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.
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 10). 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 December 9, 2019.
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ACR Meeting Abstracts - 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/