Antigen dependent cell-mediated cytotoxicity

Fig. 9.3. Immunoglobulin E (IgE) and mast cell activation are important components of the mammalian response to cestode infections (ADCC, antibody dependent cell-mediated cytotoxicity Ag, antigen EO, eosinophils Feel, high affinity receptor for Fc portion of IgE LTs, leukotrienes Mac, macrophages NO, nitric oxide PGs, prostaglandins TNFa, tumour necrosis factor alpha).

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],... 

IgE antibodies have the unique ability to bind with high affinity to Fc<-RI receptors on mast cells and basophils, and induce degranulation and cytokine secretion by these cells when they are cross-linked by antigen. In addition to its central role in the patht nesis of atopic disorders, it has been speculated that IgE-mediated mast cell degranulation may have a role in the expulsion of gut and respiratory traa parasites. IgE may also have a role in eosinophil killing of parasites by IgE-mediated antibody-dependent cell-mediated cytotoxicity. Despite these observations, it is unclear whether IgE plays an indispensable role in protection against disease. 

Hyperacute rejection may occur when preformed donor-specific antibodies are present in the recipient at the time of the transplant and may be evident within minutes of the transplant procedure. Hyperacute rejection can be induced by immunoglobulin G (IgG) antibodies that bind to antigens on the vascular endothelium, such as class I MHC, ABO, and vascular endothelial cell antigens. Tissue damage can be mediated through antibody-dependent, cell-mediated cytotoxicity or through activation of the complement cascade. The ischemic damage to the microvasculature rapidly produces tissue necrosis. 

Tiroch K, Stockmeyer B, Frank C, Valerius T Intracellular domains of target antigens influence their capacity to trigger antibody-dependent cell-mediated cytotoxicity. J Immunol 2002 168 ... 

Cells express unique carbohydrate structures upon carcinogenic transformation. Therefore, carbohydrate-based antigens offer the potential for a targeted immuno-therapeutic approach to the treatment of certain forms of cancer. Although carbohydrate cancer vaccines have been shown to be safe and to mediate con lement-dependent and/or antibody-dependent cell-mediated cytotoxicity, only a limited number of carbohydrate structures have been evaluated in preclinical and clinical settings. ... 

K-cells in this reaction, termed antibody-dependent cell mediated cytotoxicity (ADCC), Conversely humoral antibody may combine with tumor antigens shed at the cell surface to act as "blocking factors to inhibit ADCC,... 

Modification of antibodies with Gal did not cause loss of antigen binding, complement-mediated cytotoxicity, or antibody-dependent cell-mediated cytotoxicity. Thus, galactose-conjugated antibodies appear to have potential for diverse applications in regional or systemic immunotherapy [13]. 

Rituximab is a chimeric monoclonal antibody that targets CD20 lymphocytes (see Chapter 55). This depletion takes place through cell-mediated and complement-dependent cytotoxicity and stimulation of cell apoptosis. Depletion of lymphocytes reduces inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral cells although this depletion neither correlates with efficacy nor with toxicity. 

Another effector function/mode of action of mAbs is the so-called complement-dependent cytotoxicity or complement-mediated cell death . Activation of the complement system can lead to lysis of the antigen-presenting cell, or can induce inflammation reactions aimed at eliminating these cells efficiently. The successive steps of the complement activation can be summarized in a simplified way [9] ... 

In experimental mouse studies, TCDD exposure results in thymic atrophy and alterations in an array of adaptive immune responses including delayed-type hypersensitivity (DTH), cytotoxic T lymphocyte (CTL) activity, and T-cell-dependent antibody responses. In contrast, TCDD enhances neutrophil recruitment to the site of antigen challenge. Because both cell-mediated and humoral immunity are suppressed by TCDD and related HAHs, it is not surprising that administration of these compounds to mice results in increased susceptibility to challenge with viral, bacterial, or parasitic diseases, as well as syngeneic tumors. 

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