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  • 1
    ISSN: 1433-0415
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Das Immunsystem hat die Fähigkeit, bösartige Zellen zu erkennen und unter gewissen Umständen zu zerstören. Spontane Regressionen von Tumoren bei Patienten zeugen von dem Vorhandensein und der Effektivität einer natürlichen Immunüberwachung. Eine effektive Tumorabwehr setzt das Zusammenspiel von verschiedenen Zellen und Faktoren voraus, aus der idealerweise eine Tumorabstoßung resultiert. Dieses Zusammenwirken der Zellen zu verstehen, ist die Voraussetzung für die Entwicklung einer Immuntherapie gegen Krebs. In den letzten Jahren wurden malignomreaktive T-Zellen als Effektorzellen der immunologischen Tumorabwehr erkannt. Dieser Mechanismus soll genutzt werden durch den adoptiven Transfer von tumorreaktiven T-Zellen in Patienten mit malignen Erkrankungen.
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  • 2
    ISSN: 1432-0584
    Keywords: Complement system ; C1 inhibitor ; Bone marrow transplantation ; Capillary leak syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Capillary leak syndrome (CLS) is a severe complication after bone marrow transplantation (BMT). To investigate whether there is a pathogenetic role of the complement system, we monitored the levels of the terminal complement complex C5b-9 (TCC) and C3a-desArg as indicators of an activation of the complement system and the inhibitor of the classical pathway of the complement cascade, C1 inhibitor (C1-INH), in 48 bone marrow transplant recipients from 1 week before to 5 weeks after transplantation. Capillary leak syndrome developed in 7 out of 48 patients between days 1 and 12 after BMT. Complement activation as indicated by TCC levels was more pronounced in patients with CLS (n=7) from day −8 to +28 (p〈0.05; day −1) and the elevation of TCC levels lasted longer in CLS patients (peak day 21) than in patients without this complication (peak day 7). Mean C3a-desArg levels were highest in patients with CLS reaching a peak at day 7. During the early posttransplant period a significant elevation of C1-INH levels (p〈0.01 and p〈0.05 respectively) compared with baseline levels (day −8) was found in patients with and without CLS, which was more pronounced in those patients with CLS (p〈0.05). Although we could not observe an absolute C1-INH deficiency as compared to healthy individuals our data support the presence of a relative deficiency of the inhibitor which might explain the reported beneficial effects of C1-INH substitution in BMT related CLS.
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  • 3
    ISSN: 1432-0428
    Keywords: ICA 69 ; insulin-dependent diabetes mellitus ; rheumatoid arthritis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet cell antigen (ICA) 69 is a newly-recognized islet cell antigen to which autoantibodies have been observed in prediabetic relatives of patients with insulin-dependent-diabetes mellitus (IDDM). Here we extend the earlier analysis of ICA 69 antibodies to patients with recent-onset IDDM and to patients with other immune-mediated diseases. ICA 69 antibodies were determined by Western blot using an affinity purified recombinant fusion protein of ICA 69 and maltose binding protein. ICA 69 antibody quantities were determined as titres using a titration curve of a standard serum as reference. Mean logarithmic ICA 69 antibody titres were 3.4 (±1.4) in 99 patients with acute IDDM compared to 2.8 (±0.9) in 49 healthy blood donors (p〈0.001). A higher mean ICA 69 antibody titre of 4.1 (±0.8) was observed in 16 patients with rheumatoid arthritis in comparison to acute IDDM (p〈0.01) and healthy control subjects (p〈0.001). The percentage of sera with ICA 69 antibody titres above the 2 SD level of normal subjects was 21% in IDDM, 31% in rheumatoid arthritis and 6% in healthy blood donors. None of the patients with autoimmune thyroid disease (n=20), inflammatory bowel disease (n=9) or multiple sclerosis (n=7) had elevated ICA 69 antibodies. In IDDM, presence of ICA 69 antibodies persisted and the titre remained the same over 18 months of follow-up. The relationship of ICA 69 antibodies to islet cell antibodies (ICA) or insulin autoantibodies (IAA) was tested. The production of ICA 69 antibodies was not associated in diabetic patients with the presence of any of the two other autoantibodies. In conclusion, this study describes ICA 69 antibodies in acute IDDM and finds them to be independent of other islet autoantibodies. In addition ICA 69 is a target of humoural autoimmunity not only in IDDM but also in rheumatoid arthritis.
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords BB rat ; insulitis ; cytokines ; inducible NO synthase ; BCG ; tetanus toxoid ; lipopolysaccharide.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In diabetes prone BB rat pancreas the Th1/Th2 cytokine balance and the expression of inducible nitric oxide synthase (iNOS) was determined by mRNA analysis before and after the onset of insulitis. Specific mRNA was amplified by reverse transcriptase polymerase chain reaction, quantitated with radiolabelled probes by phosphoimaging and calibrated with the amount of co-amplified β -actin mRNA. At 50 days of age, prior to recognizeable insulitis, there was already significantly enhanced expression of both, Th1 and Th2 cytokines, and of iNOS mRNA, when compared to Wistar rat pancreas (p 〈 0.001). This supports the concept of an inconspicuous early phase of islet infiltration by single immunocytes, called single cell insulitis. At 70 days of age mononuclear infiltration of islets had begun and was associated with upregulation of interferon γ (IFNγ ) and iNOS, but downregulation of interleukin-10 and transforming growth factor β mRNA (p 〈 0.001). These findings correlate the onset of insulitis with a shift of the Th1/Th2 cytokine balance towards Th1 cell reactivity. Indeed there was a close correlation of the Th1/Th2 cytokine ratio but not of absolute IFNγ mRNA levels with the insulitis score. Vaccination at day 50 with tetanus toxoid did not affect cytokine gene expression while diphtheria toxoid and even more strongly BCG administration induced a shift towards Th2 reactivity (p 〈 0.001) while iNOS mRNA was decreased (p 〈 0.01). Oral dosing with immunostimulatory components of Escherichia coli also changed the quality of inflammation. Oral lipopolysaccharide (LPS) from E. coli and OM-89, an endotoxin free extract containing immunostimulatory glycolipopeptides and heat shock protein (hsp) 65, both downregulated IFNγ mRNA while only OM-89 in addition suppressed iNOS mRNA and enhanced Th2 cytokine gene expression (p 〈 0.001). We conclude that the onset of insulitis is associated with a shift towards Th1 cytokine and iNOS gene expression. Diphtheria toxoid and BCG vaccination stimulates Th2 reactivity but does not downregulate Th1. The latter can be achieved through oral administration of LPS or a glycopeptide fraction (OM-89) from E. coli. [Diabetologia (1996) 39: 1448–1454]
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  • 5
    ISSN: 1432-0428
    Keywords: Interleukin-12 ; non-obese diabetic mice ; cyclophosphamide ; T-helper type 1/2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A single dose of cyclophosphamide (250 mg/kg) is known to synchronize and accelerate development of diabetes in non-obese diabetic mice. We have reported previously that cyclophosphamide treatment of 10-week-old female non-obese diabetic mice induces a shift from T-helper type 2 to T-helper type 1 activity in islet lesions. We now show that this shift in regulatory T-cell function is preceded by the expression of interleukin-12 in the islets as well as in the spleen. In the spleen macrophages were identified as the interleukin-12 expressing cell type. At the same time there was little induction of tumour necrosis factor alpha gene expression by macrophages. Since interleukin-12 is well known to drive T-helper cell type 1 responses we assume that interleukin-12 released by macrophages mediates the accelerating effect of cyclophosphamide on islet inflammation in non-obese diabetic mice. mRNA expression of the p40 chain of interleukin-12 in response to cyclophosphamide was not seen in macrophages of Balb/c mice and thus represents an immune abnormality of non-obese diabetic mice favouring T-helper type 1 reactions.
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  • 6
    ISSN: 1432-0428
    Keywords: Keywords Immunotherapy ; in vivo animal models ; adhesion molecules.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Increased concentration of circulating adhesion molecules in human serum have been described in different immune-mediated diseases. Recently, we proposed an immunomodulatory function of soluble forms of the intercellular adhesion molecule-1 (ICAM-1) during the pathogenesis of human Type I (insulin-dependent) diabetes mellitus. To test this hypothesis in nonobese diabetic (NOD) mice, a spontaneous animal model for human Type I diabetes, two recombinant forms of soluble murine ICAM-1 were generated, one monomeric soluble ICAM-1 containing all five extracellular Ig-like domains of ICAM-1 (rICAM-1) and one dimeric protein with the N-terminal extracellular domains fused to the constant regions of murine IgG2 a (rICAM-1-Ig). Beginning at age 35 days prediabetic NOD mice received i. p. injections of 5 μg recombinant ICAM-1-proteins three times a week for 4.5 months. At day 170 diabetes development was reduced (p 〈 0.001) in NOD mice receiving rICAM-1 (8 %) or rICAM-1-Ig (8 %) treatment in comparison with sham treated animals (45 %). After termination of therapy animals treated with multimeric rICAM-1-Ig were protected longer than animals treated with rICAM-1. Prevention of diabetes was associated with decreased infiltration of pancreatic islets by mononuclear cells. A selective downregulation of Th1-type cytokine expression was observed in a second set of experiments in which diabetes development was synchronised by cyclophosphamide. These data support the hypothesis that circulating forms of adhesion molecules have an immunomodulatory function and can intervene in islet inflammation. [Diabetologia (1998) 41: 1298–1303]
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  • 7
    ISSN: 1432-0428
    Keywords: Keywords Twins ; T-cell immunity ; hsp60 ; cytokines ; superantigen.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The search for T-cell reactions that are associated with disease in Type I (insulin-dependent) diabetes mellitus is severely hampered because control groups cannot be matched for relevant immune response genes. We therefore compared T-cell responses between identical twins discordant for Type I diabetes. Methods. Pairs of monozygotic twins (n = 17) discordant for Type I diabetes were studied. Cultures were set up from whole blood immediately after sampling and cells were challenged with human recombinant hsp60, with the mitogen phytohaemagglutinin or with the staphylococcal superantigen. Supernatants were removed after 48 or 96 h and analysed for T-helper1 type cytokines interferon-γ, TNFα and T-helper2 type cytokines IL-4, IL-10 by sandwich-ELISA. Results. The height of the T-helper1 type cytokine response to hsp60, phytohaemagglutinin or staphylococcal enterotoxin B did not show disease association, i. e. it was similar between discordant twins. In contrast, the production of T-helper2 type cytokines differed between discordant twins. The IL-10 response to hsp60 was higher in twins at low disease risk (islet cell antibody-negative) than in their diabetic cotwins (p 〈 0.01), as was the IL-4 response to phytohaemagglutinin (p 〈 0.05). No difference was seen in the cytokine response between islet cell antibody-positive twins and their diabetic cotwins. Conclusions/interpretation. The data indicate an association between T-helper2 type cytokine secretion patterns and disease or disease risk. [Diabetologia (1999) 42: 1080–1085]
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  • 8
    ISSN: 1432-0428
    Keywords: Autoreactive T cells ; self-tolerance ; beta cell ; pancreatectomy ; regeneration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We studied the effect of severe reduction of beta-cell mass by 90% pancreatectomy on the immune tolerance to the endocrine pancreas. Four months after subtotal pancreatectomy all LEW.Han rats had developed mononuclear infiltration of islets and 9 of 14 rats were positive for islet-cell antibodies. Electron microscopy revealed lymphocytic invasion of endocrine tissue, lysis of beta cells and phagocytotic macrophages. None of these changes were seen 2 weeks after 90% pancreatectomy or 4 months after 10% pancreatectomy. Weekly substitution of islet antigens in the form of a homogenate of 100 islets into 90% pancreatectomized LEW.Han rats almost completely prevented the development of insulitis and autoantibodies. The dependence of insulitis on T cells was shown when 90% pancreatectomy in LEW.rnu rats (i.e., the congenic athymic nude strain), did not result in islet infiltration. The exocrine tissue remained normal in all experimental groups. During the observation period insulitis was not associated with overt diabetes but was accompanied by substantial enlargement of islets and of beta-cell mass, as shown by morphometry. Suppression of islet inflammation by injection of islet antigens abolished beta-cell regeneration, despite continuing metabolic stress in rats with 90% pancreatectomy. The findings indicate induction of islet autoimmunity in response to 90% but not to 10% pancreatectomy. We conclude that severe reduction of the islet-antigen mass allows the development of T-cell-dependent islet autoimmunity which indicates a loss of immune tolerance. In addition, the data suggest the existence of islet-antigen autoreactive immune cells in rats not genetically predisposed to autoimmune diabetes. Finally, we conclude that selective beta-cell regeneration occurs in association with insulitis.
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  • 9
    ISSN: 1432-0428
    Keywords: Keywords Oral tolerance ; oral insulin ; BB rat ; immune intervention ; gut ; cytokines.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The impact of oral treatment with insulin on disease development was studied in diabetes prone BB rats. Because of the positive outcome of a prior study in non obese diabetic (NOD) mice, BB rats received insulin in combination with a bacterial adjuvant. Porcine insulin was given orally twice weekly from 35–100 days of age, the E. coli preparation OM-89 was fed on alternate days. Other groups received vehicle, the bacterial adjuvant, or insulin alone. Both insulin containing oral dosing regimens induced a transient non significant delay in diabetes onset. Insulin alone, however did not decrease the final diabetes incidence. Oral dosing with insulin plus adjuvant caused exacerbation of disease development as judged from the decreased survival rate in comparison with the insulin treated group (p 〈 0.05). Intra-islet infiltration also increased (p 〈 0.005) compared with the insulin or vehicle treated groups. The effect correlated with enhanced interferon gamma (IFNγ) and decreased interleukin 10 (IL-10) gene expression in the gut suggesting a shift towards proinflammatory T helper 1 (Th1) reactivity (p 〈 0.01). Although treatment with adjuvant alone also increased the degree of insulitis, an enhanced incidence of diabetes and a shift in cytokine expression was only seen in the group receiving insulin plus adjuvant. Taken together, the data suggest that treatment with a bacterial adjuvant and oral insulin may alter the gut immunoregulatory state such that disease promoting rather than protective immune responses are induced. [Diabetologia (1998) 41: 844–847]
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  • 10
    ISSN: 1432-0584
    Keywords: Key words P-Glycoprotein ; AML ; ALL ; CML ; Idarubicin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of the study was to test whether fractionated (weekly) idarubicin administration to multiply pretreated leukemia patients is effective and tolerable for outpatient treatment, and whether idarubicin alone can overcome P-glycoprotein (P-gp)-related resistance. P-gp was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. P-gp expression was characterized as a percentage of P-gp-positive blasts. Additionally, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test in combination with or without verapamil and expressed as the R123 accumulation ratio. Fractionated idarubicin (12 mg/m2/week) was given to 36 acute myelogenous leukemia (AML) patients, 12 acute lymphoblastic leukemia (ALL) patients, and eight chronic myelogenous leukemia (CML) patients in blast crisis. Furthermore, 11 AML and four ALL patients were treated with fractionated daunorubicin at a dose of 50 mg/m2/week. All patients had been pretreated with drugs inducing P-gp-related resistance including daunorubicin and/or doxorubicin or vindesine (CML patients). Of 71 pretreated patients, 51 (72%) had a P-gp value between 25 and 98%. Six of these patients with increased P-gp expression had a nonpumping P-gp; four of them were CD34 positive. Of 51 patients with increased P-gp expression, 30 (59%) were CD34 positive. With regard to idarubicin monotherapy, overall response was 33/56 (59%) patients, and 23/33 (70%) responding patients showed a P-gp expression between 25 and 95%. All idarubicin-responding patients with high P-gp expression before treatment showed a clear reduction of P-gp-positive blasts. No patients with P-gp expression between 34 and 85% treated with fractionated daunorubicin showed response or reduction of P-gp-positive blasts in bone marrow. This study demonstrates that P-gp-related resistance can be overcome in multiply pretreated leukemia patients with idarubicin alone, and that the protocol used here is tolerable for outpatient treatment.
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