Transforming growth factor-βの免疫調節作用 : 特に免疫グロブリン産生に及ぼす影響

Abstract

Transforming growth factor-β(TGF-β)は,間葉系細胞の増殖を促進するが,免疫 担当細胞の機能には一般に抑制的に働くことが知られている。ところで肝硬変,肺線維症など臓 器線維化を組織学的特徴とする疾患では,高免疫グロブリソ(Ig)血症が共通した特徴であり,ま た標的臓器においてTGF-βの発現亢進が明らかになってきている。そこで線維化臓器のTGF -β産生亢進が高Ig血症の成立に関与している可能性を想定した。まずTGF-βを添加してマ ウス脾細胞を培養すると,リンパ球増殖能,Ig産生能は短期培養では抑制的に働くが,長期培養 ではむしろ促進的に働いた。次に浸透圧ミニポンプを用いてTGF-βを持続的にマウス肝内に 注入すると,脾細胞の非特異的および特異的Ig産生の亢進を認めた。これらの成績は,肝での 長期におよぶTGF-β産生亢進が高Ig血症の成立に関与する可能性を示すと考えられた。

Transforming growth factor-β(TGF-β) is known to stimulate the prolif- eration of mesenchymal cells and exert suppressive effects on many immune responses including immunoglobulin (Ig) production of lymphocytes. Recently, the hyperexpression of TGF-β has been immunohistochemically proven in the livers and lungs in patients with liver cirrhosis and pulmonary fibrosis, respectively. However, the patients with these diseases commonly show hyper-, not hypo-, gammaglobulinemia as a characteristic humor- al finding. We made a hypothesis that the increased production of TGF-β in the organs undergoing fibrosis might play a role in the pathogenesis of hypergammaglobulinemia, and we investigated the effects of TGF-β on immune responses in in vitro and in vivo. TGF -β strikingly inhibited the proliferation responses, NK activity and polyclonal Ig production of murine splenocytes during the first 4 days of cultures. However, after a 5-day culture period, the addition of TGF-β in the culture enhanced all of these immune responses. Furthermore, continuous intrahepatic administration of TGF-β using osmotic minipump augmented polyclonal Ig production of spleen cells. In addition, an antigen-specific Ig production of spleen cells was also enhanced by the continuous injection of TGF-β follow- ing an intraperitoneal immunization of the antigen, sheep red blood cells. On the other hand, the intraperitoneal administration of TGF-β had no effect on either polyclonal or antigen- specific Ig production of spleen cells, suggesting that the augmented Ig productjon of spleen cells was not due to a direct effect of TGF-β on spleen cells. Although the precise mechanism of hypergammaglobulinemia in the patients with liver cirrhosis is unknown, the continuous production of TGF-β in the livers chronically affected with fibrosis is consid- ered to play an important role in the pathogenesis of hypergammaglobulinemia in those patients.