycyclin cessation before the first or even between both immunizations resulted in CIA protection/lower pain in transgenic mice. Anti-collagen antibody and IL-6 productions were lower in IFN-α1+ mice. Protected mice show decreased polarization to Th17 and increased polarization to Th2 and IFN-γ-positive Th1/NK cells. CIA protection in IFN-α1-overexpressing mice was associated with lower osteoclastogenesis and osteoclast activity, altered BM-B cells, increased BM-CD86+ neutrophils, and particularly expansion of Treg with higher CD39/CTLA-4 expression, higher ATPase activity and higher suppressive capacity on Teff. Importantly, adoptive transfer of these Treg purified from CIA-IFN-α1+ mice impaired CIA development in recipients in comparison to Treg purified from CIA-IFN-α1– mice. In RA patients, therapy blocking IL-6 signalling was associated with increased IFN-α plasma concentrations and in vivo expansion of Treg after 3 months, with increased CD39 expression. Most importantly, blood IFN-α and Treg frequencies were correlated in these patients. Thus, results in CIA mimic thus these obtained in RA patients.

Conclusion: IFN-α1 protects against inflammatory arthritis, even in mice already seropositive, clarifying its role and showing its potent modulatory or therapeutic effect. In RA patients, IFN-α might serve as a biomarker in response to treatment.


Disclosure: M. Ribon, None; R. Hervé, None; D. Lemeiter, None; K. Matyja, None; F. Santinon, None; D. Duffy, None; K. Tsumiyama, None; S. Shiozawa, None; M. C. Boissier, None; N. Bessis, None; P. Decker, None.

To cite this abstract in AMA style:

Ribon M, Hervé R, Lemeiter D, Matyja K, Santinon F, Duffy D, Tsumiyama K, Shiozawa S, Boissier MC, Bessis N, Decker P. Interferon-Alpha Protects Against Pain and Joint Damages in Experimental Arthritis and Is Associated with Expansion of Highly Suppressive Regulatory T Lymphocytes in Protected Mice and in Tocilizumab-Treated Rheumatoid Arthritis Patients [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/interferon-alpha-protects-against-pain-and-joint-damages-in-experimental-arthritis-and-is-associated-with-expansion-of-highly-suppressive-regulatory-t-lymphocytes-in-protected-mice-and-in-tocilizumab/. Accessed .
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