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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 58 (1980), S. 593-605 
    ISSN: 1432-1440
    Keywords: Immunkomplexe ; Makrophagen ; Phagozytose ; Immune Complexes ; Macrophages ; Phagocytosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Elimination of IC by the phagocytic system occurs mainly by macrophages and contrarotates to the pathogenic effect. Decisive to prevent systemic IC disease is the capacity of the phagocytic system. In the case of its saturation, the danger of the occurrence of IC disease is greatly enhanced. Conclusive evidence seems to exist that IC of extremely small or extremely high lattice structure (precipitates) are less pathogenic than soluble IC of medium network. Small IC in extreme antigen and antibody excess or precipitates exhibit a reduced complement activating potency. Small IC in extreme antigen or antibody excess hardly interact in vitro with membrane receptors and do not induce IC disease when injected or formed in vivo. Highly lattices IC, especially precipitates, are eliminated extremely quickly from the circulation, mainly by macrophages and there deposition in the kidney is significantly reduced. Thus, lack of quality of the antibody to precipitate the antigen and a reduced capacity and effectivity of the phagocytic system to eliminate the IC may be extremely important in the generation of IC diseases. Facing the overwhelming and partly even inconsistant data of this topic, one may doubt whether IC diseases may be regarded to be a defined and coherent disease. Too many variables and questions exist concerning the nature of the antigen, especially in tumor and autoimmune diseases, concerning the quality of the antibody and the characteristics of the pathogenic IC and concerning localization and the elimination process. Nevertheless, common pathophysiological pathways of IC diseases may be recognized.
    Notes: Zusammenfassung An der Elimination von IC durch das phagozytierende System sind im wesentlichen die Makrophagen beteiligt. Die Phagozytose von IC läuft den pathogenen Auswirkungen von IC zuwider. Die Kapazität des phagozytierenden Systems ist somit entscheidend für die Verhinderung von systemischen IC-Erkrankungen. Im Falle der Sättigung dieses Systems wächst somit die Gefahr für IC-Erkrankungen. Es scheinen überzeugende Hinweise zu bestehen, daß IC sehr kleinen oder sehr großen Vernetzungsgrades (Präzipitate) weniger pathogen sind als lösliche IC mittlerer Vernetzung. Kleine IC im extremen Antigenoder Antikörperüberschuß oder Präzipitate zeigen eine verminderte Potenz, Komplement zu aktivieren. Kleine lösliche IC im extremen Antigen- oder Antikörperüberschuß treten in vitro kaum mit Membranrezeptoren in Wechselwirkung und verursachen keine IC-Erkrankung, wenn sie injiziert werden oder in vivo sich bilden. Hoch vernetzte IC, besonders Präzipitate, werden extrem schnell aus dem Kreislauf eliminiert, und dies vorwiegend durch Makrophagen. Des weiteren ist ihre Ablagerung in der Niere deutlich vermindert. Somit dürfte ein Mangel des Antikörpers Antigen zu präzipitieren und eine verminderte Kapazität und Wirksamkeit des phagozytierenden Systems IC zu eliminieren außerordentlich entscheidend für die Entstehung von IC-Erkrankungen sein. In Anbetracht der überwältigenden und teilweise sich widersprechenden Daten könnte man bezweifeln, IC-Erkrankungen als eine definierte und einheitliche Erkrankungsgruppe anzusehen. Zu viel Variabilitäten und Fragen bestehen bezüglich der Natur des Antigens, speziell in Tumor- und Autoimmunerkrankungen, betreffend der Qualität des Antikörpers und der Charakteristika der pathogenen IC und bezüglich der Lokalisation und der Elimination. Trotzdem können jedoch Gemeinsamkeiten bei den verschiedenen IC-Erkrankungen erkannt werden.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1440
    Keywords: Immune complexes ; i.v.-immunoglobulin preparations ; 7S-IgG ; F(ab')2 ; Fab ; Inflammation ; Side-effects ; Therapy ; Prophylaxis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Antibodies of the IgG class possess antibacterial, antiviral and toxin neutralizing properties and for this reason are administered prophylactically and therapeutically. In the case of the immunoglobulin preparations commercially available for i.v. application a basic distinction must be made between unsplit immunoglobulins and those antibody preparations obtained by enzymatic digestion, such as F(ab')2 or Fab antibodies. This survey deals with the largely experimental evidence describing the biological properties of these preparations. Administration of antibodies in the presence of the corresponding antigens leads to the formation of immune complexes in the organism. These immune complexes can activate, either directly or indirectly, the cellular and humoral systems which are involved in phagocytosis and the elimination of antigens, in the regulation of the body's own antibody production and in inflammatory reactions. As a result of their inability to interact with Fc receptors, immune complexes with F(ab')2 or F(ab) antibodies appear to be less active in the release of inflammation mediators from leucocytes and thrombocytes than immune complexes with unsplit immunoglobulins. These, on the other hand, can antigen-specifically and non-antigenspecifically suppress the immune system which is not the case for immune complexes with F(ba')2 or Fab antibodies. There are indications that these split products also occur in vivo due to the action of tissue and leucocyte proteases. Unlike Fab prcparations, F(ab')2 antibodies have antibacterial and antiviral potencies similar to unsplit immunoglobulins, which is probably due to the ability of F(ab')2 molecules to activate complement, not by the classical but by the alternative pathway. Like Fab preparations, F(ab')2 molecules appear to be superior to unsplit IgG in the elimination of haptens. On account of the relatively long period of time unsplit immunoglobulins remain in the blood, they are well suited for prophylactic treatment and substitution over longer periods. The extent to which indications, obtained predominantly from experimental studies, of a reduced release of inflammation mediators, a lack of immune suppression and a lack of augmentation of IgG catabolism would advocate the use of F(ab')2 split products, especially for therapeutic purposes, can only be ascertained after prospective and comparative studies have been carried out.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 55 (1977), S. 199-214 
    ISSN: 1432-1440
    Keywords: Neuraminidase ; Tumor ; Immuntherapie ; Experimentelle Untersuchungen ; Klinische Studien ; Übersicht ; Neuraaminidase ; Tumor ; Immunotherapy ; Experimental Results ; Clinical Studies ; Review
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Preliminary results of first clinical studies with the enzyme neuraminidase call attention to a new kind of cancer treatment. This promising approach to tumor immunotherapy was entered into the clinical phase as a consequence of successful experimental studies in tumor-bearing mice, rats and dogs. In this review, the presently known and essential results of experimental and clinical studies on tumor immunotherapy by means of neuraminidase are presented as well as some necessary and critical considerations in this context. Moreover, out of a broad variety of results of biochemical and biological in vitro studies, it was attempted to select the more essential knowledge which could contribute to a better understanding of the still rather unclear in vivo mode of action of the enzyme neuraminidase. In a first brief paragraph (1.0), the biochemically characteristic data of the enzyme neuraminidase is presented. In the second section (2.0), the basic knowledge about the effects of neuraminidase on cell behavior is rather amply contained. Here, on the one hand, the biophysical and biochemical alterations are mentioned, the so-called “unmasking” effects are reconsidered and, on the other hand, the effects on the immunologically responding cell are discussed. In a third section (3.0), the diverse findings from animal experiments using neuraminidase-treated tumor cells are confronted, whereby tumor transplantation experiments and tumor therapy experiments are dealt with separately. The last section (4.0) reports about the first clinical studies with neuraminidase-treated autologous as well as homologous tumor cells, which partly brought about rather surprising and astonishing success. On the basis of recent findings by the study group of the authors, the more prior and sometimes discrepant results of various groups are critically considered. The problems of alteration of antigenicity and of other properties of cells through splitting off membrane-bound neuraminic acid, the facts of adjuvanticity of neuraminidase itself, the relation of successful therapy to dose dependency as well as the relation of undesirable methods for tumor mass reduction to the immunological responsiveness of the tumor bearer were especially looked into.
    Notes: Zusammenfassung Erste Ergebnisse aus klinischen Versuchen mit dem Enzym Neuraminidase machen auf eine neue Art der wirksamen Tumorbehandlung aufmerksam. Eingang in die Klinik fand diese vielversprechende Tumor-Immuntherapie nach erfolgreichen tierexperimentellen Studien an tumortragenden Mäusen, Ratten und Hunden. In einer Übersicht sind die derzeit bekannten und wesentlichen experimentellen und klinischen Ergebnisse über die Tumor-Immuntherapie mit Neuraminidase und die in diesem Zusammenhang notwendigen kritischen Überlegungen dargestellt. Darüberhinaus wird versucht, aus der breiten Vielfalt der biochemischen und biologischen Ergebnisse aus in-vitro Studien die wichtigeren Erkenntnisse auszuwählen, die zum Begreifen der noch weitgehend ungeklärten Wirkungsweise des Enzyms in-vivo beitragen können. In einem kurzen ersten Abschnitt (1.0) sind die charakteristischen biochemischen Daten des Enzyms Neuraminidase aufgeführt. Der zweite Teil (2.0) enthält etwas ausführlicher die Erkenntnisse über die Wirkung der Neuraminidase auf das Verhalten von behandelten Zellen: Hierbei werden einerseits die biophysikalischen und biochemischen Veränderungen angesprochen sowie die sog. „demaskierenden“ Effekte überdacht und andererseits wird die Wirkung auf die immunologisch antwortenden Zellen erörtert. In einem drittenTeil (3.0) sind die unterschiedlichen Befunde aus Tierexperimenten mit Neuraminidasebehandelten Tumorzellen gegenübergestellt, wobei zwischen Tumortransplantations-Experimenten und Tumortherapie-Versuchen unterschieden wurde. Der letzte Abschnitt (4.0) berichtet über die ersten tumortherapeutischen klinischen Studien mit Neuraminidase-behandelten autologen und homologen Tumorzellen, die zum Teil sehr überraschende und erstaunliche Erfolge erbracht haben. Auf der Grundlage neuerer Befunde aus der Arbeitsgruppe der Autoren werden frühere, zum Teil widersprechende Ergebnisse aus verschiedenen Arbeitsgruppen kritisch überdacht. Auf die Fragen nach der Veränderung der Antigenität und anderer Zelleigenschaften durch die Abspaltung der membrangebundenen Neuraminsäure, der Adjuvanswirksamkeit von Neuraminidase selbst, der Beziehung zwischen erfolgreicher Therapie und Dosisabhängigkeit zum einen und der Beziehung zwischen unerwünschten Methoden zur Reduktion der Tumormasse und immunologischem Reaktionsvermögen des Tumorträgers zum anderen wird besonders eingegangen.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 58 (1980), S. 543-550 
    ISSN: 1432-1440
    Keywords: Immunkomplexe ; Antigen-Antikörper-Wechselwirkung ; Komplement ; Hagemanfaktor ; Immune Complexes ; Antigen-Antibody Interaction ; Complement ; Hageman Factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Immune complexes (IC) may be pathophysiologically active in correlation with the nature and size of the antigen, the type and the quality of the antibody, and the concentration of both. Those parameters are decisive for the composition and the lattice structure of IC. Pathogenic effects are induced: by complement activation and generation of biologically active C′ split products via the classical and the alternative pathway, by interaction with Fc and complement receptors resulting in exocytosis of lysosomal contents including degradative enzymes, cationic proteins, vasoactive amines and mediators effective on lymphocytes and macrophages; by direct and indirect activation of the Hageman factor followed by stimulation of the kinin, coagulation and fibrinolysis system; and by modulation of the immune response via the afferent and the efferent branch. All those mechanisms seem to be involved in the induction of lesions along the vessel wall in the various privileged organs.
    Notes: Zusammenfassung Die pathophysiologische Rolle von Immunkomplexen (IC) ist abhängig von deren Zusammensetzung und Vernetzungsgrad. Entscheidend für diese Parameter sind Art und Größe des Antigens, Klasse und Bindungsqualität des Antikörpers und die Konzentration beider Anteile. Pathogene Auswirkungen der IC werden hervorgerufen - durch Aktivierung von Komplement Über den klassischen und den alternativen Weg und der Bildung von biologisch aktiven Komplementspaltprodukten, - durch Wechselwirkung mit Fc und Komplementrezeptoren, was wiederum zur Exozytose lysosomaler Substanzen inklusiv kataboler Enzyme, kationischer Proteine, vasoaktiver Amine und Mediatoren, wirksam auf Lymphozyten und Makrophagen, führt. - durch direkte und indirekte Aktivierung des Hagemanfaktors, gefolgt von der Stimulation des Kinin-, Gerinnungs- und Fibrinolysesystems, - und durch Beeinflussung der Immunantwort über den afferenten und den efferenten Weg. All diese Mechanismen scheinen an der Entstehung von Läsionen entlang der Gefäßwand in den jeweiligen disponierten Organen beteiligt zu sein.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of medicinal chemistry 33 (1990), S. 166-171 
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-2307
    Keywords: Carcinoembryonic antigen ; Monoclonal antibodies ; Pancreatic tumours ; Immunoreactivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The expression of CEA and related antigens in formalin-fixed paraffin-embedded tissues of normal pancreas and different pancreatic neoplasms was studied immunocytochemically using three monoclonal antibodies (MAbs) recognizing different epitopes on CEA and related antigens. Additionally, a number of extrapancreatic malignancies were tested. The epitope recognized by MAb 250 (present on CEA and NCA 95) was expressed in all but one pancreatic ductal adenocarcinoma and ampullary carcinoma (42/43). The MAb 431 defined epitope (present only on CEA) was less frequently found (27/43). MAb 374, defining an epitope on CEA, NCA 95 and NCA 55 proved to be nearly as sensitive tive as MAb 250, but also reacted with normal duct epithelium. In contrast, MAb 250 and MAb 431 discriminated clearly between reactive duct lesions and malignant duct changes. Moreover, these MAbs differentiated between pancreatic duct carcinomas and nonduct type carcinomas as well as benign pancreatic tumours. In duct type carcinomas, the strongest staining was observed in well differentiated tumours. No discrimination was possible between pancreatic carcinomas and other adenocarcinomas of the gastrointestinal tract nor between most of the lung carcinomas and some other malignancies, specified below. MAb 250 and MAb 431 failed to react with hepatocellular carcinomas, renal cell carcinomas, carcinoids, sarcomas and melanomas. The findings suggest that paraffin-embedded tissues of pancreatic duct type carcinomas, in contrast to nonduct type tumours and normal ducts, are distinguished by the presence of a CEA and NCA 95 related epitope.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Monoclonal antibodies (mAbs) BW 625 and BW 704, of the IgG3 isotype, bound to immunochemically indistinguishable epitopes on ganglioside II3(NeuAc)2-GgOse3-Cer. Despite this fact the mAbs showed a differential binding pattern on human glioma cell lines i.e. immunohistochemical data indicate that the detected epitopes are not identical. Furthermore, either mAb is able to mediate the antibody-dependent cellular cytotoxicity reaction (ADCC) and the human-complement-dependent cytotoxicity reaction (CDC) with epitope-expressing tumor cells. All cryopreserved tissue specimens from gliomas and neuroblastomas were immunohistochemically stained, whereas the other small round cell tumors of childhood, as well as melanomas and small-cell lung carcinomas, were essentially negative. Positive staining of normal cryopreserved tissues was restricted to amyelinic axons, Hassal's bodies and some connective tissue fibers in thymus and the tegumentary epithelium of skin. The high selectivity of mAb BW 704 for gliomas and neuroblastomas, the lack of cross-reactivity with major tissues and the strong ADCC and CDC potential argue for the use of mAb BW 704 in immunotherapy of neuroblastomas and gliomas.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect produced on tumor progression by the injection of either VCN-treated tumor cells or tumor cells mixed with VCN to dogs with spontaneous mammary tumors was investigated. Dogs of different breeds and ages with at least two palpable spontaneous mammary tumors were selected. One tumor was left in the animal for further clinical examination, whereas the other tumor(s) was (were) excised for histologic diagnosis and for preparation of a single-cell suspension. Autologous M-cells were treated with VCN, subsequently extensively washed and injected SC into the neck of the dog on the day of operation and on the next day or different numbers of autologous M tumor cells (105, 106, 107, 5×107, 108) were mixed with different amounts of VCN (0, 0.65, 6.5, 65 mU), and these various mixtures were injected ID at different sites to each dog on the day of operation. This procedure has been called chessboard vaccination (Seiler and Sedlacek, 1978). Altogether 79 dogs were blindly distributed into six groups in three consecutive studies. The results show that the therapeutic effect of the injection of VCN-treated autologous tumor cells depends on the number of tumor cells injected: injection of 2×107 tumor cells repeatedly induced regression of the residual tumor mass (Studies I, II, and III) in most dogs and prevention of metastasis (Study I), while the application of 1×108 tumor cells caused enhanced tumor proliferation in all and early metastasis in most of the dogs (Study I). The injection of 2×106 tumor cells induced only a transient regression, with subsequent progression of the residual mammary tumor (Study II). Repetition of the injection of 2×106 tumor cells three times every 4 weeks did not improve this effect (Study II). The chessboard vaccination proved to be at least as effective as the injection of 2×107 VCN-treated tumor cells (Study III), although 1×108 or more tumor cells had been injected; this number of cells caused tumor enhancement when the cells were treated with VCN only and injected SC (Study I). Moreover, the DTH reaction after ID injection of autologous tumor cells could be increased by the addition of VCN: low numbers of tumor cells and high amounts of VCN or high numbers of tumor cells and low amounts of VCN caused the most pronounced skin response. The relevance of these data to overcoming the risk of tumor enhancement after injection of an inadequate number of VCN-treated tumor cells and the possible diagnostic and therapeutic relevance of the DTH response after chessboard vaccination will be discussed.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Cancer immunology immunotherapy 23 (1986), S. 192-199 
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The therapeutic effect of i. d. injection of tumor cells mixed with Vibrio cholerae neuraminidase (VCN) on tumor progression in dogs with spontaneous mammary tumors was investigated. The i. d. injections were performed in a chessboard-like manner: different numbers (105, 106, 107, and 108) of mitomycin-treated autologous tumor cells (M-TC) were each mixed with different amounts (10, 50, and 100 mU) of VCN. These different mixtures were injected i. d. at different sites in dogs on the day of resection of a part of multiple tumors. In a randomized prospective study in 71 dogs the effect of chessboard vaccination (autologous tumor cells and VCN) on the growth of the residual tumor mass was compared to chessboard-like treatments with mixtures of either autologous erythrocytes and VCN or autologous tumor cells and heat-inactivated VCN. The results show that: chessboard vaccination induced regression (6 of 23) of spontaneous mammary tumors in dogs. No dog died as a result of the tumor within an observation period of 1 year. The therapeutic effect of chessboard vaccination was dependent on the application of tumor cells and enzymatically active VCN. In contrast, control treatment with either heat-inactivated VCN or autologous erythrocytes instead of tumor cells did not induce any regressions. Some animals in both control groups died because of tumor growth (3/21 and 2/27 respectively). The delayed type hypersensitivity (DTH) response of tumor-bearing animals against i. d. applied tumor cells was not significantly enhanced by the admixture of enzymatically active VCN, nor did the DTH response seem to be predictive of a therapeutic effect on the tumor. No difference in the DTH response of dogs to autologous tumor cells mixed with active or inactivated VCN or autologous erythrocytes mixed with active VCN could be found. Thomsen-Friedenreich antigens were serologically detected on canine erythrocytes after treatment with VCN and on untreated cells of mammary tumors from dogs. Exposure of Thomsen-Friedenreich antigens after treatment with VCN was enhanced on canine mammary tumors. As chessboard vaccination proved to be unsuccessful when canine autologous erythrocytes were used instead of autologous tumor cells, it can be concluded that the exposure of Thomsen-Friedenreich antigen plays no decisive role in tumor therapy with tumor cells and VCN. Chessboard vaccination was tolerated without any side effects. Tumor enhancement was never observed. Chessboard vaccination appears to be an effective and safe procedure for tumor therapy using tumor cells and VCN. The mechanism underlying the therapeutic effect of chessboard vaccination is completely unknown.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The murine monoclonal antibody (MAb) BW 494 was characterized in relation to its tissue specificity, the epitope recognized, in vitro and in vivo radiolocalization and its potential to mediate antibody dependent cellular cytotoxicity (ADCC) and complement mediated cytolysis (CMC). The MAb defined carbohydrate epitope located on a 〉200 k daltons glycoprotein was mainly expressed on the majority of well differentiated adenocarcinomas of the pancreas. Furthermore, the epitope is accessible to MAb BW 494 in vivo, allowing an enrichment of radioactive antibody at the tumor site in nude mice. Additionally, MAb BW 494 is able to use human peripheral blood lymphocytes as effector cells for ADCC reactions against appropriate tumor target cells in vitro. In contrast, the antibody does not mediate human or rabbit CMC.
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