The immunosuppressive role of hepatic Kupffer cells

描述（由申请方提供）：免疫介导的药物不良反应（IADR）不可预测，可能危及生命。尽管目前的研究表明IADR是由免疫原性药物-蛋白质加合物引起的，但仍不清楚为什么这些反应仅限于易感患者群体。本提案的目的是检验Kupffer细胞（KG）是不称职的抗原呈递细胞（APC），本质上导致T细胞耐受性的假设，以及KC的致耐受性功能受损可能是调节免疫反应的关键因素，对蛋白加合物，并显着影响IADR的易感性。拟议研究的具体目标将是确定以下内容：1.共刺激分子表达不足和IL-10产生在KC诱导T细胞耐受机制中的作用KC诱导T细胞活化的能力将与有效的APC（如脾树突状细胞和腹膜渗出液巨噬细胞）的能力进行比较。将在体内和体外确定共刺激分子表达不足在KC诱导的T细胞无能中的作用。此外，KC产生IL-10的能力和IL-10在KC介导的T细胞耐受中的作用将被研究。 2.“危险信号”是否可以将KC从致耐受性转变为免疫原性APC。有证据表明，易感个体IADR风险增加可能与并发感染和/或炎症有关，其中可能产生“危险信号”以刺激免疫系统。因此，我们假设致耐受性KC可能通过“危险信号”转化为有效的免疫原性APC，从而导致发生IADR的倾向增加。这一假设将使用两个广泛认可的“危险信号”进行检验：脂多糖和热休克蛋白。3. KC是否在诱导对来自引起IADR的治疗剂的蛋白加合物的免疫耐受中起重要作用。在初步研究中使用模型半抗原来证明KC的致耐受性作用。然而，重要的是进一步研究KC的免疫抑制作用是否可以扩展到导致IADR的治疗剂。将使用氟烷对这一假设进行检查，氟烷已知可引起过敏性肝炎，其临床特征与IADR一致。

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.