title: Suppression of autoimmune arthritis in interleukin-1-deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells.
abstract: OBJECTIVE
  To elucidate the roles of interleukin-1 (IL-1) in the development of 2 etiologically different rheumatoid arthritis (RA) models: the type II collagen (CII)-induced arthritis (CIA) model and the human T cell leukemia virus type I transgenic (HTLV-I Tg) mouse model.
  
  
  METHODS
  For the CIA model, DBA/1J-background IL-1alpha-/-, IL-1beta-/-, IL-1alpha/beta-/-, and wild-type littermate mice were immunized with CII. For the HTLV-I Tg model, BALB/c IL-1beta-/- or IL-1alpha/beta-/- mice were crossed with HTLV-I Tg mice. The effects of IL-1 deficiency were assessed as follows: Development of arthritis was assessed both macroscopically and microscopically. Serum antibody titer was measured by enzyme-linked immunosorbent assay. Proliferative response of lymph node cells was assayed by measurement of (3)H-thymidine incorporation. Expression of T cell surface molecule CD40 ligand (CD40L) and OX40 was determined by multicolor flow cytometric analysis.
  
  
  RESULTS
  The development of arthritis was markedly suppressed in IL-1alpha/beta-/- mice in both models, although the effect was less prominent in HTLV-I Tg mice. Deficiency of only IL-1alpha or only IL-1beta was also associated with disease suppression. Antibody production after immunization with CII was normal in IL-1alpha/beta-/- mice, while autoantibody production was suppressed in IL-1alpha/beta-/- HTLV-I Tg mice. In IL-1alpha/beta-/- mice, the T cell proliferative response against CII was greatly reduced in both the CIA and the HTLV-I Tg models, suggesting inefficiency of T cell activation. Furthermore, expression of CD40L and OX40 on T cells was greatly reduced in IL-1alpha/beta-/- mice.
  
  
  CONCLUSIONS
  These observations suggest that T cell activation by IL-1 is important for the development of autoimmunity and arthritis in these mice.
authors.affiliation: Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Saijo
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis / Q000235:genetics*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology; D023201:CD40 Ligand / Q000032:analysis / Q000096:biosynthesis*; D002455:Cell Division / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood; D007375:Interleukin-1 / Q000235:genetics*; D015850:Interleukin-6 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D013643:Tarsus, Animal / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000943:Antigens, Differentiation; D001323:Autoantibodies; D007074:Immunoglobulin G; D007375:Interleukin-1; D015850:Interleukin-6; C406562:OX40Ig; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand