[Research on compounds with histaminase-liberating effect on guinea pigs].
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Biomedical subjects
Publications and source records attributed to W Schmutzler.
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Similar to other chronic inflammatory diseases such as rheumatoid arthritis the distribution of macrophage subtypes seems to be disturbed in post-traumatic osteomyelitis. This atypical distribution is clearly locally restricted in osteomyelitis. 27E10-positive macrophages found only during the acute phase of inflammation were reduced in 39%, the 25F9-positive subtype, predominating in the late stage of inflammation, was missing in 33%. The antiinflammatory macrophage RM3/1 was decreased in 40% of the osteomyelitis biopsies. Local suppression of macrophage subsets has to be discussed as one of the reasons for the persistence of chronic inflammatory processes in osteomyelitis.
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Monocytes and lymphocytes from human blood contain 0.043 +/- 0.007 and 0.053 +/- 0.014 pg histamine/cell, respectively, which can be released by a number of stimulants (A 23187, C5a, substance P, specific allergen). The release process takes 60-120 min to reach its end point, in contrast to tissue mast cells which complete the release within 1-3 min. Both, ketotifen (10(-7) - 10(-5) M) and disodium cromoglycate (10(-5) - 10(-3) M) inhibited histamine release dose dependently up to 40-45%, which might be particularly relevant during the later stages of acute allergic or pseudoallergic reactions.
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Subsets of macrophages (BM 8-, la- and esterase-positive subtypes) in the spleen and the peritoneum of mice were affected differently by immunomodulators during the humoral immune response. I.p. application of inosine pranobex (INPX), as well as of its salt moiety (DIPPACBA) and its dimethylaminopropanol (DIP) and acetamidobenzoic acid (PACBA) components, increased the number of nonspecific esterase-bearing cells in the peritoneum on day 3. INPX and DIPPACBA stimulated the la+ macrophage on day 3, DIPPACBA the BM 8+ macrophage only on day 1 and DIP on day 5. In spleen, DIP and PACBA had marked effects on the la+ subset in addition to a marginal effect on the BM 8+ phenotype on day 1. DIPPACBA also influenced the BM 8+ macrophage slightly on day 1. In contrast, the microbial product OK-432 stimulated BM 8+ and la+ macrophages in spleen markedly on day 1, but only marginally on days 3 and 5. However, it exerted a strong effect on both subtypes in peritoneum on days 3 and 5. OK-432 was found to be without any influence on esterase-bearing macrophages. The results show that the heterogeneity of macrophages is not only represented by subset markers, but also by their susceptibility to immunomodulators in different organs and stages of the immune response.
"Immunopharmacology" evolved as a field of research in its own right when it was appreciated that pharmacological methods can contribute to the understanding of immune mechanisms on the one hand or can be used to influence or even control immune reactions at all stages and levels. The best studied subjects of immunopharmacology are release and effects of the chemical mediator substances which are responsible for the reactions of effector cells thus causing the clinical symptoms in allergic or inflammatory diseases. In the type I allergic (anaphylactic) reactions the primary target cells are tissue mast cells or basophil granulocytes which discharge their granular contents upon interaction of immunoglobulin E fixed to their surface with the specific antigen or--in the anaphylactoid reaction--upon stimulation with an appropriate chemical substance (so-called histamine-liberator). In both cases the stimulus leads to an influx or intracellular shift from one compartment to another of calcium ions, which in turn trigger membrane fusion and degranulation. This process can vary from a physiological secretion (in the case of IgE-antigen-interaction) to a pathological cytolysis (in the case of high concentrations of activated complement components or other chemical histamine releasers). As long as it is secretory it is subject to vegetative and hormonal modulation and regulation, mainly by catecholamines and other substances which increase cellular cAMP levels or inhibit calcium fluxes. Although cholinergic stimuli under certain circumstances induce mast cell degranulation and histamine release no definite role has yet been established for cholinergic mechanisms in type I allergies. Type II (Cytotoxic) and type III (immune complex mediated) allergies share the complement requirement. As far as mast cells and basophils are involved in such reactions their sensitivity towards pharmacological modulators is comparable to reactions induced by chemical histamine releasers. Otherwise these types of allergic reactions are dominated by phenomena of general inflammation. In those mainly cytotoxic effects of lipases and hydrolases are involved. cAMP active agents have, therefore, only limited modulating effects and steroid hormones are more effective in inhibiting the acute lesions in type II and III allergies. Only during the last decade the involvement of chemical mediators in type IV (cellular immunity) allergic reactions has been appreciated. 26 different factors called lymphokines have been discovered and classified as mediators of cellular immune reactions. However, rather little is yet known about their chemical nature and about the influence of drugs on their production or action.