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K Lechner

Publications and source records attributed to K Lechner.

At least 19 recordsLinked to original sources
PubMed1992

Recurrent, isolated factor X deficiency in myeloma: repeated normalization of factor X levels after cytostatic chemotherapy followed by late treatment failure associated with the development of systemic amyloidosis.

We describe the case of a 64-year-old woman with isolated severe factor X deficiency associated with kappa light chain myeloma. At the time of diagnosis there was no evidence for amyloidosis. Complete remission (CR) of myeloma as well as normalization of factor X levels were achieved after cytostatic chemotherapy. Subsequently, factor X deficiency recurred twice without any evidence for relapse of myeloma. The first time factor X normalized again following cytostatic treatment, the second time, however, factor X deficiency was refractory to chemotherapy. Finally, relapse of myeloma became evident associated with rapidly progressing, systemic amyloidosis, which was fatal within a few months. Initially, factor X infusion studies showed a normal recovery, but when amyloidosis became overt the recovery decreased to 0%. We assume that factor X deficiency was due to a binding of factor X to kappa light chains associated with the proliferation of the malignant myeloma cell clone.

Amyloidosis↗
PubMed1992

Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture.

In the murine system, a number of cytokines (including interleukin-3 [IL-3], IL-4, and stem cell factor [SCF]) promote the growth of mast cells (MCs). However, so far little is known about factors controlling differentiation of human MCs. Recent data suggest that human MCs express receptors (R) for SCF. The aim of the present study was to investigate whether recombinant human (rh) SCF induces differentiation of human MCs from their precursor cells. For this purpose, bone marrow (BM; normal donors, n = 6) and peripheral blood (PB; normal donors, n = 11) mononuclear cells (MNC) were cultured in the presence of rhSCF, rhIL-3, rhIL-4, rhIL-9, recombinant human macrophage colony-stimulating factor (rhM-CSF), or control medium in long-term (8 weeks) suspension cultures. After 4 weeks, up to 5% of the MNC (BM and PB) cultured in the presence of rhSCF, but not in the presence of other cytokines, were found to exhibit the characteristics of MCs. These MCs expressed the YB5.B8-reactive domain of the SCF R as well as IgE R, as determined by combined toluidine blue/immunofluorescence staining. Myeloid antigens, likewise expressed on human basophils (ie, CD11b, CDw65, and Bsp-1), could not be detected on these cells. Furthermore, rhSCF, but not rhIL-3, rhIL-4, rhIL-9, or rhM-CSF, induced dose- and time-dependent increases in the formation of cellular tryptase (an MC-specific enzyme) (rhSCF [100 ng/mL], 1,308 +/- 679 ng/mL v control medium, 18 +/- 6 ng/mL tryptase on day 35 of PB cell cultures), as well as an increase in cellular histamine. After 6 to 8 weeks, when other mature hematopoietic cells decreased, MCs still could be detected in culture, with up to 40% of all cells being MCs. To test whether rhSCF also activates tissue MCs, we performed histamine release experiments (dispersed tissue; lung, n = 3; uterus, n = 3). SCF was found to enhance (by up to 3.4-fold) the capacity of the MCs to release histamine upon cross-linkage of IgE R with anti-IgE. Together, these observations suggest that rhSCF induces in vitro differentiation of human MCs from their BM and PB precursor cells in long-term culture and upregulates MC releasability.

Antibodies, Monoclonal↗
PubMed1992

Type beta transforming growth factors promote interleukin-3 (IL-3)-dependent differentiation of human basophils but inhibit IL-3-dependent differentiation of human eosinophils.

Basophils and eosinophils share a common differentiation pathway. Factors regulating terminal commitment toward one cell type, however, have so far not been defined. Interleukin-3 (IL-3) is a potent differentiation factor for both human eosinophils and basophils. In the present study, the effects of various recombinant human (rh) growth regulators on IL-3-dependent growth of eosinophils and basophils were studied in a bone marrow (BM) suspension culture system (normal donors, n = 13). We found that type beta transforming growth factors (TGFs) lead to a significant increase in the absolute numbers of basophils in BM cultures grown in the presence of IL-3 (day 14 of culture; IL-3: 133 +/- 20 v IL-3 + TGF-beta 1: 231 +/- 28 x 10(3)/mL [P less than .01]) and to an increase in the total histamine values (IL-3: 72.6 +/- 22.2 v IL-3 + TGF-beta 1: 142.9 +/- 37.3 ng/mL [P less than .015]) compared with rhIL-3 alone. In contrast, type beta TGFs were found to inhibit the IL-3-dependent growth of eosinophils (IL-3: 170.4 +/- 37.2 v IL-3 + TGF-beta 1: 16.7 +/- 5.2 x 10(3)/mL [P less than .01]) and formation of eosinophil cationic protein in the same culture system. The effect of TGF-beta 1 (and TGF-beta 2) on IL-3-dependent differentiation of basophils and eosinophils was dose- and time-dependent (maximum effects observed with 1 to 10 ng/mL of rhTGF-beta 1 or TGF-beta 2) and could be neutralized by an antibody specific for TGF-beta 1. In contrast to the TGFs, interferon-alpha (IFN-alpha) and IFN-gamma were found to downregulate IL-3-dependent formation of both basophils (IL-3: 167 +/- 33 v IL-3 + IFN-alpha: 67 +/- 25 v IL-3 + IFN-gamma: 65 +/- 33 x 10(3)/mL [P less than .01]) and eosinophils (IL-3: 239 +/- 5 v IL-3 + IFN-alpha: 81 +/- 4 v IL-3 + IFN-gamma: 67 +/- 17 x 10(3)/mL [P less than .05]) in our culture system. Type beta TGFs as well as the IFNs failed to directly induce differentiation of human basophils or eosinophils in the absence of other growth factors. Together, these results show that type beta TGFs and IFNs are potent regulators of cytokine-dependent growth and differentiation of human allergic effector cells.

Antibodies, Monoclonal↗
PubMed1992

Characterization of prostaglandin (PG)-binding sites expressed on human basophils. Evidence for a prostaglandin E1, I2, and a D2 receptor.

Recent data suggest that prostaglandins (PGs) are involved in the regulation of basophil activation. The aim of this study was to characterize the basophil PG-binding sites by means of radioreceptor assays using 3H-labeled PGs. Scatchard analysis for pure (greater than 95%) chronic myeloid leukemia (CML) basophils revealed two classes of PGE1-binding sites differing in their affinity for the natural ligand (Bmax1 = 217 +/- 65 fmol/10(8) cells; Kd1 = 0.5 +/- 0.2 nM; Bmax2 = 2462 +/- 381 fmol/10(8) cells; Kd2 = 47 +/- 20 nM; IC50 = PGE1 less than PGI2 less than PGD2 less than PGE2 less than PGF2 alpha) as well as two classes of PGI2 (iloprost)-binding sites (Bmax1 = 324 +/- 145 fmol/10(8) cells; Kd1 = 0.5 +/- 0.3 nM; Bmax2 = 2541 +/- 381; Kd2 = 27 +/- 6 nM; IC50 = PGI2 less than PGE1 less than PGD2 less than PGE2 less than PGF2 alpha. In addition, CML basophils exhibited a single class of PGD2-binding sites (Bmax = 378 +/- 98 fmol/10(8) cells; Kd = 13 +/- 4 nM; IC50: PGD2 less than PGI2 less than PGE1 less than PGE2 less than PGF2 alpha). In contrast, we were unable to detect specific saturable PGE2-binding sites. Primary and immortalized (KU812) CML basophils revealed an identical pattern of PG receptor expression. Basophils (KU812) expressed significantly (p less than 0.001) lower number of PGE1 (PGI2)-binding sites (Bmax1: 9% (20%) of control; Bmax2: 36% (50%) of control) when cultured with recombinant interleukin 3 (rhIL-3), a basophil-activating cytokine, whereas rhIL-2 had no effect on PG receptor expression. Functional significance of binding of PGs to basophils was provided by the demonstration of a dose-dependent increase in cellular cAMP upon agonist activation, with PGE1 (ED50 = 1.7 +/- 1.1 nM) and PGI2 (ED50 = 2.8 +/- 2.3 nM) being the most potent compounds. These findings suggest that human basophils express specific receptors for PGE1, PGI2 as well as for PGD2.

Alprostadil↗
PubMed1992

In vivo synergism of recombinant human interleukin-3 and recombinant human interleukin-6 on thrombopoiesis in primates.

Using a primate model, we examined the effect of recombinant human interleukin-3 (rhIL-3) and rhIL-6 on thrombopoiesis in vivo. Administration of 33 micrograms/kg/d of rhIL-3 for 11 to 14 days increased levels of circulating colony-forming units megakaryocyte (CFU-Mk) by approximately 15-fold in five rhesus monkeys without raising their platelet counts. In contrast, administration of 30 micrograms/kg/d of rhIL-6 for 10 days in four animals did not increase CFU-Mk levels but significantly raised platelet counts from a mean pretreatment value of 460 x 10(3)/microL (range 360 to 610) to a mean maximum of 746 x 10(3)/microL (665 to 790) on day 8. If monkeys were pretreated with rhIL-3 (33 or 100 micrograms/kg/d for 11 days) to expand their CFU-Mk compartment, the thrombopoietic effect of rhIL-6 was synergistically enhanced leading to platelet counts above 1,000 x 10(3)/microL (mean maximum value 1,247) in all three primates studied. The sequential administration of rhIL-3 and rhIL-6 might represent a powerful strategy to stimulate thrombopoiesis in vivo.

Animals↗
PubMed1992

Treatment of de novo acute myelogenous leukemia with recombinant granulocyte macrophage-colony-stimulating factor in combination with standard induction chemotherapy: effect of granulocyte macrophage-colony-stimulating factor on white blood cell counts.

GM-CSF is a major regulator of myelopoiesis. Recombinant human GM-CSF (250 micrograms/m2 per day i.v.) was used prior to chemotherapy ("3 + 7" scheme) to recruit leukemic blasts in vivo (de novo AML patients, n = 20) into the chemotherapy sensitive phases of the cell cycle. The stimulatory effect of GM-CSF on peripheral blood AML blasts was associated with a rapid redistribution of leukemic blood cells and with an increase in "S-phase positive" cells. Standard induction chemotherapy ("3 + 7") following GM-CSF induced complete aplasia in 19/20 patients. In the same patients, rhGM-CSF (given after chemotherapy) was found to shorten the time of complete aplasia compared to historical controls whereas post-chemotherapy- and follow-up data suggest no significant differences for CCR and survival. Together, our studies show that GM-CSF can safely be administered to AML patients in combination with induction chemotherapy to recruit leukemic cells into the cell cycle.

Adult↗
PubMed1992

Studies on the effect of two angiotensin-converting enzyme inhibitors, captopril and cilazapril, on platelet and vascular prostaglandin metabolism in vivo.

We have studied in 12 healthy volunteers the effects of two angiotensin-converting enzyme (ACE) inhibitors, captopril and cilazapril, on vascular and platelet prostaglandin metabolism, in a double-blind, placebo-controlled, randomized cross-over study. Formation of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) was measured locally at the site of a microvascular injury. Similar amounts of TxB2 and 6-keto-PGF1 alpha were generated following administration of either ACE inhibitor as compared to placebo. It is concluded that neither captopril nor cilazapril significantly influence vascular and platelet prostaglandin metabolism.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Differential expression of cell surface integrins on human mast cells and human basophils.

Integrins are multifunctional recognition molecules and are expressed on various hematopoietic cells. In the present study expression of integrins on the cell surface of human mast cells and human basophils was investigated by using monoclonal antibodies (mAbs) and indirect immunofluorescence. Human mast cells were obtained from lung (n = 5), uterus (n = 5) and skin (n = 4). Human blood basophils were obtained from normal donors (n = 2). In addition, HMC-1 cells (human mast cell line) and KU-812 cells (a basophil cell line) were analyzed. Primary mast cells were found to react with mAbs directed against the common beta chain of beta 1 integrins (CD 29), the alpha chain of VLA-4 (CD 49 d) and VLA-5 (CD 49 e), the beta chain of beta 3 integrins (CD 61), and the alpha chain of the vitronectin receptor (VNR) (CD 51). Mast cells were not recognized by mAbs to beta 2 integrins (CD 18, CD 11 a, CD 11 b, CD 11 c), the alpha chain of VLA-2 (CD 49 b), and VLA-6 (CD 49 f). No differences in expression of integrins on human mast cells obtained from different organs were found. HMC-1 cells and primary mast cells expressed an almost identical pattern of integrins. Human basophils and KU-812 cells were found to react with mAbs directed against beta 1-integrins (CD 29, CD 49 b, CD 49 d, CD 49 e) and beta 2-integrins (CD 18, CD 11 a, CD 11 b, CD 11 c). Together, mast cells and blood basophils express a unique pattern of integrins. These cell surface structures may be involved in the distribution of basophils and tissue mast cells and their accumulation and function in inflammed tissues.

Antibodies, Monoclonal↗
PubMed1992

Simultaneous occurrence of t(14;18) and t(8;22) common acute lymphoblastic leukemia.

A young male patient progressed rapidly from localized abdominal lymph node enlargement to overt acute lymphoblastic leukemia. Despite aggressive treatment, he died of progressive CNS leukemia 5 months after initial presentation. At diagnosis, karyotypic analysis of an abdominal lymph node revealed the coexistence of t(14;18) (q32;q21), specific for follicular lymphoma, and t(8;22) (q24;q11), a variant Burkitt translocation. Such cases might be considered as a model for a general mechanism of tumor progression with cascade-like involvement of oncogenes.

Adult↗
PubMed1992

Cerebral sinus thrombosis in a patient with hereditary protein S deficiency: case report and review of the literature.

Hereditary protein S deficiency is an established risk factor for venous thrombosis. The common sites of thrombosis are the deep leg and pelvic veins. We report on a 38-year-old female patient with hereditary protein S deficiency and a previous history of deep leg vein thrombosis, who developed thrombosis of the cerebral straight and superior sagittal sinus while taking oral contraceptives. The diagnosis was established by computerized tomography and carotid angiography. Lysis of the thrombus occurred during heparin treatment. The hereditary nature of protein S deficiency was documented by family studies, since nine additional family members deficient in protein S were identified. Nineteen published cases of cerebral vein thrombosis and a deficiency of either anti-thrombin III, protein C, or protein S were reviewed. Compared with patients without a deficiency state, the clinical features of cerebral vein thrombosis were similar except for an earlier onset and a positive medical history of venous thromboembolic events in a considerable number of patients.

Adult↗
PubMed1992

Factor VIII concentrates in HIV-1-positive hemophiliacs--is pure better?

39 human immunodeficiency-virus-1 (HIV-1)-positive hemophiliacs who had been regularly treated with non-virus-inactivated intermediate-purity factor VIII concentrates were divided into two groups. Group A consisted of 21 patients with a CD4/CD8 cell ratio of less than 1.0 and group B of 18 patients with a CD4/CD8 cell ratio of greater than 1.0. All patients of group A were switched to a high-purity virus-inactivated factor VIII concentrate, whereas patients of group B continued to receive the intermediate-purity concentrate. There was no significant difference in the average decline of CD4 cells between the two groups during the observation period. 9 patients of group A and 4 patients of group B developed AIDS. 5 patients of group A but 11 patients of group B remained clinically asymptomatic. We conclude that the 15-fold increase in purity of the factor VIII concentrate had no apparent beneficial effect on the CD4 cell counts in this patient group.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening.

Data in the literature on the prevalence of hereditary deficiency of the natural coagulation inhibitors are conflicting. We conducted a prospective study on 680 consecutive patients with a history of venous thrombosis to determine the prevalence of hereditary deficiency of antithrombin III (AT III), protein C(PC) and protein S(PS) and to establish selection criteria for rational patient screening. The mean age of the patients at investigation was 44.3 +/- 15.4 years, while that at the first thrombotic event was 38.5 +/- 14.8 years. The total prevalence of inhibitor deficiency states was 48/680 (7.1%). 19/680 patients (2.8%) had AT III-deficiency, 17 (2.5%) PC-deficiency, nine (1.3%) PS-deficiency and three (0.4%) a combined deficiency. In 37/48 deficient patients family studies were performed and the hereditary nature was established in 19 cases (2.8% of total patient population, six with AT III-deficiency, eight with PC-deficiency, four with PS-deficiency and one with a combined deficiency). Family studies in these 19 patients revealed 46 additional individual patients with a hereditary deficiency state. A positive family history was found in 15/19 (79%) with a proven hereditary deficiency state, in 153/619 (25%) of non-deficient patients and in 11/29 (38%) of deficient patients without established hereditary nature. The mean age at the first thrombotic event was significantly lower in patients with a hereditary deficiency state (26.8 years) compared with the other two groups (39.0 and 39.7 years, respectively). In all patients with a hereditary deficiency the first thrombotic event occurred before the age of 45 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

[Problems of long-term therapy with anticoagulants].

Oral anticoagulants are highly effective for the prevention of recurrence of venous thromboembolism and of thromboembolic complications in rheumatic and non-rheumatic atrial fibrillation, dilated cardiomyopathy and in patients with prosthetic heart valves, but less effective for prevention of arterial thrombosis. Bleeding is the main side effect, the risk of fatal bleeding is 0.2 to 0.4% per year, depending on the intensity of treatment. The problem of the standardization of the prothrombin time determination has been solved by the introduction of the international normalized ratio. Recent studies have shown that a lesser degree of anticoagulation (INR 2.0 to 3.0) is sufficient to prevent venous thromboembolism and cardiac emboli. The measurement of activation markers of coagulation will probably allow a more rational monitoring in the near future.

Administration, Oral↗
PubMed1991

IL-4 regulates c-kit proto-oncogene product expression in human mast and myeloid progenitor cells.

The c-kit proto-oncogene encodes the receptor for a novel hemopoietic cytokine, termed stem cell factor (SCF) or mast cell growth factor (MGF) according to its stimulating spectrum. The human receptor for SCF/MGF is expressed in a subset of normal bone marrow progenitor cells, in leukemic myeloid cells, and in mast cells. In the present study, the effects of recombinant human growth regulators (IL-1 through -9, granulocyte-macrophage/granulocyte/macrophage-CSF, IFN, and TNF) on c-kit proto-oncogene product expression were analyzed by indirect immunofluorescence, by using the anti-SCF/MGFR mAb YB5.B8, and Northern blot analyses, by using a c-kit oligonucleotide probe. Of all cytokines tested, IL-4 was found to down-regulate expression of YB5.B8 Ag in the human mast cell line HMC-1 (maximum inhibition, 51.05 +/- 16.36% mean fluorescence intensity of control; p less than 0.02), as well as in primary leukemic myeloid cells. IL-4 was also found to down-regulate expression of YB5.B8 Ag in normal enriched bone marrow progenitor cells. The effects of IL-4 on expression of YB8.B8 Ag in myeloid/mast cell progenitors was dose and time dependent (maximum effects observed on days 2 and/or 4, by using 50 U/ml of rIL-4) and could be neutralized by using anti-IL-4 mAb. Moreover, IL-4 was found to down-regulate expression of c-kit mRNA in leukemic myeloid cells as well as in HMC-1 cells. Together, these observations identify IL-4 as a regulator of c-kit proto-oncogene product expression in the human system. The effects of IL-4 on human hemopoietic progenitor cells and mast cells may be mediated in part through regulation of SCF/MGFR expression.

Antibodies, Monoclonal↗