The experience of a clinical pharmacology unit based in the U.S.A.

Abstract

At present, apoptosis is considered as a result of intracellular genetic program independently of the reason, regular or pathological, which launched it. Apoptosis is essentially different from necrosis, when swelling and rupture of cells with the effusion of their contents take place, inevitably followed by the development of inflammation. In phagocytosis of apoptotic cells and bodies, the macrophages do not produce proinflammatory cytokines, but increase the production of antiinflammatory cytokines. A late sign of apoptosis is internucleosomal decomposition of nuclear DNA, which can be exploited to reveal apoptotic cells in situ by means of TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling) reaction. Caspases are the key enzymes involved in the intracellular cascade pathway of apoptosis. The damage of mitochondria results in the release of a potent activator of the caspases—cytochrome C—into the cytoplasm. This phenomenon is connected with a change in the expression of Bcl-2 family genes which are under the control of the p53 gene; the activity of the latter determines the start of a cell's advance to apoptosis. The completion of many immunological processes ends with apoptosis, which involves the interaction of Fas (CD95/APO-1) receptor and its FasL ligand both widely expressed in the cells of the immune system. This latter either independently or together with the perphorin–granzyme system represents the main mechanism of cytotoxic killing by T and NK cells. Elimination of immune effector cells which have already fulfilled their function is also carried out by FAS-mediated apoptosis. Clonal deletion of immature T cells in the thymus takes place without the assistance of the Fas/FasL system. Apoptosis is realized during such immunological reactions as deletion of B lymphocytes in germinal centers post antigen activation. Adequately regulated apoptosis maintains cellular balance in the immune system. Both decreases and increases in apoptosis rates lead to pathology of the immune system.