Immune-mediated cytotoxicity

GZ (23) is known to decrease elevated plasma levels of AST and ALT in various liver diseases. Thus it has been widely used for the treatment of chronic liver diseases (chronic viral hepatitis) in Japan for several years [82]. However, the mechanism of its transaminase-lowering action is not fully understood. Some studies suggested that the decrease of transaminase levels by GZ in patients with chronic viral hepatitis is mediated in part by inhibition of immune-mediated cytotoxicity against hepatocytes [83]. GZ (23) was shown to inhibit the cytotoxicity of CTL against antigen-presenting cells and also to suppress TNF-a induced cytotoxicity in the TNF-a sensitive cell line in vitro. A clinical study reported the use of GZ to bring about an improvement of hepatitis after liver transplantation performed for cirrhosis secondary to hepatitis B complicated by a small hepatocellular carcinoma [84],... 

The mammalian and avian immune systems function similarly both incorporate humoral and cell-mediated cytotoxic mechanisms, " and are thought to share a 160m year old relationship with the reptilian immune system. The immune system of mammals shows sexual dimorphism " a greater immune response is normally observed in females, which has been attributed to differences in steroid hormone concentration. In the toad Bufo regularis, sexual dimorphism of the immune system is also apparent. ... 

Types II and III Hypersensitivity. No simple animal models are currently available to assess Type II (antibody-mediated cytotoxicity) hypersensitivity reactions. IgE antibodies and immune complexes in the sera of exposed animals can be assayed using ELISA or RIA techniques that require the use of specific antibodies to the drug. 

Most anaphylactoid reactions are due to a direct or chemical release of histamine, and other mediators, from mast cells and basophils. Immune-mediated hypersensitivity reactions have been classified as types I-IV. Type I, involving IgE or IgG antibodies, is the main mechanism involved in most anaphylactic or immediate hypersensitivity reactions to anaesthetic drugs. Type II, also known as antibody-dependent hypersensitivity or cytotoxic reactions are, for example, responsible for ABO-incompatible blood transfusion reactions. Type III, immune complex reactions, include classic serum sickness. Type IV, cellular responses mediated by sensitised lymphocytes, may account for as much as 80% of allergic reactions to local anaesthetic. 

Figure 7.78 Postulated mechanism of halothane immune-mediated hepatotoxicity. This figure is only a partial explanation, involving Tc cells (cytotoxic lymphocytes). See text for complete description. CYP2E1 in liver cell activates the halothane to a reactive acyl chloride shown), which reacts with proteins (e.g., enzymes in the SER). These are transported to cell surface and presented to immune system by APC. Abbreviations APC, antigen-presenting cell SER, smooth endoplasmic reticulum MHCII, major histocompatability complex.

IgG Immunoglobulin G is present in lymph fluid, blood, cerebrospinal fluid and peritoneal fluid. It is composed of 2 y chains of 50 kDa and 2 L chains (k or ) of 25 kDa with a total molecular weight of 150 kDa. The functions of IgG include agglutination and formation of precipitate, passage through placenta and thus conferring immunity to fetus, opsonization, antibody-dependent cell-mediated cytotoxicity (ADCC), activation of complement, neutralization of toxins, immobilization of bacteria and neutralization of virus. 

About 10 days after transplantation, acute rejection of the graft begins as a result of cell-mediated immunity. Acute rejection is a result of infiltration of large numbers of macrophages and lymphocytes into the graft. Helper T-cell activation and proliferation play a major role in this process, and both complement-dependent cell-mediated cytotoxicity and ADCC are involved in the destruction of the graft. Acute rejection could be in the form of acute vascular rejection, acute cellular rejection or both. Acute vascular rejection involves the necrosis of the blood vessel cells of the graft... 

Two types of immunity may be induced in response to an antigen, namely humoral immunity mediated by antigen-specific antibodies produced by B lymphocytes, and cell-mediated immunity produced by activated macrophages and cytotoxic T lymphocytes. Antibodies may neutralize pathogens, whereas... 

In humans, there are five isotypes of antibodies, IgG, IgA, IgD, IgE, and IgM, which are defined by the structures of their heavy chains and their abilities to form multimers (Figure 10.1) [8], IgG is the most abundant isotype present in serum with average serum concentrations ranging from 0.5 to 9mg/ml depending on the IgG subtype. This is followed by IgA (3mg/ml), IgM (1.5mg/ml), IgE (0.05 mg/ml), and IgD (trace). Each antibody isotype has unique functions. Critical functions of IgG include opsonization, complement activation, antibody-dependent cell-mediated cytotoxicity (ADCC), passive immunity, and regulation of B cells. Both IgM and IgD act as antigen receptors on naive B cells, and soluble, multimeric forms of IgM are involved in complement activation. IgA is involved in mucosal and passive neonatal immunity, while IgE is involved in immediate hypersensitivity [8],... 

G22. Gravagna, P., Gianazza, E., Arnaud, P., Neels, M., and Ades, E. W., Modulation of the immune response by plasma protease inhibitors. II. Alpha 2-macroglobulin subunits inhibit natural killer cell cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Scand. J. Immunol. 15, 115-118 (1982). 

Adams, S., Miller, G. T., Jesson, M. I., Watanabe,T, Jones, B., Wallner, B. P. (2004). PT-100, a small molecule dipepfi-dyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 64, 5471-5480. 

The importance of the plasma membrane as the site of action of im-munologically mediated cytotoxicity reactions involving humoral or cellular factors has recently become evident. In this regard, several studies have shown that humoral immune killing reactions involve a complex series of biochemical interactions between the attacker moieties and the cell surface membrane.One approach in studying and elucidating such interactions could therefore focus on the effects of the immune attack processes on the synthesis and/or turnover of cell surface macromolecules known to be structural and functional components of the plasma membrane (e.g., proteins and lipids). 

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