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Biomedical subjects

J Fehr

Publications and source records attributed to J Fehr.

At least 73 records · Page 4Linked to original sources
PubMed1991

Fc III receptors (FcRIII) on granulocytes: a specific and sensitive diagnostic test for paroxysmal nocturnal hemoglobinuria (PNH).

The FcRIII on human granulocytes is a glycosyl-phosphatidylinositol-anchored membrane protein. In PNH, proteins with this type of membrane linkage are known to be deficient on blood cells. The purpose of this study was to assess the diagnostic value of flow cytometric FcRIII quantification on granulocytes in PNH. Immunofluorescence measurements were performed in 105 patients, including 7 patients with PNH, 16 patients with aplastic anemia, and 12 with myelodysplastic syndrome, by a whole blood immunofluorescent staining procedure using monoclonal antibodies to FcRIII. In all 7 PNH patients and in 3 patients with aplastic anaemia, a distinct FcRIII-deficient granulocyte population of variable size was found. None of the remaining patients showed a similar population of FcRIII-deficient granulocytes. Quantification of FcRIII-deficient neutrophils is shown to be a highly specific and sensitive diagnostic test for PNH. It is easy, fast and highly reproducible and, therefore, suitable for routine diagnostic and follow-up studies in PNH patients and patients with aplastic anemia.

Antigens, CD↗
PubMed1991

[Eosinophilic granulocytes: on the way to knowledge of their functional significance].

Although the eosinophilic granulocyte has been recognized as a blood cell type for more than 100 years, its functional significance has long remained an enigma. The introduction of successful isolation procedures resulted in rapidly progressive research efforts, but the concept of the functional role of this cell type made a full about turn between the 1970s and 1980s. In the 1970s, the role of the eosinophil was thought to be a homeostatic one, with its main task being to repair mast-cell-dependent tissue damage in parasitic and allergic disease. Further structural analysis and improved biological and clinical integration of such knowledge led to the completely revised concept of the 1980s: the eosinophil is now seen as the main culprit in the damage that accompanies allergic disease, as a result of mistaken identity between the parasite (where cytotoxic power against the aggressor is desirable) and the allergen (where the eosinophil's cytotoxic power results in self-damage). The latest research news about cytokine-dependent regulatory mechanisms governing the eosinophilic reaction supports our hope that by specific blocking of tissue hormones, such as the lymphocyte-derived IL-5, elegant ways of manipulating hypereosinophilic reactions will be found in the near future.

Chemotactic Factors, Eosinophil↗
PubMed1990

The tumor necrosis factor receptor and human neutrophil function. Deactivation and cross-deactivation of tumor necrosis factor-induced neutrophil responses by receptor down-regulation.

Despite numerous reports, the role of tumor necrosis factor (TNF) in polymorphonuclear leukocyte (PMN) function remains controversial. We found TNF to be a potent, pertussis toxin-independent stimulator of PMN adhesion (ED50 2.6 pM). TNF-stimulated PMN under adherent conditions released up to 65% of their transcobalamine content (ED50 3.9 pM) and increased their burst activity 10-fold (ED50 3.2 pM) as measured by the hexose monophosphate shunt, whereas PMN held in suspension hardly degranulated at all and only little burst activity was demonstrable. However, preincubation of PMN with TNF in suspension led to a decrease in cellular adhesiveness, degranulation, and burst activity in response to a secondary stimulus of TNF under adherent conditions, although cells remained fully responsive toward phorbol myristate acetate. A concomitant dose-dependent decline of TNF receptor numbers that correlated well with the inhibition of PMN function (r = 0.91) suggests receptor down-regulation as the mechanism of functional PMN deactivation. Remarkably, preincubation with other PMN stimuli such as N-formyl-methionyl-leucyl-phenylalanine, platelet-activating factor, leukotriene B4, complement component fragment 5a (C5a)/C5a (desarginated), and endotoxin also led to a reduction of TNF-specific PMN responses (cross-deactivation) from 35% (LTB4) to 90% (endotoxin), corresponding with the down-regulation of TNF receptors. Deactivation and receptor down-regulation are independent of pertussis toxin-sensitive G proteins and protein kinase C but seemed to depend on changes in calcium metabolism. Granulocyte hyporesponsiveness towards TNF in sepsis (with elevated blood levels of endotoxin and TNF) might be a mechanism of self-protection or, to the contrary, might impair a possibly central mode of host defense.

Calcium↗
PubMed1990

Promotion of transendothelial neutrophil passage by human thrombin.

Thrombin has been reported to elicit two temporally different effects on neutrophil-endothelial interaction, categorically described as 'neutrophil adhesion': one expressed within a few minutes, the other after several hours of endothelial preincubation. Prolonged activation resulted in often elongated, tightly interacting neutrophils in contact with human umbilical vein endothelial cells (HUVE) mainly at the intercellular region. In contrast, the neutrophil-endothelial interaction due to short-time priming with thrombin was dominated by round, randomly distributed neutrophils, loosely adhering on the endothelial surface. Sheer stress, introduced to characterize these morphological entities in a quantitative manner, clearly defined the neutrophil response due to short time priming as sheer stresslabile compared to the sheer stress-resistant interaction expressed after prolonged preincubation of HUVE with thrombin. Quantitative determination of neutrophil transendothelial migration served to demonstrate the relevance of such differences in neutrophil binding with respect to subsequent layer penetration. Dependent upon endothelial protein synthesis and inhibited by antithrombin-III-heparin and hirudin, neutrophil layer penetration only occurred after prolonged activation of HUVE whereas the neutrophil-endothelial interaction due to short time priming with thrombin was limited to superficial neutrophil adhesion. We conclude that thrombin can be added to the list of activators capable of inducing the neutrophil passage-guiding principle, an effect that has recently been detected as closely related to neutrophil adhesion to endothelial ligands expressed upon activation with interleukin-1 and tumor necrosis factor. This biological activity, which can be separated from superficial attachment of polymorphonuclear leukocytes (PMN) to endothelial cells, is a catalytic site-dependent and late phase-specific effect of thrombin on HUVE.

Cell Movement↗
PubMed1989

The cell surface glycoprotein Mac-1 (CD11b/CD18) mediates neutrophil adhesion and modulates degranulation independently of its quantitative cell surface expression.

It has previously been shown that during degranulation Mac-1 (CD11b/CD18)--a glycoprotein that plays a central role in neutrophil adhesion-is up-regulated on PMN surfaces. It has been assumed that this quantitative change in adhesion Ag expression on the cell surface would in turn lead to increased cellular adhesiveness. In contrast, we found that at an incubation temperature of 16 degrees C, stimulated neutrophil adhesion to plastic tissue culture dishes in the presence of FMLP (2.5 x 10(-6) M), TNF (10 ng/ml), or PAF (1 x 10(-4) M) occurred without cellular degranulation or Mac-1 surface up-regulation as measured cytofluorometrically. As shown by functional inhibition studies employing monoclonal antibodies 60.3 (anti-CD18) and 60.1 (anti-CD11b), adhesion at 16 degrees C, where no CD11b/CD18 up-regulation was seen, is mediated by CD11b/CD18 just as it is at 37 degrees C, where degranulation and CD11b/CD18 up-regulation could be demonstrated. The physiologic importance of these findings was underscored by experiments done on endothelial monolayers, which showed that PMN association with endothelial cells is absolutely independent from the quantitative up-regulation of Mac-1 on PMN surfaces. When neutrophils were stimulated at 37 degrees C by endotoxin, an agent that does not induce aggregation (a form of intercellular adhesion), Mac-1 surface expression increased only after cells had become adherent, whereas cells held in suspension to prevent cell-substrate adhesion neither degranulated nor up-regulated their Mac-1 surface expression. Thus, not only is adherence independent of degranulation and Mac-1 cell surface up-regulation, but both degranulation and Mac-1 surface up-regulation appear to depend on the process of adhesion. Correspondingly, incubation of neutrophils with antibodies 60.1 and 60.3 inhibited not only adhesion of cells stimulated with FMLP at 37 degrees C but degranulation as well. These results indicate that Mac-1 influences degranulation as well as it controls adhesion not by its mere quantity on the cell surface, but rather by an yet undefined molecular modulation.

Antibodies, Monoclonal↗
PubMed1989

Progressive dilated cardiomyopathy in a patient with longstanding and complete prednisone-induced hematological remission of idiopathic hypereosinophilic syndrome.

A female patient is described in whom the diagnosis of idiopathic hypereosinophilic syndrome (HES) with heart disease and peripheral neuropathy was made at the age of 32 years. Although prednisone induced a prompt and longstanding complete hematological remission, progressive and eventually intractable heart failure developed, and the patient died 6 years later. Endomyocardial biopsy at diagnosis showed infiltration with intact and disintegrated eosinophils and Charcot-Leyden crystals. Echocardiographic follow-up (including Doppler-Echocardiography) revealed mitral regurgitation with thickening and impaired motility of the posterior mitral leaflet, as well as progressive dilated cardiomyopathy. At autopsy, a diffuse interstitial fibrosis with patchy prominence in an eccentric hypertrophic and highly dilated heart was found. There were no significant endocardial thickening and no mural thrombi. In contrast to the findings of the initial endomyocardial biopsy, autopsy revealed no eosinophilic infiltrate. In this case, eosinophil-induced heart disease manifested as dilated cardiomyopathy, without endocardial fibrosis as originally described by Löffler. We speculate, that eosinophils have been deposited predominantly in the myocard at an early stage of disease, and - activated locally - secreted their granule proteins producing an initial damage to capillary endothelial cells and myocytes. After prednisone-induced clearance of eosinophils from blood and tissues, progressive, self-perpetuating interstitial fibrosis of the myocard and loss of myocytes eventually resulted in end-stage dilated cardiomyopathy.

Adult↗
PubMed1989

Cyclosporin-A therapy of pure red cell aplasia in a patient with B-cell chronic lymphocytic leukemia.

A 65-year-old woman with B-cell chronic lymphocytic leukemia (CLL) and pure red cell aplasia (PRCA) is described. After initial chemotherapy with three different regimens over 3 months (prednisone, chlorambucil/vincristine, cyclophosphamide, bleomycin/cyclophosphamide, etoposide, prednisone), normalization of the blood lymphocyte count was observed, but lymphocyte infiltration of the bone marrow persisted and erythropoiesis remained virtually absent. Monotherapy with cyclosporin-A (CyA) was begun. After 35 days, a marked increase in the reticulocyte count was observed, and with continuing therapy, there was a rapid increase in the hemoglobin level. Follow-up after 13 months of uninterrupted treatment with CyA revealed remission of both CLL and PRCA. CyA should be investigated further as a therapeutic modality for PRCA in patients with CLL, and such trials might provide further clues to the pathogenesis of this peculiar association.

Aged↗
PubMed1989

[Erythropoiesis and serum erythropoietin concentrations before and after kidney allotransplantation].

Hematological parameters and serum erythropoietin (EPO) levels were measured before and sequentially after grafting in 50 consecutive cadaver renal transplant recipients. EPO was estimated using a sensitive radioimmunoassay. Values for nonanemic controls were 15-25 mU/ml. Mean hematological values before transplantation were as follows: hemoglobin 9.7 +/- 2.4 g/dl; hematocrit 29 +/- 8%; corrected reticulocytes count 15 +/- 8% and EPO 29 +/- 23 (11-131) mU/ml. In the entire studied population, 35 patients had inadequate low EPO levels for their degree of anemia. In the whole population, there was a significant positive exponential correlation between EPO and hematocrit (r = 0.31; p less than 0.05). In the subset of patients with underlying cystic kidney disease and in hemodialysis patients treated with recombinant human EPO, hemoglobin, hematocrit and EPO levels were higher when compared to hemodialysis or CAPD patients with other kidney diseases. Following successful renal transplantation, EPO increased to 45 +/- 31 mU/ml at 1 month and then decreased to 25 +/- 18, 18 +/- 7 and 19 +/- 4 mU/ml at 3,6 and 9 months, respectively. Within the 1st month after transplantation there was a 4-fold increase in reticulocytes from 9 +/- 5 to 38 +/- 14%, followed by a slow decrease over the next several months to 23 +/- 11% at 9 months. In contrast, the hematocrit level rose more gradually from 28 +/- 7 to 44 +/- 6% at 9 months. In 25 of 36 patients with a functioning graft who were followed for more than 6 months, anemia was corrected and 11 patients remained slightly anemic with a mean hematocrit level of 36 +/- 4%.

Erythropoiesis↗
PubMed1989

Interleukin 1 and tumor necrosis factor stimulate human vascular endothelial cells to promote transendothelial neutrophil passage.

In an attempt to understand the regulatory mechanisms governing passage of neutrophils from the vascular bed to the interstitial tissue, we analyzed the effect of the pleiotropic monokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) on transendothelial neutrophil traffic. Short-time preincubation of human umbilical vein endothelial cell (HUVE) monolayers with IL-1 and TNF led to an impressive time- and dose-dependent increase of endothelial cell-associated neutrophils when working in a full plasma system on petri dishes. Electron microscopic analysis revealed junctional penetration of monolayers by neutrophils. More quantitatively, when using a monolayer-on-filter-system, priming led to a severalfold increase in complete layer passage occurring in the absence of an external chemotactic gradient. Direct comparison with an upside-down modification of the system together with data demonstrating the vectorial behavior of such migration revealed that IL-1-stimulated transendothelial neutrophil traffic is polarized. The described enhancement of neutrophil transendothelial passage was found to be a unique feature of IL-1/TNF-activated HUVE since HUVE-dependent transmigration potentiation was not observed as a consequence of mere neutrophil attachment to endothelial cells (e.g., induced by Fc-mediated adherence of PMN to HUVE). IL-1 acts selectively on endothelial cells as demonstrated by total inhibition of its effect by actinomycin D. Moreover, IL-1 does not induce HUVE monolayers to secrete a chemotaxin, and the neutrophil passage guiding principle is removable from the HUVE surface by short trypsin exposure. Congruent results were obtained with human adult arterial as well as saphenous vein endothelial cells. As shown by blockade of neutrophil migration with pertussis toxin, IL-1- and TNF-inducible transendothelial migration can be dissected into an initial anchoring step, which is succeeded by active neutrophil migration, possibly along a putative endothelial membrane-bound gradient.

Cell Adhesion↗
PubMed1988

[Efficacy of recombinant interferon alpha-2 in 34 patients with hairy cell leukemia. Effect of splenectomy and dosage reduction results of therapy].

In a retrospective study of 34 patients with hairy cell leukemia treated with recombinant interferon-alpha 2, we have observed a hematological remission rate of 97%. The true complete remission rate based on bone marrow findings was 17%. Although complete remissions can be obtained only in a few cases, treatment with interferon is justified in cytopenic patients since long-standing clinically meaningful improvement of the peripheral blood values can be attained. If interferon is stopped in the remission phase, the blood values deteriorate in 40% of the patients within 5 months. In contrast, it appears that the remission can be maintained with intermittent administration of interferon weekly or even every other week. As compared to splenectomized patients, granulocyte recovery is delayed in nonsplenectomized patients. However, after several months of treatment there is no difference in peripheral blood values between splenectomized and non-splenectomized patients. In the light of the present results, primary splenectomy remains justified in a selected group of patients for whom the risk of surgery (due to low granulocytes and/or platelets) is low and for whom careful evaluation predicts a high potential for long-standing remission after splenectomy. In the other cases, initial interferon therapy seems justified.

Adult↗
PubMed1988

Functional hyposplenia after allogeneic bone marrow transplantation is detected by epinephrine stimulation test and splenic ultrasonography.

Splenic function was evaluated after subcutaneous epinephrine injection (0.5 mg/m2) in 15 bone marrow transplant (BMT) recipients, 10 healthy volunteers and 5 healthy asplenic men. Healthy volunteers and BMT recipients with minor primary induction chemotherapy (mRx) showed similar rise in platelet (plt) and neutrophil granulocyte (PMN) counts and similar contraction of spleen. Patients with intensive primary induction chemotherapy (MRx), however, had significantly smaller spleens and spleen contraction (p less than 0.02) and no plt increase (p less than 0.05) when compared with healthy volunteers. 2 patients with MRx even exhibited a decrement of plt count after epinephrine, similar to that observed in all 5 healthy asplenic subjects tested. Our results suggest that mRx and conditioning for BMT including total body irradiation (TBI) does not alter the splenic function, but that the combination of MRx and conditioning regimen including TBI may cause functional hyposplenism, sensitively revealed by reduction in plt count after epinephrine stimulation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

[Reversible azathioprine associated dysmyeloproliferative syndrome after kidney allotransplantation].

Three recipients of kidney allotransplants developed dysmyeloproliferative syndromes which were fully reversible after switching from azathioprine to cyclosporin A for immunosuppression. Similar bone marrow changes described in the literature progressed to leukemia. Whether the abnormalities observed in our patients could be early stages of the disease described in the literature and whether a fatal development can be prevented by changing the immunosuppressive therapy remains to be elucidated.

Adult↗