The immunosuppressive role of hepatic Kupffer cells

描述（由申请人提供）：免疫介导的药物不良反应（IADR）是不可预测的，可能危及生命。虽然目前的研究表明，IADR是由免疫原性药物-蛋白加合物引起的，但尚不清楚为什么这些反应仅限于易感患者群体。本研究的目的是验证以下假设：Kupffer细胞（KG）是一种无能的抗原呈递细胞（APC），其本质上导致T细胞耐受；KC耐受原功能的损害可能是调节针对蛋白质加合物的免疫反应的关键因素，并显著影响对IADR的易感性。拟议研究的具体目的将是确定下列各项：共刺激分子表达不足和IL-10的产生在kc诱导的T细胞耐受机制中的作用。KC诱导T细胞活化的能力将与强效apc（如脾树突状细胞和腹膜渗出巨噬细胞）的能力进行比较。共同刺激分子表达不足在kc诱导的T细胞能量中的作用将在体内和体外被确定。此外，KC产生IL-10的能力以及IL-10在KC介导的T细胞耐受中的作用将被研究。

DESCRIPTION (provided by the applicant): Immune-mediated adverse drug reactions (IADR) are unpredictable and can be life-threatening. Although current studies suggest that IADR are caused by immunogenic drug-protein adducts, it remains unclear why these reactions are restricted to susceptible groups of patients. The objective of the present proposal is to test the hypotheses that Kupffer cells (KG) are incompetent antigen presenting cells (APC) that intrinsically cause T cell tolerance, and that impairment of the tolerogenic function of KC may be a key factor that modulates immune reactions against protein adducts and significantly affects susceptibility to IADR. The specific aims of the proposed studies will be to determine the following: 1. The roles of inadequate expression of co-stimulatory molecules and production of IL-10 in the mechanisms of KC-induced T cell tolerance. The capability of KC to induce T cell activation will be compared with that of potent APCs, such as splenic dendritic cells and peritoneal exudate macrophages. The role of inadequate expression of co-stimulatory molecules in KC-induced T cell anergy will be determined in vivo and in vitro. Further, the capacity of KC to produce IL-10 and the role of IL-10 in KC-mediated T cell tolerance will be investigated. 2. Whether "danger signals" may convert KC from tolerogenic to immunogenic APC. Evidence suggests that an increased risk of IADR in susceptible individuals may be linked to concurrent infection and/or inflammation, in which "danger signals", may be generated to stimulate the immune system. Thus, it is our hypothesis that tolerogenic KC may be converted to potent immunogenic APC by "danger signals", thereby, leading to an increased propensity toward developing IADR. This hypothesis will be examined using two widely recognized "danger signals": lipopolysaccharides and heat shock proteins. 3. Whether KC plays an important role in inducing immunological tolerance against protein adducts derived from a therapeutic agent that causes IADR. A model hapten was used in the preliminary studies to demonstrate the tolerogenic effects of KC. However, it is important to further investigate whether the immunosuppressive effects of KC may be extended to a therapeutic agent that causes IADR. This hypothesis will be examined using halothane, which is known to cause allergic hepatitis with clinical features consistent to IADR.