Complement-mediated cytotoxicity

Sheeja K, Kuttan G. (2007) Modulation of natural killer activity, antibody dependent cellular toxicity, and antibody dependent complement mediated cytotoxicity by andrographolide in normal and Ehrlich ascites carcinoma bearing mice. Integr Cancer Ther 6 66-73. 

Weisburg JH, Roepe PD, Dzekimov S, Scheinberg DA (1999) Intracellular pH and multidrug resistance regulate complement-mediated cytotoxicity of nucleated human cells.) Biol Chem 274 10877-10888... 

Antihepatotoxic actions of traditional Chinese medicines. 2. The pharmacological interaction of components of a dai-saiko to-employing complement-mediated cytotoxicity in primary cultured mouse hepatocytes. Phytother Res 1990 4(1) 36-38. 

Complement-mediated cytotoxicity of cells expressing membrane-bound TNF Yes Yes No... 

GMK vaccine is capable of producing a specific immune response against a defined and chemically purified melanoma antigen. Anti-GM2 antibodies in melanoma patients induced by the GMK demonstrate binding to melanoma cells, complement-mediated cytotoxicity, and antibody-dependent cellular cytotoxicity (54). 

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]. 

Diaz, T. M. Pertega, S. Ortega, D. Lopez, E. Centeno, A. Manez, R. Domenech, N. FDA/PI flow cytometry assay of complement-mediated cytotoxicity of antibodies generated during xenotransplantation. Cytometry, Part A 2004, 62A, 54-60. 

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. 

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... 

By the time they have reached the lungs, schistosomula are innately resistant to immune effector mechanisms that are capable of killing schistosomula newly transformed from cer-cariae. In part, this is a reflection of the fact that growing schistosomula develop the ability to avoid activating complement and to evade recognition by antibodies (see below), and therefore are no longer susceptible to antibody or complement-mediated cellular cytotoxicity. However, studies in which these evasion mechanisms have been experimentally bypassed have revealed underlying resistance to immune effector molecules (Moser et al., 1980) the basis of this resistance is unknown. 

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 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],... 

For complement-dependent cytotoxicity, a complex cascade of protein binding and cleavage occurs that culminates in final complement mediated effector functions of phagocytosis, recruitment and activation of leukocytes, and osmotic lysis. It has been reported that Rituximab (anti-CD20) utilizes a complement-dependent mechanism for tumor cell destruction [14], If the desired effect of a therapeutic antibody is complement-dependent activity, the isotype subgroup chosen should be one that binds to complement proteins (IgGl or IgG3). 

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