Protein cytotoxic

Eosinophils migrate to the airways and release inflammatory mediators (leukotrienes and granule proteins), cytotoxic mediators, and cytokines. 

Cytotoxicity assays based on the Fc-mediated killing can be used as bioactiv-ity/potency assays to evaluate product quality when the desired MoA of the therapeutic protein is to induce death of certain types of cells (e.g., tumor cells). It is well known in the industry and in the literature that some therapeutic proteins (mAbs or molecules of similar structure) with an intact Fc region can exhibit the nontargeted Fc-mediated functions (ADCC, CDC, phagocytosis), which can cause undesired effects, thereby compromising patient safety. The same types of assays can be used to evaluate product s safety profile by testing the ability of the therapeutic protein to exhibit the undesired, nontargeted Fc- mediated functions. In those cases when the Fc function is not a part of the MoA of the therapeutic protein, cytotoxicity assays should be used only as a characterization tool. 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Enzymes Degrading Macromolecules. Enzymes that degrade macromolecules such as membrane polysaccharides, stmctural and functional proteins, or nucleic acids, have all shown oncolytic activity. Treatment strategies include the treatment of inoperable tumors with pepsin (1) antitumor activity of carboxypeptidase (44) cytotoxicity of ribonudease (45—47) oncolytic activity of neuraminidase (48—52) therapy with neuraminidase of patients with acute myeloid leukemia (53) antitumor activity of proteases (54) and hyaluronidase treatment in the management of human soHd tumors (55). 

British investigators (Haddow and Timmis 1951) synthesized and studied esters of the methanesulfonic acid. The most active derivative was the dimethylsulfonic ester of 1,4-butanedione, known as busulfan. Busulfan interacts with the thiol groups of proteins and amino acids some of its metabolites can alkylate the thiols of cysteine, peptides and proteins. Busulfan exerts selective cytotoxic activity in hematopoietic bone marrow cells and inhibits the formation of granulocytes and platelets. It slightly affects the lymphoid tissue. 

COPD is a chronic inflammatory disease that results from prolonged and repeated inhalation of particles and gases, chronic (or latent) infection or an interaction of these factors. In many cases, the inflammation persists even when the exposure (in most cases smoking) is stopped. Prominent among the infiltrating leukocytes are neutrophils, CD8+ lymphocytes (Co-receptor for the T-cell receptor. CD8+ is specific for the class IMHC protein. It is expressed on the surface of cytotoxic T-cells and natural killer cells.) and CD68+ monocytic cells (A lysosomal antigen. All cells that rich in... 

The field of DNA vaccination started when eukaryotic expression vectors were injected into the muscle of laboratory animals [2]. The authors observed protein expression for more than 2 months after injection and noted that no special delivery system was required to obtain this expression. Subsequently, it was demonstrated that antibodies can be induced simply by injecting plasmid DNA into the muscle of mice [3]. Subsequent studies found that the injection of expression plasmids also leads to the induction of a cytotoxic T-cell response. After injection, the DNA enters cells of the vaccinated host and the encoded gene becomes expressed. This eventually leads to the induction of a cellular cytotoxic T-cell, T-helper, and/or humoral (antibody) immune response. 

This is an immunoglobulin fusion protein with the cytotoxic lymphocyte antigen 4 (CTLA-4) receptor. By binding to CD80/86 on APCs it inhibits the CD28 costimulatory signal in lymphocytes. It is speculated that this can result in tolerance but up to now there is only experimental data [3,4]. 

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

Ab, B.K., Kiessling, R., Van, E.J.D., Thole, J.E.. Kumararatne, D.S., Pisa, P., Wondimu. A., Ottenhoff, T.H. (1990). Induction of antigen-specific CD4+ HLA-DR restricted cytotoxic lymphocytes as well as nonspecific nonrestricted killer cells by the recombinant mycobacterial 65 kDa heat shock protein. Eur. J. Immunol. 20, 369-377. 

Jaattela, M., Wissing, D., Bauer, P.A., Li, G.C. (1992). Major heat shock protein hsp70 protects tumor cells from tumor necrosis factor cytotoxicity. EMBO J. 11, 3507-3512. 

Otenhoff, T.H., Kale, A.B., VanEmbden, J.D.A., Thole, J.E.R., Kiessling, R. (1988). The recombinant 65-kD heat shock protein of Mycobacterium bovis bacillus calmette guerin/M. tuberculosis is a target molecule for CD4 + cytotoxic T lymphocytes that lyse human monocytes. J. Exp. Med. 168, 1947-1952. 

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