실험적 항섬유화 치료법의 임상적용 Anti-Fibrotic Therapy from Bench to Clinic 카이스트 의과학대학원 정 원 일 Until now, there is no ordinary treatment of liver fibrosis although many studies have been performed to find out the best therapeutic methods for the amelioration of liver fibrosis. Indeed, the worth of most developed drugs has not been proven in humans. Now, scientists and clinicians are trying and developing cell-based therapy using innate immune cells and bone marrow cells for the treatment of liver fibrosis. Interestingly, normal liver contains many different types of immune cells including innate immune cells such as natural killer (NK) cell and NKT cells. These cells are especially enriched in liver. Among them, NK cells and interferon-gamma (IFN-γ) shows antifibrotic effects in early liver fibrosis of animal models via suppress activation of hepatic stellate cells. However, IFN-γ treatment has no beneficial effects in the amelioration of advanced liver fibrosis at clinical trials. This is because liver fibrosis could be diminished by activation of innate immunity in early stage of liver fibrosis, whereas advanced liver fibrosis at chronic stage was resistant to antifibrotic effects of innate immunity via activation of TGF-β1 and enhanced expression of SOCS1. The role of NKT cell in fibrosis is still controversial. Recently, autologous bone marrow cell infusion (ABMI) has been performed and now applicable for the recovery of liver cirrhosis in patients and the underlying mechanisms are still investigated. It is an important case how bench works could be applicable to bed works. Key words: Liver; Fibrosis; Innate immunity; Hepatic stellate cell 간섬유화 치료와 관련되어 많은 기초연구들이 진행되어 왔으나 현재까지 뚜렷한 임상 치료법이 없 는 실정이다. 또한 개발된 약제들의 효과도 임상에서 검증 되지않고 있으며 현재 과학자들과 임상가 들은 간내 선천성면역세포들과 골수세포들을 이용한 간섬유화 치료법을 연구중에 있다. 흥미롭게도 간은 여러가지 면역세포들 특히 선천성 면역을 담당하는 자연살해세포(NK cell)과 자연살해T세포 (NKT cell)를 많이 가지고 있으며, 이중 자연살해(NK)세포들과 인터페론-감마(IFN-γ)는 마우스에서 간 섬유화 초기 항섬유화 기능을 가지는 것으로 알려져 있으나, 실제 임상에서 인터페론-감마(IFN-γ) 처 치가 중등도 이상의 간섬유화에서는 효능이 없는 것으로 판명되었다. 이러한 이유는 선천성 면역의 경우 초기 간섬유화에만 효과가 있는 반면, 만성간섬유화시는 간내 TGF-β1과 SOCS1의 발현으로 그 효능이 감소되기 때문이다. 자연살해T세포의 경우 항섬유화 기능에 대한 논란이 있다. 최근 자가골수 48 정원일 실험적 항섬유화 치료법의 임상적용 세포치료법(ABMI)이 간경변증 환자를 상대로 시도가 되고 있으며 이들에 대한 기전연구가 계속되고 있다. 이것은 항섬유화와 관련되어 실험실 연구(Bench works)들이 어떻게 임상(bed works)에 적용되는 지 보여주는 좋은 예가 될 것이다. Introduction Liver fibrosis is a common wound healing response to all forms of chronic liver disease and is characterized by an excessive accumulation of extracellular matrix (ECM) in the liver.1,2 A line of evidence suggests that several types of liver cells contributes to liver fibrogenesis including hepatic stellate cell (HSCs), myofibroblasts, bone-marrow derived progenitor cells, and hepatocytes.1, 2 Among them, HSCs are believed to play a crucial role in the liver fibrogenesis via production of collagen fibers. In normal liver, quiescent HSCs are generally storing retinol droplet (vitamin A) in their cytoplasm. In response to liver injury, however, HSCs are activated and transformed into myofibroblast-like cells by a variety of inflammatory cytokines and mediators. Among them, transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF) are considered the most potent activator of HSC transformation and proliferation, respectively.3,4 Recently, liver has been considered as immunologic organ and actually it has enriched innate immune cells such as resident macrophages (Kupffer cells), natural killer (NK) cells, NKT cell and other lymphocytes.5-7 For example, mouse liver lymphocytes contain approximately 10% NK cells, whereas rat and human liver lymphocytes contain about 30% to 40% NK cells. NKT cells constitute up to 30% and 10% of the intrahepatic lymphocytes in mice and human, respectively. Therefore, many scientists and clinicians are interesting about their roles and several recent studies have suggested that innate immunity plays an important role in controlling the development and progression of liver fibrosis, which will be discussed below. Also, in the present paper, I will discuss about the applicable therapeutic ways with animal studies into clinical trials. Antifibrotic effects of NK cell/Interferon-gamma (IFN-γ) The innate immunity is the first line of defense against pathogenic microorganism and tumors.6 In contrast to previous conceptualization of the innate immune system, it recognizes the overall molecular patterns of pathogens with receptors referred to as pattern recognition receptors (PRRs) and those patterns found on pathogens are called pathogen-associated molecular patterns (PAMPs). The most well known PAMP is lipopolysaccharide (LPS), a component of the gram-negative bacteria wall. PRRs include toll-like receptors (TLRs), nucleotide-binding oligomeri- 49