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SummarySystemic sclerosis (SSc) is an autoimmune disease characterized by fibrotic changes in skin and other organs involving excessive collagen deposition. Here we investigated the effect of intravenous immunoglobulin (IVIG) on fibrosis in a murine model of bleomycin (BLM)-induced scleroderma. Scleroderma was induced in C3H/He J mice by subcutaneous BLM injections daily for 35 days. The collagen content in skin samples from the BLM-injected group (6·30 Ϯ 0·11 mg/g tissue) was significantly higher than the PBS group (5·80 Ϯ 0·10 mg/g tissue), and corresponded with dermal thickening at the injection site. In contrast, mice treated with IVIG for 5 consecutive days after initiating BLM injection showed lesser collagen content significantly (IVIG group, 5·61 Ϯ 0·09 mg/g tissue; BLM vs. IVIG). In order to investigate the cellular and protein characteristics in the early stage of the model, the skin samples were obtained 7 days after the onset of experiment. Macrophage infiltration to the dermis, monocyte chemoattractant protein (MCP-1)-positive cells, and increased TGF-b1 mRNA expression were also observed in the BLM group. IVIG inhibited these early fibrogenic changes; MCP-1 expression was significantly lesser for the IVIG group (1·52 Ϯ 0·19 pg/mg tissue) than for the BLM group (2·49 Ϯ 0·26 pg/mg tissue). In contrast, TGF-b1 mRNA expression was significantly inhibited by IVIG. These results suggest that IVIG treatment may inhibit macrophage recruitment to fibrotic sites by down regulating MCP-1 and TGF-b production, and thus could be a potential drug for managing fibrotic disorders such as SSc.

Recurrent pregnancy loss (RPL), which mostly is of unknown etiology (unexplained RPL, uRPL), is defined as three or more consecutive spontaneous abortions. Some women with uRPL display a higher fraction and cytotoxicity of natural killer (NK) cells in the periphery and endometrium. Therefore, some uRPL cases have been explained by autoimmune abnormalities. The efficacy of intravenous immunoglobulin (IVIg) for uRPL has been confirmed in several clinical trials; however, its mechanism remains unknown, mainly because the abortion mechanism remains to be elucidated. In the present study, we analyzed the mechanisms of both abortion and IVIg action using a uRPL mouse model in which abortion was induced by lipopolysaccharide injection. IVIg attenuated the abortion rate in the uRPL model mice. The suppressive effect of IVIg was maximized by high dose administration early after lipopolysaccharide injection. Specifically, we discovered the presence of two distinct uterine NK (uNK) subsets: CD44(bright) and CD44(mid) In uRPL model mice, we observed an increase in the number of CD44(bright) uNK cells, while the CD44(mid) uNK subset remained unchanged. Furthermore, when abortion was reduced by IVIg administration, the cell number of the CD44(bright) uNK subset did not increase, which might allow differentiating pathological from normal uNK cells based on CD44 expression. Based on these results, we propose not only an effective administration protocol of IVIg to the uRPL model mice, but also a novel mechanism of abortion related to the increase in the CD44(bright) subset and of IVIg, which suppresses the increase of the CD44(bright) subset.

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Abstract:The effect of adriamycin-oxidized dextran (ADM-OXD) on hepatic macrophage (Kupffer cell) was studied using male Wistar rats. Kupffer cell function was measured using as an index the clearance rate from circulating blood of extrinsic carbon particles (phagocytic index). This index fell markedly from soon after a single intravenous injection of ADM-OXD at a dose of 30 or 60mg/kg in terms of ADM content. Carbon uptake in periportal Kupffer cells, evaluated using HE stained liver sections, was markedly lower in ADM-OXD treated animals than in control animals. The relationship between damage to parenchymal cells and to sinusoidal lining cells, especially Kupffer cells, was monitored morphologically and biochemically for 48 hours after a single injection at a dose of 60mg/kg. Serum biochemical changes showing parenchymal cell dysfunction and morphologically regressive changes such as diffuse centrilobular necrosis were observed in pronounced form at 48 hours. Kupffer cells, in contrast, were found to be degenerative or necrotic ultrastructurally as early as at 8 hours. Immunohistochemically, the number of ED2-positive Kupffer cells in the periportal area decreased from 8 hours. Activity of serum cathepsin D, thought to be leaked from Kupffer cell lysosomes, was elevated from an early stage. It was judged that Kupffer cell damage preceded parenchymal cell damage. Pretreatment with estrogen, which has a proliferative action on hepatic macrophages, mitigated ADM OXD-induced hepatotoxicity. Damage to sinusoidal lining cells (Kupffer cells) would therefore seem to participate closely in the onset of parenchymal cell damage. (J Toxicol Pathol 7: 199-210, 1994)