CpG oligodeoxynucleotides prevent the development of scleroderma-like syndrome in tight-skin mice by stimulating a Th1 immune response.
Tight-skin (Tsk/+) mice develop a disease similar to human scleroderma, characterized by the spontaneous appearance of cutaneous hyperplasia, anti-nuclear antibodies, and emphysema. T helper (Th) 2 cells secreting interleukin (IL)-4 are known to play a critical role in the etiopathogenesis of this disease. Th2-mediated responses can be blocked by treatment with synthetic oligodeoxynucleotides (ODN) containing immunomodulatory CpG motifs. Thus, we examined whether CpG ODN might be of therapeutic benefit in Tsk/+ mice. Administering CpG ODN to Tsk/+ mice every 3 wk starting at 1 wk of age abrogated skin fibrosis. This reduction in skin thickness persisted even after the cessation of therapy, and was accompanied by increased serum levels of IL-12 and an increased ratio of T cells available to secrete interferon-gamma rather than IL-4. CpG ODN therapy also reduced autoantibody production, but did not inhibit the incidence of lung emphysema. Delaying the initiation of CpG ODN treatment until 6 wk of age failed to prevent skin disease. These results indicate that by preferentially promoting the development of a Th1-biased immune milieu in young Tsk/+ mice, CpG ODN can ameliorate Th2-driven scleroderma-like syndrome.
Shen
Yan
Y
Department of Immunology, Yokohama City University School of Medicine, Yokohama, Japan. shenyan0127@lycos.com
Ichino
Motohide
M
Nakazawa
Masatoshi
M
Minami
Mutsuhiko
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000917:Antibody Formation; D004195:Disease Models, Animal; D005355:Fibrosis; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012594:Scleroderma, Localized / Q000235:genetics / Q000517:prevention & control*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase