CpG Oligodeoxynucleotides Prevent the Development of Scleroderma-Like Syndrome in Tight-Skin Mice by Stimulating a Th1 Immune Response

Abstract

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.