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PubMed1983

On the biological role of lipid chemotactic factors.

Our experimental data of the past seven years cover the generation of a non-preformed lipid-mediator which primarily assayed with guinea pig eosinophils proved to be eosinophil chemotactic. The analysis of the various stimuli led in 1978 to the concept of the phospholipase-arachidonic sequence as a common link for membrane activation. Immunopharmacological studies using either arachidonic acid as stimulus or arachidonic acid analogues provided an early evidence that the lipid chemotactic factor was a lipoxygenase product. These results were supported by analytical studies using thin layer chromatography, reversed phase HPLC, mass spectrometry, the comparison of the lipid chemotactic factor with endogeneous HETEs and by the synthesis of mono- and di-HETEs. It became also evident that mono- and di-HETE are not only mediators but also modulators of inflammatory reactions as was demonstrated for the C5a induced eosinophil chemotactic response. A less pronounced effect on the C5a induced eosinophil and neutrophil chemotactic response was exerted by PAF and its structural analogues. It is also demonstrated that isolated bacterial exotoxins trigger the cells via the phospholipase-arachidonic acid sequence thus generating mono- and di-HETEs leading to the amplification of an inflammatory response.

Animals↗
PubMed1989

Factors influencing antibody-mediated cytotoxicity during the immunotherapy of Rauscher-virus-induced myeloid leukemic cells.

The present study was undertaken to determine the factors that influence antibody-mediated cytotoxicity during immunotherapy of virally transformed tumor cells. As model a Rauscher-virus-induced myeloid leukemic cell line of BALB/c origin (RMB-1) was used, which forms disseminated tumors, when inoculated intravenously in BALB/c mice. As previously reported, prolonged survival was obtained when tumor-bearing mice were treated in vivo with a single high dose of a tumor-specific IgG2a monoclonal antibody. This study shows that antibody-dependent cellular cytotoxicity is an important mechanism involved in tumor cell destruction. Since in vitro studies showed that peritoneal macrophages were capable of killing RMB-1 cells in the presence of tumor-specific monoclonal antibody and since in the tumors of mice treated with monoclonal antibody a high influx of macrophages was observed histologically, it is likely that macrophages play an important effector role in elimination of tumor cells. Successful therapy in C5-complement-deficient tumor-bearing mice suggests that complement-dependent cytotoxicity does not play a major role. In nude (T-cell-deficient) mice the therapeutic effect of tumor-specific IgG2a antibody was significantly less than in immunocompetent mice. Although infiltration analysis of tumors of treated and untreated mice showed equally low numbers of helper-T and suppressor/cytotoxic T-cells, the mortality studies of T-cell-deficient and immunocompetent mice indicate that T-cells play a substantial, auxiliary role during antibody-mediated, tumor destruction in our model.

Animals↗
PubMed1990

[Immunohistochemical C5b-9-complement complex demonstration in early stages of myocardial necroses using paraffin sections].

With conventional staining techniques it was nearly impossible to differentiate with certainty between early ischemic myocardial lesions, autolytic changes and intact myocardium without a nuclear section. In 1986 it was introduced an immunohistochemical method, which presented C5b-9 Complement Complex as a necrosis marker in cryostat sections. Our further development of this process has resulted in a technique for application on routine paraffin sections: C5b-9 Complement Complex is particularly well-suited for the exact and autolytically insensitive presentation of disseminated necroses of fiber bundels and single fibers of myocardium. The application of the technique on paraffin sections will lead to the use of the same in forensic medicine routine diagnostics of early ischemic myocardial lesions, even in cases of "sudden" cardiac death.

Complement C5↗
PubMed1981

Isolation of three separate anaphylatoxins from complement-activated human serum.

Recent methodologies used in preparing anaphylatoxins from complement-activated serum are described. Activation of the alternative pathway generates C3a and C5a; however, activation of the classical pathway is required to generate the anaphylatoxin from C4. This article describes an activation scheme that simultaneously generates all three of the anaphylatoxins (e.g., C3a, C4a and C5a) in human serum and outlines a procedure for isolating each as homogeneous products. Purification of intact anaphylatoxins directly from complement-activated serum takes place only if an exopeptidase in serum, known as carboxypeptidase N (SCPN), is properly inhibited. A new series of mercapto derivatives of arginine analogs are introduced as potent and effective inhibitors of SCPN. These inhibitors permit normal complement activation but prevent degradation of the released activation fragments C3a, C4a or C5a. The SCPN inhibitor previously used was 6-aminohexanoic acid (EACA), but it required a 1 M concentration for effective inhibition, the substituted mercapto-guanido compounds prove to be effective in the mM range.

Aminocaproic Acid↗
PubMed1985

Detection of complement activation in human serum using C5a-induced chemiluminescence of human granulocytes.

The complement system can be activated by many factors, including immune complexes, leading to the generation of biologically active split products like C5a anaphylatoxin. This study presents a technique which may be used for measuring C5a activity in human serum. The tetanus-anti-tetanus immune complex and aggregated human IgG were used as model activators of the complement cascade. The C5a activity was measured by C5a-induced chemiluminescence of granulocytes; furthermore, a radioimmunoassay was used to detect the C5a peptide. There was a strongly positive correlation between the two assay systems. The described method should be useful as an alternative means of detecting complement activation in the serum of patients with inflammatory diseases.

Antigen-Antibody Complex↗
PubMed1983

Chemotaxis: basic aspects of methodology, mechanisms and pathology.

This review is an attempt to discuss the basic conceptual tools that are a prerequisite for any clinical study of chemotactic defects. They include familiarity with definitions of common terms and with the merits and drawbacks of the several possible in vivo and in vitro assay methods. Cellular mechanisms involved in locomotion are complex. They include basic requirements for cell metabolism as well as receptor recognition, attachment to surfaces and contraction of the cytoskeleton of the cell. Of the many chemotactic factors reported, few are well characterized and universally agreed upon. Similarly, with the use of more stringent criteria, a number of clinical defects of chemotaxis have proven transitory or even artifactual.

Adult↗
PubMed1989

Analysis of the proinflammatory property of epidermal cyst contents: chemotactic C5a anaphylatoxin generation.

We investigated in vitro the contents of epidermal cysts for complement activation and found that they activated complement mainly through the alternative pathway. Chemotactic C5a anaphylatoxin produced by the cyst contents after contact with serum most likely plays a significant role in the initiation and aggravation of inflammation in ruptured epidermal cysts. Our additional study disclosed that components of three representative follicular resident microorganisms (Pityrosporum ovale, Propionibacterium acnes, and Staphylococcus epidermidis) also produced C5a anaphylatoxin mainly through the alternative pathway; the C5a production was more vigorous than that by a virulent pathogen, Staphylococcus aureus. These results suggest that accidental colonization of the cyst contents by these follicular microbial flora further augments the inflammatory changes in ruptured epidermal cysts.

Adult↗
PubMed1988

Epidermal lymphocyte chemotactic factor specifically attracts OKT4-positive lymphocytes.

Epidermal lymphocyte chemotactic factor (ELCF) from skin overlying a positive tuberculin reaction was compared with the chemoattractants leukotriene B4 (LTB4), N-formyl-methionyl-leukyl-phenylalanine (FMLP), and complement split product C5a (C5a). The chemotactic assay used is a modified Boyden chamber technique. The lymphocytes were subsets of T lymphocytes from healthy young individuals first separated by flotation of E rosettes on Isopaque Ficoll followed by incubation of T cells with anti-CD4 and anti-CD8 monoclonal antibodies and further separation using fluorescence-activated cell sorting. ELCF specifically attracted OKT4+ lymphocytes, while LTB4, FMLP, and C5a induced significant migration in both OKT4+ and OKT8+ lymphocytes without any clear difference between the various chemoattractants or cell populations. We found no blocking of the chemotactic capacity of ELCF when we added antibodies towards IL-1 alpha and IL-1 beta to the chemotactic assay. Further recombinant IL-1 alpha and Il-1 beta did not induce any chemotactic response. Our observation may be of significance in explaining the predominance of OKT4+ cells in allergic contact dermatitis and certain other skin diseases.

CD4-Positive T-Lymphocytes↗
PubMed1985

Involvement of complement in psoriasis and atopic dermatitis--measurement of C3a and C5a, C3, C4 and C1 inactivator.

Normal complement components and activation products were determined in the peripheral blood of 35 patients with atopic dermatitis (AD) and 24 patients with psoriasis at a mild to intermediate stage. None of the patients had received systemic or local steroid therapy 6 weeks prior to blood collection. Levels of C3, C4 and C1 inactivator (C1 INA) were determined in serum by radial immunodiffusion, whereas C3a and C5a levels were measured by radioimmunoassay. In comparison to healthy non-atopic controls, the levels of C3, C4 and C1 INA were found to be significantly increased in both diseases. No substantial differences were detected between patients with psoriasis vulgaris and psoriasis guttata, which suggests that the dissimilarities found were not due to preceding or concomitant infections. In AD, there was a tendency towards increased C3a levels, whereas in psoriasis, C3a levels were significantly increased. In both diseases, no measurable amounts of C5a could be detected. The results indicate that, in both AD and psoriasis, the complement participates in the inflammatory process. Elevated levels of C3a suggest that there is a continuous activation of the complement system leading to the generation of inflammatory mediators.

Adolescent↗
PubMed1976

Induction of platelet aggregation by the complement-derived peptides C3a and C5a.

The effect of two complement-derived peptides, hog serum C3a and C5a, on platelet aggregation in platelet-rich plasma and suspensions in Tyrode solution was investigated. 1. Guinea-pig platelets were aggregated by both C3a and C5a; the spasmogenically inactive product of C3a, C3ai, also induced aggregation. Threshold concentrations were in the range of 10(-6)--10(-9) M depending on the peptide and platelet preparation. 2. Cat platelets were aggregated by C5a (threshold concentrations 10(-7)--10(-8) M) but not by C3a. 3. Platelets from pig, rabbit and man were not aggregated by either of the two peptides in concentrations of up to 5 X 10(-6) M. 4. When C5a was administered repeatedly in subthreshold doses guinea-pig platelets became tachyphylactic to C5a but were still aggregable by C3a or ADP. Conversely, platelets desensitized to C3a still reacted to C5a or ADP. Tachyphylaxis towards C5a developed also when platelets were incubated with C5a in the absence of free Ca2+ under which condition they do not react. The tachyphylaxis in this case became evident after recalcification of the medium. The lack of cross-desensitization indicates that C3a and C5a react via different receptors. 5. C3a and C5a were injected i.v. into guinea pigs. Histological examination of the lungs revealed that some of the smaller vessels (20-30 mu in diameter) were occluded by platelet aggregates. In addition signs of severe acute emphysema were seen in animals treated with C5a, but only slight emphysema in C3a-treated animals. Intravenous injections of C3a into guinea pigs caused but weak respiratory distress and drowsiness and never killed an animal (at doses of up to 20 mg per kg body weight), whereas C5a caused the well-known severe respiratory failure and death already at doses of 0.03 mg/kg body weight.

Anaphylatoxins↗
PubMed1981

Comparative study on biological activities of various anaphylatoxins (C4a, C3a, C5a). Investigations on their ability to induce platelet secretion.

Several anaphylatoxic substances (human C3a, guinea pig C3a, human C4a, guinea pig C5a, and a synthetic C3a-related hexapeptide) were compared with regard to their ability to induce secretion of [3H] serotonin from guinea pig platelets. Functional identity of the C3a preparations, C4a, and the hexapeptide was demonstrated by the phenomenon of crossed desensitization. Whereas C3a of human and guinea pig origin proved to be qualitatively and quantitatively identical, C4a expressed only 3% of the activity of the C3 fragments on a molar basis. Investigations with goat anti-guinea pig C3a demonstrate that human and guinea pig C3a possess one antigenic determinant in common; however, this determinant is not the C-terminal amino acid sequence. Addition of the anaphylatoxins with low doses of thrombin led to a potentiation of [3H] serotonin release from the platelets. Under these conditions C3a concentrations of 1.5 X 10(-10) mumol/liter (65 pg of C3a) could be detected. Thus the platelet system represents the most sensitive in vitro assay known for evaluation of biological activity of the C3a anaphylatoxins.

Anaphylatoxins↗
PubMed1985

Stimulus interactions in release of superoxide anion (O2-) from human neutrophils. Further evidence for multiple pathways of activation.

A wide variety of agents stimulate superoxide anion (O2-) release from human neutrophils. To determine whether the same or different cellular pathways are utilized, neutrophils were stimulated to release O2- with combinations of f-Met-Leu-Phe (FMLP) (10(-7)M), C5a (25 nM), Con A (100 micrograms/ml), arachidonic acid (100 microM), and PMA (1 microgram/ml). These concentrations produced maximal O2- production when used alone. A synergistic response was observed when Con A was used in combination with FMLP or C5a. This response was twice the expected release in cytochalasin B-treated cells and three to five times the expected release in untreated cells. Additional studies showed that synergism was dependent upon the simultaneous presence of both agents. Additive O2- responses were observed when either FMLP, Con A, or C5a was tested in combination with arachidonic acid and when FMLP and C5a were tested together. When PMA was tested with C5a, FMLP, or Con A, a nonadditive O2- response resulted, whereas mixtures of PMA and arachidonic acid resulted in a less than additive response. These contrasting results using different soluble stimuli in combination suggest that multiple pathways exist for the stimulation of neutrophil O2- release, with some stimuli being totally independent of each other (possibly activating separate pools of oxidase), while other stimuli show cooperative effects on oxidase activation.

Adult↗