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03.26 Early mouse interferon-alpha1 overexpression in vivo triggers an expansion of highly suppressive regulatory t lymphocytes protecting against experimental arthritis
  1. Matthieu Ribon1,2,
  2. Katarzyna Matyja1,2,
  3. Roxane Hervé1,2,
  4. Delphine Lemeiter1,2,
  5. Ken Tsumiyama3,
  6. Shunichi Shiozawa3,
  7. Marie-Christophe Boissier1,2,4,
  8. Natacha Bessis1,2,
  9. Patrice Decker1,2
  1. 1University of Paris, Sorbonne Paris Cité, France
  2. 2Inserm UMR 1125, Li2P,, Bobigny, France
  3. 3Kyushu University Beppu Hospital, Department of Medicine, Rheumatic Diseases Unit, Beppu, Japan
  4. 4Avicenne Hospital, Rheumatology Department, AP-HP, Bobigny, France

Abstract

Background Type I interferons (IFN-I) can be both anti- and pro-inflammatory. Their role is controversial in rheumatoid arthritis (RA) and experimental models. A not-understood IFN-I signature has been reported in RA patients. In mice, IFN-I enhance/inhibit arthritis according to IFN subtype and arthritis models/kinetics. We have evaluated the effects of early IFN-α production in collagen-induced arthritis (CIA) which mimics RA.

Materials and methods CIA was induced by 2 immunizations with collagen/CFA. Disease development was studied in conditional transgenic mice over-expressing mouse IFN-α1 (Tet-off system) and in IFN-α1-negative littermates. Arthritis was followed by clinical evaluation. Inflammation/bone destruction were estimated by histology. Plasma cytokines/anti-collagen antibodies were measured by Luminex/ELISA. Lymphocyte sub-populations were analysed by flow cytometry. Bone marrow cells were cultured with M-CSF/RANKL to study osteoclasts. CD4+CD25+ regulatory T cells (Treg) and CD4+CD25- effector T cells (Teff) were purified by magnetic sorting. ATPase activity was determined in vitro by a luminescent assay. Treg inhibition of Teff proliferation was measured by flow cytometry 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 between the two immunizations resulted in CIA protection, in contrast to IFN-α1 induction after both immunizations. Both immunised IFN-α1- and IFN-α1+ mice produced anti-collagen antibodies, however the latter produced less. IFN-α1+ mice produced less IL-6 but more IL-5. Protection in IFN-α1+ mice was associated with decreased polarisation to Th17 and increased polarisation to Th1/Th2 lymphocytes and IFN-γ-positive NK cells. Osteoclast differentiation/activity were decreased in IFN-α1+ mice. Particularly, CIA protection in IFN-α1-overexpressing mice was associated with an in vivo expansion of Treg with a higher ectonucleotidase 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 IFN-α1- recipients in comparison to adoptive transfer of Treg purified from CIA IFN-α1- mice.

Conclusions This is the first study evidencing a potent therapeutic window in which IFN-α1 protects against CIA. Protection is associated with an expansion of more suppressive Treg able to confer protection upon adoptive transfer.

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