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  • 1
    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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  • 2
    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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  • 3
    ISSN: 1573-8280
    Keywords: C-kit Ligand ; GM-CSF ; Hemopoiesis ; IL-3 ; MGF ; Myelosuppression ; Radiation ; SCF
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulatorin vitro. In these studies, we examined thein vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of60Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100Μg/kg/day), rmGM-CSF (100Μg/kg/day), rmIL-3 (100Μg/kg/day), or combinations of these cytokines on days 1–17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 either produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results ofin vitro studies evaluating the effects of these cytokines on induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size. These studies demonstrate a dichotomy between MGF-induced effectsin vivo andin vitro and emphasize that caution should be taken in attempting to predict cytokine interactionsin vivo in hemopoietically injured animals based onin vitro cytokine effects.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Langenbeck's archives of surgery 327 (1970), S. 281-284 
    ISSN: 1435-2451
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    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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  • 6
    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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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Cancer immunology immunotherapy 5 (1978), S. 153-163 
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The divergent experimental results in immunotherapy of spontaneous, chemically induced or virus-induced solid tumors or leukemias with neuraminidase are reviewed and analyzed under the various aspects of the possible modes and conditions of action of the enzyme: Immunocompetence of the host, animal residual tumor volume, enzymatic activity of the neuraminidase, and identity of the antigenic specificity within the tumor system are well-known prerequisites for an effective tumor immunotherapy. In addition, there seems to be evidence that the number of tumor cells used for vaccination and the dose of enzymatically active VCN, whether bound to VCN-treated tumor cells or injected intratumorally, may be decisive in the negative or positive outcome. Moreover, there are indications that a preexistent sensitization against the so-called Thomsen-Friedenreich antigen, which seems to be unmasked after VCN treatment of cells, may influence the tumor therapeutic success. The effect of nonspecific immunostimulators given in addition to neuraminidase or to neuraminidase-treated cells is controversial. Thus, this combination cannot be recommended unless it is fully explored. To overcome the problem of the dependence of the tumor therapeutic effect on the dose of cells and the amount of neuraminidase with respect to different tumors and different adjuvant treatments, a new immunization concept, named ‘chessboard vaccination’, has been proposed. The data obtained so far in vitro and in vivo with this chessboard vaccination are briefly reviewed. They show that chessboard vaccination might be of diagnostic as well as of therapeutic interest.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Treating MRL/1pr mice, which spontaneously develop systemic lupus erythematosus and rheumatoid arthritis, with 15-DOS resulted in a decrease in the amount of autoantibodies and inhibited proteinuria of the developing glomerulonephritis with an improved survival rate of these autoimmune mice. 15-DOS treatment also lowered the percentage of animals with swollen lymph nodes and inhibited the development of splenomegaly. In the established disease 15-DOS returned urine-protein values and renal function (serum urea and creatinine) to normal levels. Circulating rheumatoid factor and autoantibodies to double-stranded DNA were reduced and the increase in paw volume (signs of a polyarthritis) was inhibited.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We examined the therapeutic effect of 15-DOS in the two models of acute and chronic relapsing EAE in Lewis rats. In the first model adult rats developed an acute severe EAE and by day 16 all animals died. Lewis rats treated with 15-DOS showed a delayed and reduced onset of clinical symptoms and mortality was prevented. In the second model Lewis rats (aged animals) developed a chronic relapsing EAE with up to three relapses. The second and third episodes were both milder and shorter in duration. All animals treated with 15-DOS survived the delayed first attack and developed no further relapses.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The anti-ratα/β-TCR, MAb-R73 has been investigated as to its disease modifying activity on adjuvant arthritis (AA), on experimental allergic encephalomyelitis (EAE) and on a local graft versus host (GvH) reaction (popliteal lymph nodes=PLN) in Lewis or Brown-Norway rats. R73 was able to prevent the onset of the AA and even if therapy started after the establishment of AA the MAb was still able to reduce the degree of chronic inflammation and arrest its progress. Intraveneous MAb-R73 application also reduced the signs of EAE and prevented mortality. This was even seen when the substance was given after the outbreak of the clinical symptoms or when the F(ab)2 fragment of this MAb was used. Also in the model of local GvH reaction R73 acted therapeutically and lowered the PLN weights.
    Type of Medium: Electronic Resource
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