The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice
Article first published online: 6 JUN 2002
Copyright © 2002 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 46, Issue 6, pages 1689–1690, June 2002
How to Cite
Blank, M., Levy, Y., Amital, H., Shoenfeld, Y., Pines, M. and Genina, O. (2002), The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice. Arthritis & Rheumatism, 46: 1689–1690. doi: 10.1002/art.10363
- Issue published online: 6 JUN 2002
- Article first published online: 6 JUN 2002
- The Chief Scientist, Israel Ministry of Health. Grant Number: 5148
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by microvascular damage, extracellular matrix deposition, and fibrosis. Although the cause of the disease is unknown, interleukin-4 (IL-4) and transforming growth factor β (TGFβ) have been postulated to play a major role in the fibrogenesis. It has been demonstrated that mutation of the IL-4 receptor α and TGFβ genes prevents the development of the disease in animal models (1).
Intravenously administered human immunoglobulin (IVIG) has been used successfully in controlled clinical trials, and its effectiveness has been established, for the treatment of various autoimmune conditions (2). Previously, we reported on 3 patients with SSc in whom IVIG treatment reduced the degree of cutaneous fibrosis as measured by an objective skin score (3).
In the present study, we assessed the effect of IVIG on skin fibrosis in tight skin (Tsk/+) mice. The Tsk/+ mouse represents a murine model of scleroderma-like disease with heritable fibrosis resembling the skin fibrosis seen in human SSc. The excessive fibrosis in these mice is the result of increased synthesis and accumulation of collagen in the skin (4). Tsk/+ mice (n = 5) received IVIG (Omrix, Nes-Ziona, Israel) beginning at the age of 4 weeks. IVIG was administered twice weekly for 4 weeks. The total dose was 2 gm/kg. Control mice (n = 5) were infused with 2% maltose. The mice were killed at the age of 9 weeks.
As depicted in Figures 1a and b, collagen expression (Sirius red staining) was decreased in the skin of Tsk/+ mice treated with IVIG compared with that in control mice. The decreased collagen expression after exposure to IVIG was associated with decreased type I collagen gene expression as documented by in situ hybridization using digoxigenin-labeled Colα1 probe (Figures 1c and d). The reduction in skin fibrosis upon IVIG treatment was accompanied by inhibition of TGFβ1 and IL-4 secretion by splenocytes (Figure 2). Significant inhibition of TGFβ1 secretion (P < 0.02 to P < 0.01 versus control) was observed in 4 of 5 mice. IL-4 expression was significantly decreased as well (P < 0.001). No significant change in levels of the antifibrotic cytokine interferon-γ (IFNγ) was documented.
One of the hypotheses regarding the emergence of the fibrotic reaction is that excessive fibrogenesis results from elevated expression of profibrotic cytokines such as TGFβ1 and IL-4 (1, 5). Although the precise mode of action of IVIG in autoimmunity is unknown, one postulated mechanism involves modulation of cytokine production (6). Recently, IVIG was shown to inhibit IL-4, but not IFNγ or tumor necrosis factor α, secretion following in vitro stimulation of mononuclear cells with staphylococcal superantigen (7). Moreover, TGFβ1 messenger RNA and protein in the muscles of patients with inflammatory myopathies were down-regulated after treatment with high-dose IVIG (8). Modulation of matrix metalloproteinase expression was documented in Kawasaki disease patients treated with IVIG (9). IVIG was found to down-regulate the gene expression of chemokines (macrophage inflammatory protein 1α [MIP-1α], MIP-1β, and IL-18) (10). In the present study we demonstrated that IVIG decreased splenocyte secretion of IL-4 and TGFβ, resulting in abrogation of fibrogenesis in tight skin mice. We suggest that IVIG affects the cytokine profile of these mice and consequently prevents the accumulation of fibrous tissue. We do not exclude the possible involvement of other molecular mechanisms leading to inhibition of the development of scleroderma-like disease in IVIG-treated tight skin mice.
IVIG is a compound that has almost no side effects (11). Therefore, it might be a novel therapy for fibrosis in SSc.
Supported by grant 5148 from The Chief Scientist, Israel Ministry of Health.