: 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.
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