Somatic hypermutation occurs in B cells of terminal deoxynucleotidyl transferase-, CD23-, interleukin-4-, IgD- and CD30-deficient mouse mutants.
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Animals↗
Biomedical subjects
R Kühn
Publications and source records attributed to R Kühn.
Plasmodium chabaudi chabaudi: differential susceptibility of gene-targeted mice deficient in IL-10 to an erythrocytic-stage infection.
Female and male mice deficient in IL-10 production by targeted disruption of the IL-10 gene were infected with Plasmodium chabaudi chabaudi (AS) blood-stage parasites. Both male and female mutant mice exhibited more severe signs of disease than did +/+ or heterozygous control mice. Female defective mice also displayed an increased mortality; 56% of mice died within 20 days of infection. Mortality did not appear to be due to a fulminating parasitemia as death occurred at different levels of parasitemia in the individual mice. The acute infection was accompanied by an enhanced Th1 IFN-gamma response. This response was retained in the chronic phase of infection of both male and female mutant mice, whereas in controls the responding CD4+ T cells were predominantly Th2 cells secreting IL-4. The data suggest that IL-10 regulates the inflammatory response to the parasite and that in its absence the combined effects of malaria toxins and the sustained or enhanced IFN-gamma response lead to increased pathology. In the case of female mice absence of IL-10 is sufficient to induce a lethal endotoxin-like reaction.
Anemia↗
Dynamic shape effect in 126Ba at low spin.
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Journal Article↗
Impaired immunosuppressive response to ultraviolet radiation in interleukin-10-deficient mice.
Exposure to mid-range ultraviolet radiation (UVR) [280-320 nm, ultraviolet B (UVB) radiation] inhibits the acquisition of delayed-type hypersensitivity in mice and contact hypersensitivity in rodents and humans. Intraperitoneal administration of interleukin 10 (IL-10) inhibits the sensitization of mice to alloantigens for a delayed-type hypersensitivity reaction and administration of neutralizing antibodies to IL-10 largely, but not totally, blocks the UVR-mediated suppression of the ability to sensitize mice. This suggests that these inhibitory effects of UVB radiation may be mediated by release of IL-10. To test this hypothesis directly, IL-10 gene-targeted (IL-10T) mice lacking expression of IL-10 were examined for the ability of UVB radiation to suppress induction of delayed-type hypersensitivity to alloantigens. IL-10T mice were completely resistant to UVB-induced immunosuppression in this system. Interestingly, UVB radiation could suppress in IL-10T mice the induction of contact hypersensitivity to a hapten applied to the skin at a site distant of irradiation, supporting the concept that regulation pathways of delayed-type hypersensitivity and contact hypersensitivity responses by UVR differ. These data provide additional understanding of the mechanisms of immunosuppression induced by UVR and suggest that IL-10 release subsequent to UVB radiation may play a role in the growth immunogenic UVB-induced cutaneous malignancies in the primary host.
Animals↗
Transfer of bovine microsatellites to the cervine (Cervus elaphus).
Bovine microsatellites were used to amplify DNA of red deer (Cervus elaphus). Fourteen of 27 bovine systems (52%) displayed polymorphism, while no (CA)n-repeat was detected in seven systems and six systems gave no amplificates in red deer. The allele number ranged from 2 to 7, the polymorphism information content between 0.24 and 0.76. The results demonstrate that transfer of microsatellite systems between families of the same order (artiodactyla) is possible. Molecular genetic research will help to clarify the differentiation and ecology of wild animals and will contribute to define criteria needed for the preservation of endangered species.
Alleles↗
[Radiochemotherapy and simultaneous hormonal therapy of locally advanced prostatic carcinoma].
PURPOSE: The results of radiotherapy alone in the prostate cancer stage T3-T4 are not satisfactory. We investigated, whether the combination of radio-chemotherapy with hormone therapy, possible most effective therapy in stage III, will be tolerated without serious side effects. PATIENTS AND METHODS: Eight patients with prostate cancer T3/T4 were treated with concurrent radio-chemotherapy and hormone therapy. The mean doses in reference point was 61.7 Gy, the single dose was 1.8 Gy. The patients received epirubicin 20 mg/m2 and 5-fluorouracil 800 mg/m2 on day 1 to 5 and 29 to 33 of radiotherapy. The hormone therapy began before the radio-chemotherapy started. RESULTS: Only the hematological side effects were relevant. Three out of 8 patients had leucopenia grade III and 1 of 8 patients leucopenia grade IV according WHO. Other serious complications could not be observed. CONCLUSION: The concurrent radio-chemotherapy with epirubicin and 5-fluorouracil in the combination with hormone therapy was tolerated well. The effectiveness of this new treatment should be examined prospectively in prostate cancer stage T3-T4.
Adenocarcinoma↗
[Interdisciplinary surgical therapy of renal tumors with intracardiac tumor thrombi].
A combination of increased perioperative morbidity, together with the technical difficulty of an R 0 (curative) resection, is responsible for the poor prognostic factors of supradiaphragmatically extending renal tumors. Six patients aged 53-70 years with vena cava thrombosis extending into the right atrium or ventricle underwent en bloc resection of the primary tumor and tumor thrombus removal. If the atrial tumor mass was large or extended into the ventricle, resection was performed during cardiopulmonary arrest using a cardiopulmonary bypass method with the patient in deep hypothermia (< 18 degrees C). Alternatively if the cardiac tumor infiltration was minimal, resection was performed during an optionally short cardiopulmonary arrest period using a cardiopulmonary bypass method with the patient in hypothermia (23 degrees C). The operative procedure was determined by intracardiac tumor extension, tumor wall adhesions and tumor wall infiltrations, all of which were assessed intraoperatively by vena cava sonography. Six patients were strongly symptomatic preoperatively. Three developed sudden life-threatening cardiopulmonary insufficiency, possibly due to longer-lasting tricuspital valve prolapse with a consecutive right-to-left shunt through a newly reopened foramen ovale. One patient died 14 months postoperatively because of multiple metastases (hepatic, pulmonary and bone). One patient is still alive and has had a local recurrence for 2 months, which was diagnosed 65 months postoperatively. The remaining four patients are alive and well. They have been tumor-free for extended periods of time (29, 34, 62 and 84 months, respectively).
Aged↗
Expression of c-erbB2 oncogene product in different tumours and its standardised evaluation.
In order to evaluate the reliability and reproducibility of the immunohistochemical demonstration of the c-erbB2 oncoprotein and define criteria for positivity assessment in paraffin-embedded material from different tumours, we examined immunohistochemically 79 gastric, 100 colorectal and 20 bladder carcinomas using 5 different c-erbB2 antibodies. To determine criteria for the evaluation of c-erbB2 positivity, the observed immunohistochemical staining was compared with the actual protein prevalence, determined by Western blot analysis of each tumour. The comparison of protein levels obtained from Western blot with corresponding immunohistochemistry revealed that positive staining can only be considered to be specific for c-erbB2 oncoprotein if: (i) there is a definite staining along the tumour cell membrane with no predominant immunoreactivity inside the tumour cell cytoplasm, (ii) the intensity of immunoreactivity is comparable with a positive standard (e.g. in this study breast carcinoma) and (iii) the surrounding normal, non-neoplastic tissue shows no immunoreactivity. The graduation of staining intensities did not correlate to the actual amount of protein detected in Western blots. This study stresses the importance of defined and controlled criteria for evaluation of c-erbB2 oncoprotein positivity in immunohistochemistry.
Blotting, Western↗
Inducible gene targeting in mice.
A method of gene targeting that allows the inducible inactivation of a target gene in mice is presented. The method uses an interferon-responsive promoter to control the expression of Cre recombinase. Here, Cre was used to delete a segment of the DNA polymerase beta gene flanked by IoxP recombinase recognition sites. Deletion was complete in liver and nearly complete in lymphocytes within a few days, whereas partial deletion was obtained in other tissues. This method can be used for the inducible inactivation of any other gene in vivo.
Animals↗
Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses.
We have examined the role of endogenously produced interleukin (IL) 4 and IL-10 in the regulation of inflammatory and immune reactions in the skin. In these experiments, irritant and contact hypersensitivity (CH) responses were elicited in mice with targeted disruptions of the IL-4 (IL-4T) or IL-10 (IL-10T) gene. Our study showed that IL-4T and wild-type (wt) mice exhibited equivalent responses to the irritant croton oil. In contrast, the response of IL-10T mice challenged with croton oil was abnormally increased. When IL-10T mice were exposed to a higher dose of irritant, irreversible tissue damage occurred. By comparison, any treatment of wt mice with croton oil resulted in far less tissue damage and resolution of inflammation. Neutralizing antibody studies demonstrated that the necrosis that occurred in IL-10T mice was due to the overproduction of tumor necrosis factor. The anti-tumor necrosis factor antibody treatment of IL-10T mice did not significantly reduce the edema or the influx of inflammatory cells, suggesting that these changes were due to the uncontrolled production of other proinflammatory cytokines. T cell-dependent immune responses were also evaluated using the contact sensitizer oxazolone. The response of IL-4T mice did not differ from wt mice. In contrast, IL-10T mice mounted an exaggerated CH response, increased in both magnitude and duration as compared with wt mice. Based on these studies, we have concluded that IL-10, but not IL-4, is a natural suppressant of irritant responses and of CH, and it limits immunopathologic damage in the skin.
Animals↗
Common cytokine receptor gamma chain (gamma c)-dependent cytokines: understanding in vivo functions by gene targeting.
The common cytokine receptor gamma chain (gamma c) plays a critical role in lymphoid development through its participation in the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Absence of gamma c results in abnormal lymphopoiesis and immunodeficiency, as evidence by X-linked severe combined immunodeficiency (SCIDX1) in man, and in the corresponding canine and murine models of SCIDX1. Comparison of the phenotypes of mutant mice made deficient for gamma c-dependent cytokines by gene targeting, allows us to define a hierarchy of gamma c-dependent cytokine function in lymphoid development. The participation of distinct cytokine/receptor interactions in the generation, maintenance and regulation of the immune system suggests that developmental steps may be controlled by individual cytokines. The mechanisms by which different cytokine signaling pathways achieve this process remain to be elucidated.
Animals↗
Antiviral immune responses in mice deficient for both interleukin-2 and interleukin-4.
Antiviral immune responses of mice lacking interleukin-2 (IL-2) or IL-4 or both IL-2 and IL-4 (IL-2/4) were compared by using different viruses. Primary cytotoxic T-lymphocyte (CTL) responses against lymphocytic choriomeningitis virus (LCMV) were only moderately reduced in mice lacking IL-2 and were normal in mice lacking IL-4. Mice deficient in both interleukins exhibited variable and more strongly reduced but nevertheless in vivo protective LCMV-specific CTL responses. Similar results were obtained with vaccinia virus. Upon virus-specific restimulation in vitro, spleen cells from IL-2- and IL-2/4-deficient mice failed to generate CTL responses against virus-infected target cells, whereas the response of mice deficient in only IL-4 was comparable to that of control mice. The addition of IL-2 during in vitro restimulation completely restored the responses of both IL-2 and IL-2/4-deficient mice. T-helper-cell-independent immunoglobulin M and T-helper-cell-dependent immunoglobulin G antibody responses against vesicular stomatitis virus glycoprotein were within normal ranges for the various mutant mice. After LCMV infection, specific antibody responses against LCMV nucleoprotein were reduced four- to eightfold. These results show that mice lacking IL-2/4 have an overall tendency to exhibit more severely reduced CTL responses than IL-2- or IL-4-deficient mice. Nevertheless, and surprisingly, in vivo protective immune responses were mounted in the absence of IL-2/4, suggesting that besides a minor contribution from IL-4, other interleukins compensate in vivo for the lack of IL-2 in IL-2-deficient mice.
Animals↗
Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance.
Previous studies in vivo have shown that IL-10 infusion can prevent lethal endotoxic shock. Mice deficient in the production of IL-10 (IL10T) were used to investigate the regulatory role of IL-10 in the responses to LPS in three experimental systems. In a model of acute endotoxic shock, it was found that the lethal dose of LPS for IL10T mice was 20-fold lower than that for wild type (wt) mice suggesting that endogenous IL-10 determines the amount of LPS which can be tolerated without death. The high mortality rate of IL10T mice challenged with modest doses of LPS was correlated to the uncontrolled production of TNF as treatment with anti-TNF antibody (Ab) resulted in 70% survival. Additional studies suggested that IL-10 mediates protection by controlling the early effectors of endotoxic shock (e.g., TNF alpha) and that it is incapable of directly antagonizing the production and/or actions of late appearing effector molecules (e.g., nitric oxide). We also found that IL10T mice were extremely vulnerable to a generalized Shwartzman reaction where prior exposure to a small amount of LPS primes the host for a lethal response to a subsequent sublethal dose. The priming LPS dose for IL10T mice was 100-fold lower than that required to prime wt mice implying that IL-10 is important for suppressing sensitization. In agreement with this assumption, IL-10 infusion was found to block the sensitization step. Interestingly, IL-10 was not the main effector of endotoxin tolerance as IL10T mice could be tolerized to LPS. Furthermore, IL-10 infusion could not substitute for the desensitizing dose of LPS. These results show that IL-10 is a critical component of the host's natural defense against the development of pathologic responses to LPS although it is not responsible for LPS-induced tolerance.
Animals↗
[Ureteral injuries caused by external force].
The pathologic mechanism responsible for ureteral injuries is no different now than in past decades. Nowadays, however, we distinguish diagnostically between partial traumatic tears and complete ones. This distinction leads to different therapeutic strategies: endoscopic surgery for the former and open surgery for the latter. We further distinguish between the pathophysiology of closed and of open urinomas; the latter have a less favourable prognosis. This means that the treatment strategies and the degree of urgency are also different. We report on 16 cases treated over the past 22 years and review the international literature.
Abdominal Injuries↗
[Therapeutic approach to hemobilia].
AIM OF THE STUDY: Hemobilia, defined as hemorrhage arising from pathological changes in the biliary tract, represents a rare entity. In a retrospective study the presentation, diagnosis, and management of hemobilia were investigated. PATIENTS AND METHODS: Since January 1991 six patients suffering from severe hemobilia presented to our department. Jaundice, right upper quadrant abdominal pain, hematemesis and melaena were the most frequent symptoms leading to admission. Hemobilia originated from iatrogenic injury following percutaneous liver biopsy and endoscopic removal of common bile duct stones, and malignant hepatic or biliary tumors. Duodenoscopy revealed bleeding from the papilla in all patients. Diagnosis was confirmed by ERCP in all patients and angiography in 5 of 6 patients. RESULTS: Angiographic occlusion of an arterial lesion with coils was successfully achieved in one patient. One patient was treated conservatively. In 3 patients liver resections were performed to control bleeding and the underlying tumorous pathology. In another patient, operative ligation of the supplying artery had to be performed. Within a minimum follow-up of six months none of the six patients showed recurrence of hemobilia. CONCLUSION: Considering the impact of etiologic, diagnostic and therapeutic aspects in treatment of hemobilia we suggest an algorithm for a rational approach to hemobilia. Angiographic occlusion may control the bleeding and improve the patient's general condition. Definitive surgical treatment of hemobilia is safe and effective.
Aged↗
[The status of duodenum-preserving resection of the head of the pancreas in therapy of chronic pancreatitis].
AIM OF THE STUDY: To evaluate the efficacy of duodenum-preserving resections of the head of the pancreas in the treatment of chronic pancreatitis this study was devised. So far studies on the natural course and the different therapeutic approaches have primarily focused on pain measurement in rough categories and hard data as mortality and morbidity. In this study the improvement of the quality of life was assessed to determine the therapeutic success of both procedures. PATIENTS AND METHODS: In a prospective randomized study 24 patients underwent either Beger's (n = 11) or Frey's procedure (n = 13) so far. 15 patients suffered from distal common bile duct stenosis, 2 from segmental duodenal stenosis, 4 from segmental portal hypertension, and one from pancreato-pleural fistula. The quality of life questionnaire of the European Organization for Research and Treatment of Cancer was assessed before surgery and during follow-up. The multidimensional questionnaire incorporates functional scales (physical, cognitive, emotional, and social), symptom scales (fatigue, pain, dyspnea, loss of appetite, sleep disturbance, obstipation, diarrhea, nausea, and vomiting), and a global quality of life scale. Follow-up was 12 months in all patients. RESULTS: There was no postoperative mortality in neither group. Postoperative morbidity was 17% (n = 2 in either group). This included one transitory common bile duct stenosis, one bronchopneumonia, and two postoperative bleedings which were treated conservatively. The pain index was reduced by 94% in the Beger- and 90% in the Frey group. The physical status, working ability, emotional and social functioning, and global quality of life score had significantly improved by 46%, 50%, 69%, 60%, and 67% in the Beger group and by 38%, 50%, 64%, 80%, and 67% in the Frey group. CONCLUSION: The duodenum-preserving resections of the head of the pancreas according to Beger and Frey are equivalently safe and effective. Both techniques result in a significant improvement of the patients' quality of life.
Adult↗
IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma.
Dense CD4+ T cells isolated from naive mice produce only trace amounts of IL-9 when stimulated by immobilized anti-CD3 in combination with anti-CD28 Abs. In this situation, IL-9 production is significantly stimulated by TGF-beta and further enhanced by the addition of IL-4, which, by itself, has only a minimal influence. IFN-gamma was found to inhibit the enhancing effect of IL-4. However, increasing amounts of IL-4 in the presence of a constant concentration of IFN-gamma could overcome the inhibitory activity of IFN-gamma. The application of CD4+ T cells isolated from IL-2 knockout mice unequivocally revealed that IL-2 is essential for the production of IL-9 by T cells. In addition, the use of T cells from IL-4 knockout mice elucidated that the basic (IL-2 + TGF-beta) mediated IL-9 production is independent of IL-4. Therefore, our results demonstrate that optimal IL-9 production of naive dense CD4+ T cells is positively regulated at different levels: 1) by IL-2, which is essential for IL-9 secretion; 2) followed by TGF-beta, which promotes a considerable increase in IL-9 production above the level induced by IL-2; and 3) finally, by IL-4, which requires the presence of IL-2 and TGF-beta to strongly enhance the production of IL-9. IFN-gamma inhibits the production of IL-9 mainly at the level of IL-4 by neutralizing the effect of this cytokine.
Animals↗
Critical behavior of the randomly spin diluted 2D Ising model: A grand ensemble approach.
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Journal Article↗