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 also 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 the IFN subtype, arthritis model and the kinetics. Because of the reported IFN-I/TNF cross-regulation, and TNF being a key pathogenic cytokine in RA, we have evaluated the therapeutic effect of early IFN-α production in collagen-induced arthritis (CIA).

Methods:  CIA was induced by 2 immunizations with collagen/CFA. Disease development was studied in conditional transgenic mice over-expressing mouse IFN-α1 after cessation of doxycyclin (Dox) administration (Tet-off system). IFN-α1-negative littermates were used as controls. All mice express endogenous IFN-α. All mice were treated with Dox. Arthritis was followed by clinical evaluation. Inflammation/bone destruction were estimated by histology. Plasma cytokines and anti-collagen antibodies were measured by Luminex/ELISA. Leukocytes sub-populations and Th1/Th2/Th17 polarization were analyzed by flow cytometry. Bone marrow cells were cultured with M-CSF/RANKL to evaluate osteoclast differentiation and activity. CD4⁺CD25⁺ regulatory T cells (Treg) and CD4⁺CD25^– effector T cells (Teff) were purified by magnetic sorting. Treg ATPase activity was determined in vitro by a luminescent assay. Treg inhibition of Teff proliferation/activation was measured by flow cytometry/ELISA in co-cultures. The in vivo therapeutic capacity of purified Treg was estimated by adoptive transfer.

Results:  Induction of mouse IFN-α1 production before the first or even before the second immunization resulted in CIA protection. Both immunized IFN-α1^– and IFN-α1⁺ mice produced anti-collagen antibodies, however the latter produced less. Likewise, IFN-α1⁺ mice produced less IL-6 but more IL-5. Protection was associated with decreased polarization to Th17 and increased polarization to Th1 and Th2 lymphocytes. Moreover, IFN-α1⁺ mice showed increased levels of IFN-γ-positive NK cells. On the contrary, osteoclastogenesis and osteoclast activity were decreased in IFN-α1⁺ mice. Particularly, CIA protection in IFN-α1-overexpressing mice was associated with an expansion of Treg with a higher CD39 expression, higher ATPase activity and a higher capacity to inhibit Teff. Most importantly, adoptive transfer of those highly suppressive Treg purified from CIA IFN-α1⁺ mice impaired CIA development in recipients in comparison to adoptive transfer of Treg purified from CIA IFN-α1^– mice.

Conclusion:  This is the first study analyzing the impact of IFN-α on CIA development. Induction of IFN-α1 production before immunization or even after the first immunization nearly completely protects against arthritis. Protection is associated with an expansion of more suppressive Treg able to confer protection upon adoptive transfer. This work better defines the role of IFN-α and shows its potent modulatory effect in inflammatory arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/early-in-vivo-induction-of-mouse-interferon-alpha1-overexpression-triggers-an-expansion-of-highly-suppressive-regulatory-t-lymphocytes-protecting-against-experimental-arthritis/