[Interferon-alpha in therapy of malignant hemoblastoses].
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Combined Modality Therapy↗
Biomedical subjects
C Huber
Publications and source records attributed to C Huber.
Expression of c-fos correlates with IFN-alpha responsiveness in Philadelphia chromosome positive chronic myelogenous leukemia.
This study evaluates (i) constitutive levels of oncogene and p53 transcripts in chronic phase CML patients and (ii) their modulations subsequent to in vivo therapy with rIFN-alpha 2c. Peripheral blood mononuclear cells (pbmc) and bone marrow cells of 26 patients were examined for c-fos, c-myc, p53 and the hybrid bcr/abl mRNA levels. Results indicated that (i) constitutive c-fos transcript levels are significantly higher in patients subsequently responding to IFN-alpha therapy (p < 0.01) and positively correlated with the proportion of lymphocytes (r = 0.6895, p < 0.01) and negatively with the proportion of immature cells (r = -0.568, p < 0.01) contained in the pbmc preparations tested, (ii) constitutive mRNA levels of the hybrid bcr/abl, c-myc and p53 are positively correlated with each other, but failed to relate to disease parameters, and (iii) acute and chronic in vivo exposure to IFN-alpha is accompanied by upregulation of c-fos and downregulation of c-myc mRNA levels in responder patients.
Bone Marrow Cells↗
Deficient cell cycle control in myeloid cells of patients with newly diagnosed chronic myeloid leukemia.
Cell cycle control subsequent to gamma irradiation or growth factor starvation has been studied in immative hematopoietic cells of 19 previously untreated chronic myeloid leukemia (CML) patients in chronic phase compared with 18 normal controls. CD34-positive cells were cultured for seven days in the presence of optimal concentrations of appropriate growth factors. At day 7 of culture both S-phase fraction and differentiation were identical in normal and leukemic cells. In normal cells the proportion of S-phase cells was reduced by irradiation with 500 rad from 40 +/- 3% to 16 +/- 2%. In contrast, in CML cells a reduction of S-phase cells from 35 +/- 2% to 25 +/- 3% was observed. Moreover, irradiated CML cells arrested at a smaller number of cells in G2. Similarly, a significantly higher proportion of CML cells remained in S phase after withdrawal of growth factors. Semiquantitative PCR of p21 (waf1/cip1) induction by gamma irradiation provided no evidence for a major functional deficiency of p53 response to irradiation in these cells. Our results demonstrate an abnormal cell cycle arrest in chronic-phase CML cells both after gamma irradiation and after growth factor removal. This observation might have important implications for understanding the pathogenesis of both hyperplasia of chronic phase and the development of blast crisis in CML. The molecular mechanisms underlying these abnormalities in bcr-abl-positive cells remain to be clarified.
Actins↗
[Secondary neoplasia after immunosuppression].
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Anemia, Aplastic↗
Cellular immune response to human renal-cell carcinomas: definition of a common antigen recognized by HLA-A2-restricted cytotoxic T-lymphocyte (CTL) clones.
Cytotoxic T lymphocyte (CTL) clones directed against autologous renal-cell carcinoma (RCC) cell lines were generated by mixed lymphocyte/tumor-cell culture (MLTC) using peripheral blood lymphocytes (PBL). A CD8+, CD4- CTL clone MZ1257-CTL 5/30 with high cytolytic activity for the autologous tumor cell line MZ1257-RCC was established. No lysis of the autologous EBV-transformed B lymphocytes (EBV-B) or K562 cells was observed. A panel of HLA-A2-matched allogeneic RCC lines was recognized by CTL 5/30. Further specificity analysis showed a cross-reactivity with HLA-A2-matched allogeneic tumor cells of various origins, especially melanoma. CTL 5/30 was also cross-reactive with several HLA-A2-positive allogeneic normal kidney cells in culture. The restriction element identified for CTL 5/30 was HLA-A2, as shown by blocking of cytotoxicity using an anti-HLA-A2 monoclonal antibody (MAb) and by resistance of an HLA-A2-negative melanoma variant SK29-MEL. 1.22 against lysis by CTL 5/30. In this report we demonstrate HLA-A2-restricted recognition of a T-cell-defined antigen on autologous renal-cancer cells. This antigen is also expressed and recognized in association with HLA-A2 on normal kidney cells in culture and other HLA-A2-positive tumor cells. It may therefore be a normal differentiation antigen to which tolerance is incomplete in the renal-cell cancer system investigated.
Antibodies, Monoclonal↗
Regulation of cytokine expression by interferon-alpha in human bone marrow stromal cells: inhibition of hematopoietic growth factors and induction of interleukin-1 receptor antagonist.
We investigated the effects of interferon-alpha (IFN-alpha) on the expression of cytokines by human bone marrow stromal cells. Production of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-CSF (G-CSF), and interleukin-1 beta (IL-1 beta) in stromal cell layers was induced by incubation with IL-1 alpha, tumor necrosis factor (TNF), or lipopolysaccharide (LPS). Addition of IFN-alpha to such stimulated cultures resulted in a strong downregulation of mRNA expression of GM-CSF and IL-1 beta. Similarly, the protein levels of GM-CSF and IL-1 beta were significantly reduced by IFN-alpha, whereas G-CSF production was only moderately inhibited. In contrast, IFN-alpha markedly stimulated the production of IL-1 receptor antagonist (IL-1RA) by stromal cells. The inhibition of cytokine expression resulted in a reduced hematopoietic activity of stromal cells, indicated by a reduced proliferation of the factor dependent cell line MO7e on IFN-alpha-treated stromal cells. In the presence of cycloheximide (CHX), IFN-alpha failed to inhibit IL-1 mRNA expression, whereas the regulation of GM-CSF and IL-1RA by IFN-alpha was not affected. Our results indicate that the myelosuppressive effects of IFN-alpha, as observed in therapeutic applications or associated with viral infections, are, in part, indirectly mediated by inhibition of the paracrine production of hematopoietic growth factors.
Base Sequence↗
Human interleukin-4 enhances stromal cell-dependent hematopoiesis: costimulation with stem cell factor.
Interleukin-4 (IL-4) has distinct hematopoietic activities, primarily as a costimulant with other cytokines to enhance colony formation of hematopoietic progenitors. We investigated the influence of IL-4 on stromal cell-supported long-term cultures (LTCs) of normal human bone marrow. Addition of IL-4 to LTCs of unseparated bone marrow or highly enriched CD34+ cells resulted in a significant increase of myeloid progenitors in the nonadherent, as well as in the stromal cell-adherent cell populations. In contrast, the total cell number was not influenced by IL-4, suggesting a selective effect on primitive progenitor cells. Cord blood cells or CD34+ bone marrow cells were incubated with stem cell factor (SCF) and/or IL-4 in stromal cell-free cultures. In these experiments, a twofold to fivefold increase of myeloid progenitor cells was observed in the presence of SCF and IL-4 as compared with SCF alone. Preincubation of the stromal cell cultures with IL-4 resulted in an enhanced adherence of CD34+ cells to the stromal layer. Secretion of hematopoietic growth factors produced by the stromal cells, such as granulocyte-macrophage colony-stimulating factor (G-CSF), and IL-1, was inhibited by IL-4. Thus, the increase of hematopoietic progenitors in LTCs, as observed in the presence of IL-4, can be at least partially explained by a costimulation of SCF and IL-4 on primitive progenitor cells and by an enhancement of hematopoietic cells to stroma. The downregulation of CSFs by IL-4 might prevent the expansion of the mature hematopoietic cell compartment.
Antigens, CD↗
Biologic activity of low dosage IL-2 treatment in vivo. Molecular assessment of cytokine network interaction.
The sequence of activation of the components of the cytokine network subsequent to in vivo application of different dosages of IL-2 is still poorly understood. Although side effects of IL-2 therapy are dose dependent, the dose-response relationship for induction of potentially beneficial or harmful cytokine genes still remains to be studied. We examined the patterns of cytokine gene expression after treatment of chronic hepatitis B patients with various doses of IL-2 in a phase 1 trial. Total RNAs were isolated from PBMC harvested at various time points after s.c. injection of natural IL-2 ranging from 30,000 to 1,000,000 U. Dose-dependent effects on mRNA expression of IL-2, GM-CSF, IFN-gamma, TNF-alpha, and IL-6 were assessed using Northern blotting and slot blotting techniques. A single application of 30,000 U nIL-2 induced selective and long-lasting expression of IL-2, IFN-gamma, and GM-CSF genes, which was not accompanied by accumulation of TNF-alpha and IL-6 mRNAs. Larger dosages of IL-2 induced activation of monokine genes and were associated with systemic side effects. mRNA levels of the different cytokines related to biologic activity and correlated with expression of specific proteins and cellular parameters: IL-2 mRNA with soluble IL-2R serum levels and induction of lymphopenia, GM-CSF mRNA with induction of neutrophilia, and IL-6 mRNA with c-reactive protein serum concentrations. Taken together these data indicate unexpected immunoregulatory activities of very low and nontoxic dosages of IL-2 in vivo.
Adolescent↗
A potentially functional V kappa gene at a distance of 1.5 Mb from the immunoglobulin kappa locus.
An amplicon that is highly homologous to a part of the human kappa locus was found at the 3' or telomeric side of C kappa at a distance of about 1.5 Mb. From analysis of sequence divergence, it is concluded that the amplicon was formed after the duplication of the kappa locus, which may have taken place about 1 million years ago. A V kappa gene of subgroup III within the amplicon turned out to have no defects in its sequence and to have a 5'-3' orientation opposite to the one of J kappa C kappa. Theoretically, a functional V kappa-J kappa-C kappa gene could be formed by an inversion mechanism, but no rearrangement products were observed so far.
Base Sequence↗
Clinical applications of cytokines.
Cytokines are multifunctional signaling peptide molecules which regulate a plethora of cellular activities in the immune system. Cytokines provide a means of communication between the immune system and its non-immune neighbours. Several clinical entities have been recognized as targets for clinical applications including interaction with malignant cell growth, host defence against infectious agents, negative regulation of autoagressive disorders and regulation of tissue and cell regeneration. Interferon-alpha (IFN-alpha) can effectively regulate malignant growth in hairy-cell leukaemia, the first example of a biological treatment modality which tames a malignant disease and noramlizes life expectancy, although cure is not achieved. INF-alpha can also control myeloid hyperplasia in approximately two-thirds of the patients with chronic myelogenous leukaemia. In 30% of the patients, treatment is accompanied by partial or complete restoration of normal haematopoiesis. Such cytogentic responses have not been observed with conventional chemotherapy. INF-alpha is also effective in infectious viral hepatitis B, C and D. A long-term beneficial response is observed in 25-40% of the patients. Promising results have also been seen with INF-gamma and interleukin-2 for the treatment of chronic leishmania infection and lepromatous leprosy. Activation of monocytes or macrophages induces these cells to intracellularly destruct leishmania parasites. Growth factors have been identified which influence erythrocyte, granulocyte and macrophage production. Their clinical use has been studied in patients with bone marrow failure, chronic renal failure, acquired immunodeficiency syndrome and in patients with cancer undergoing chemotherapy or bone marrow transplantation. Additional work is needed to appreciate the immunnodulation effect of cytokines and their role in wound healing and tissue regulation.
Autoimmune Diseases↗
[Stage-oriented therapy in nonseminomatous testicular tumors].
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Aftercare↗
Capillary zone electrophoresis and micellar electrokinetic chromatography of 4-aminobenzonitrile carbohydrate derivatives.
Aldoses, ketoses and uronic acids were derivatized successfully within 15 min at a temperature of 90 degrees C by reductive amination with 4-aminobenzonitrile. Subsequently, the derivatives were separated as their borate complexes by capillary zone electrophoresis, using 175 mM borate buffer, pH 10.5, as carrier. The electrophoretic mobilities were determined by the complex stability, which was found to depend on the number of hydroxyl groups on any given carbohydrate derivative, the presence of substituents, and most strongly on the configuration of the vicinal hydroxyl groups at C-3 and C-4 in aldoses and uronic acids, and with regard to ketoses on those at C-4 and C-5. Time of analysis could be reduced considerably by the use of micellar electrokinetic chromatography, which separated 4-aminobenzonitrile sugar derivatives on the basis of their differential partitioning into an electroendosmotically driven aqueous phase and into sodium dodecyl sulfate micelles. Optimum resolution was achieved with a Tris-phosphate buffer, pH 7.5, containing 100 mM of sodium dodecyl sulfate. The method made it possible to resolve several carbohydrates which had not been resolved successfully by means of capillary zone electrophoresis, such as glucose and fructose. Moreover, separation selectivity could be adjusted by varying the capillary temperature. Finally, on-column UV monitoring at 285 nm allowed the detection of glucose with a lower mass detection limit of 1 fmol and a concentration sensitivity of 0.3 microM.
Borates↗
Removal of the submaxillary salivary glands first increases and then abolishes the agonistic response of male mice in repeated social encounters.
Adult male mice of the CD-1 strain were sialectomized (bilateral removal of submaxillary salivary glands) under IP Nembutal anesthesia and then individually housed for 5 weeks. Control mice were sham operated. The behaviors of sialectomized and control mice towards untreated, intact, matched opponents were videotaped during the first 10 min of a 20-min social encounter repeated for 10 consecutive days (isolation days 36-46). On the first session, sialectomized mice exhibited significant increases in elements of aggression (attack, bite, offensive sideways, offensive upright, and tail rattling). These behavioral changes significantly decreased over the remaining encounters, while defensive behaviors (defensive upright, oblique, parry, and defensive sideways) and elements of arrested flight increased progressively. The results suggest that sialectomy, perhaps by removing salivary NGF, interferes with the coping response of mice towards repeated agonist challenge from a conspecific.
Adaptation, Psychological↗
Interferon-alpha as an antagonist to proinflammatory and hematopoietic cytokines.
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Bone Marrow↗
Needle Park: what can we learn from the Zürich experience?
Needle Park in Zürich existed as an open air drug scene from 1986 until February 1992. Within this six year period the City Government, City Parliament, governmental and non-governmental organizations implemented a wide range of permissive and restrictive drug policies, from extensive harm reduction to closing the park. Police statistics and several studies suggest that tolerating an open air drug scene can have unforeseen and unfortunate consequences. Low drug prices, lack of law enforcement and lack of social control seem to attract drug users towards the open drug scene and the increase in problems appears to have been more rapid than the increase in the population of addicts.
Crime↗
Molecular analysis of the erythropoietin receptor system in patients with polycythaemia vera.
Erythropoietin (EPO) is a potent regulator of the viability, proliferation and differentiation of erythroid progenitor cells. Its effect is mediated by binding to the erythropoietin receptor (EPO-R), a member of a new cytokine receptor family. Alterations of the EPO/EPO-R system have recently been shown to be involved in the pathogenesis of familial erythrocytosis and polycythaemia vera (PV). In order to define whether genetic changes in the EPO-R gene and its ligand play a role in the development of PV, the structure and expression levels of the EPO-R and EPO genes were examined in samples from bone marrow and/or peripheral blood mononuclear cells of 24 patients with PV. As expected, EPO serum levels were low and no detectable level of EPO mRNA was found by reverse polymerase chain reaction (RT-PCR) in the peripheral blood mononuclear cells of our PV patients. To search for structural alterations of the EPO-R, cDNA samples were subjected to PCR and SSCP analysis as well as sequencing. Heterogenous expression of EPO-R mRNA was observed without any structural changes, as revealed by RT-SSCP analysis using overlapping primers spanning the whole coding region of the EPO-R gene. Structural integrity of the EPO-R was further confirmed by sequencing of cloned PCR products. These data suggest that the mechanisms for the development of PV do not involve structural changes of the EPO-R gene.
Adult↗
Epidural butorphanol does not reduce side effects from epidural morphine after cesarean birth.
In this prospective, double-blind, randomized study of women undergoing elective cesarean birth, the hypothesis that epidural butorphanol in various doses could effectively reduce or eliminate the side effects caused by epidural morphine was tested. Patients were randomly assigned to one of four groups. All received a standard epidural anesthetic and 20 min after delivery each received 3 mg epidural morphine with either 1 mg butorphanol (Group A), 2 mg butorphanol (Group B), 3 mg butorphanol (Group C), or 3 mL normal saline (Group D). Patient evaluations were made preoperatively and 2, 8, and 24 h after delivery. These consisted of visual analog scores for pain, satisfaction, nausea, itch, and somnolence. At each evaluation, a CO2 challenge test, using portable equipment, was performed. Data from 71 patients were analyzed and all four groups were comparable in terms of age, height, weight, level of sensory block, and volume of local anesthetic used. There were no significant differences among groups in terms of pain, satisfaction, nausea, or pruritus. Groups A, B, and C had significantly higher somnolence scores at 8 h compared to Group D (P < 0.001). There were no significant differences among groups in CO2 challenge test data at any point during the study, but overall a reduced sensitivity to CO2 after opioid administration was observed across all groups. There were no clinically significant incidents of respiratory depression. Epidural butorphanol, in doses of 1-3 mg, failed to reduce the side effects from 3 mg epidural morphine given after cesarean birth. Patients who received epidural butorphanol reported significantly higher levels of somnolence.
Anesthesia, Epidural↗
Interleukins. Clinical pharmacology and therapeutic use.
With interleukins (IL), a new class of potential drugs has been introduced into clinical research. These signal peptides are involved in the regulation of many physiological and pathophysiological processes. IL-1, -2, -3, -4, -6 and -11 have been tested in clinical trials. The growth promoting, growth inhibiting or immunomodulatory activities of interleukins represent the theoretical basis for large scale clinical testing, predominantly in malignant disease. Dose-dependent effects on numbers of peripheral blood cells and recovery from bone marrow failure have been demonstrated for IL-1, -3, -6 and -11. Phase III trials are in progress to determine their value for clinical practice. However, investigations on the immunomodulatory activities proved to be more difficult. This is because key mechanisms for successful treatment of malignant disease by immunomodulation are not clearly defined and the methodology for assessment of immunostimulatory effects is not well established. Besides treatment of renal cell carcinoma and malignant melanoma with IL-2, no successful trials have been reported. However, phase I clinical trials with IL-1, IL-4 and IL-6 have just been completed. Thus, it seems too early to conclude on their therapeutic potential.
Adjuvants, Immunologic↗