Cellular and humoral mechanisms of immunotoxicological tissue manifestations induced by immunotoxic drugs.
The adverse effects on the immune system resulting from acute and subchronic exposure to immunotoxic compounds can be divided into the following three categories. One is the tissue manifestations induced by either immunosuppressive or immunomodulative compounds through the interactions of the drug or its metabolites with cellular/humoral constituents directly or indirectly. For the detection, the functional tests especially NK activity in short-term administration were found to be valuable in the assessment of immunotoxicity of drugs in comparison with hematological and morphological alterations. The second is manifested as an allergic reaction, consisting of three sequential events: (1) sensitization by the exposure of a drug primarily recognized as an antigen; (2) the interaction of antigen and antibody and/or sensitized mononuclear cell (M), and its sequelae, which initiate the chain of events leading to tissue injury: and (3) tissue injury and inflammation. The third is manifested as autoimmunity. Of these, in the first two reactions, a primary manifestation seems to be cellular injury. In this experiment, the morphological and biochemical changes occurring in the cultured cells were analyzed when the compound was added to cultured cells obtained from (a) normal animals, (b) drug-sensitized animal models prepared by using drug-protein conjugates, and (c) animals administered drugs at the dosage equivalent to therapeutic dose. When a test compound was added to short cultured sensitized M, morphological responses observed were characterized by either diffuse swelling of the cells and decrease of pseudopod movement, or gradual shrinking. No such changes were observed in non-sensitized M. In contrast, when immunosuppressants or immunomodulators were used, increases of pseudopod movement and pinocytosis, and excitation of cytoplasmic movement, were observed in both sensitized and non-sensitized M if compounds were cytotoxic. In both cases, inflammatory cytokines responsible for tissue damage were released from the M. Little release of these factors was observed from the non-stimulated cells. For the third category, an attempt is being made to analyze autoimmune disorders immunotoxicologically by using experimentally induced MDP-arthritis in rodents.
Udaka
K
K
Nippon Roche Research Center, Kanagawa, Japan.
D000818:Animals; D002478:Cells, Cultured; D004342:Drug Hypersensitivity / Q000276:immunology*; D006168:Guinea Pigs; D006801:Humans; D007107:Immune System / Q000187:drug effects*; D051379:Mice; D011817:Rabbits; D051381:Rats