[Malignant hematologic diseases].
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Hematologic Diseases↗
Biomedical subjects
J Fehr
Publications and source records attributed to J Fehr.
High grade malignant lymphoma with clinical characteristics and immunophenotype of natural killer cells.
The malignant proliferation of natural killer (NK) cells which are morphologically characterized as large granular lymphocytes (LGL) is a well known clinical entity which was named after its morphological appearance as LGL-leukemia/lymphoma. Similar to non-malignant NK-cells, these tumors can be divided into those which express the CD3-T-cell receptor complex and those which do not. The CD3-positive type of LGL-leukemia is immunophenotypologically characterized by the expression of CD16, and variably CD 56 and CD 57, and generally follows a more indolent course. In contrast, malignant proliferations of CD3-negative LGL express either CD16 or CD 56, and only occasionally CD 57 on their cell surface. Clinically, CD3-negative NK-lymphomas tend to progress rapidly. We report here the case of a high grade malignant lymphoma which was characterized by an immunophenotype typical for CD3-negative NK-cells (CD2+, CD3-, CD16+, CD56(+), CD57-). The disease proved to be rapidly fatal despite aggressive chemotherapy. Interestingly, the patient suffered from a high turn over pancytopenia, which also characterizes NK-cell leukemias/lymphomas of the LGL-type. However, our patient's lymphatic cells appeared highly immature, and cytoplasmic granules, characteristic for LGL-cells, could not be discerned either microscopically or electronmicroscopically. Furthermore, the malignant lymphatic population had the T-cell receptor beta-chain rearranged. We therefore concluded that our patient might have suffered from a malignant proliferation of a putative precursor cell intermediate between T-cells and NK-cells.
Adult↗
The influence of leukocyte filtration during cardiopulmonary bypass on postoperative lung function. A clinical study.
The accumulation of activated leukocytes in the pulmonary circulation plays an important role in the pathogenesis of lung dysfunction associated with cardiopulmonary bypass. Animal studies have demonstrated that the elimination of leukocytes from the circulation reduces postoperative lung injury and improves postoperative pulmonary function. We conducted a prospective randomized clinical study to evaluate whether postoperative lung function could be improved by use of a leukocyte filter during cardiopulmonary bypass. Elective coronary artery bypass grafting was done with a leukocyte-depleting arterial blood filter incorporated in the extracorporeal circuit (14 patients, leukocyte filter group) or without the filter (18 patients, control group). Blood samples collected at intervals before, during, and after operation were used for analysis of blood cell counts, elastase concentrations, and arterial blood gases. The use of the leukocyte filter caused no significant reduction in leukocyte count (p = 0.86). There were no differences in postoperative lung function between the groups, as assessed through (1) oxygenation index (290 for leukocyte filter group compared with 329 for control group, 95% confidence interval, 286 to 372, p = 0.21), (2) pulmonary vascular resistance (p = 0.10), and (3) intubation time (16.6 hours for leukocyte filter group versus 15.7 hours for control group, 95% confidence interval, 12.1 to 19.1 hours, p = 0.72). The levels of neutrophil elastase were significantly higher at the end of cardiopulmonary bypass in the leukocyte filter group (460 microgram/L in leukocyte filter group versus 230 microgram/L in control group, 95% confidence interval, 101 to 359 microgram/L, p = 0.003). We conclude that the clinical use of the present form of leukocyte-depleting filter did not improve any of the postoperative lung function parameters analyzed in this study.
Cardiopulmonary Bypass↗
GM-CSF-induced acute eosinophilic pneumonia.
There is increasing evidence that haemopoietic growth factors are effective in reversal of neutropenia associated with large granular lymphocytes (LGLs) proliferation. A 19-year-old woman with CD3+/TCR gamma delta+, CD4-, CD8- LGL proliferation and severe neutropenia repeatedly developed blood eosinophilia, fever and dyspnoea after administration of GM-CSF. Acute eosinophilic pneumonia with a lobar lung infiltrate pleural effusion, and marked bronchoalveolar lavage fluid eosinophilia was diagnosed. Treatment with corticosteroids and discontinuation of GM-CSF lead to rapid improvement. In addition, haematological analysis revealed that H*1 Technicon, a widely-used automated cell counter, may misinterpret eosinophils erroneously as neutrophils, therefore examination of blood smears to prevent eosinophil-mediated toxicity during GM-CSF treatment is recommended.
Acute Disease↗
Prediction of iron deficiency in chronic inflammatory rheumatic disease anaemia.
We prospectively studied 45 anaemic patients (37 women, 8 men) with chronic inflammatory rheumatic diseases. The combination of serum ferritin and CRP (as well as ESR) in its predictive capacity for bone marrow iron stores was examined. The relationship between other iron-related measurements (transferrin, transferrin saturation, soluble transferrin receptor, erythrocyte porphyrins and percentage of hypochromic/microcytic erythrocytes) and bone marrow iron stores was also investigated. Stainable bone marrow iron was taken as the most suitable standard to separate iron-deficient from iron-replete patients. 14 patients (31%) were lacking bone marrow iron. Regression analysis showed a good correlation between ferritin and bone marrow iron (adjusted R2 = 0.721, P < 0.0001). The combination of ferritin and CRP (ESR) did not improve the predictive power for bone marrow iron (adjusted R2 = 0.715) in this cohort of patients with low systemic inflammatory activity. With respect to the bone marrow iron content the best predictive cut-off value of ferritin was 30 micrograms/l (86% sensitivity, 90% specificity). The other iron-related parameters both individually and when combined were less powerful in predicting bone marrow iron than ferritin alone. Only zinc bound erythrocyte protoporphyrin in combination with ferritin slightly improved prediction (adjusted R2 = 0.731). A cut-off point of 11% hypochromic erythrocytes reached a high specificity (90%), but was less sensitive (77%).
Adult↗
Epinephrine test and plasma elastase as diagnostic tools in a patient with CD3+ large granular lymphocyte proliferation.
Large granular lymphocytes (LGL) proliferation is characterized by expansion of cytotoxic lymphocytes and associated with neutropenia. In a case of CD3+ LGL-proliferation the epinephrine stimulation test (EST) induced a striking elevation of CD3+, CD8+, CD57+ LGL in peripheral blood from 2.7 x 10(9)/l to 20 x 10(9)/l and might be an additional diagnostic tool in patients with normal or low absolute numbers of circulating LGL. After treatment with steroids, plasma elastase--a marker of neutrophil destruction--decreased from 162 to 40 micrograms/l (normal < 47 micrograms/l) which correlated well with a simultaneous increase in peripheral neutrophil counts from 0.14 to 1.0 x 10(9)/l. This finding supports the hypothesis that neutropenia in CD3+ LGL proliferation is due to neutrophil destruction, possibly mediated by LGL.
Aged↗
Acute lung injury during cardiopulmonary bypass. Are the neutrophils responsible?
To test the hypothesis that acute lung injury during cardiopulmonary bypass (CPB) is related to the activation of neutrophils and the body temperature during bypass, we determined the differential WBC count, plasma elastase concentrations, and lung function before, during, and after CPB in 38 patients undergoing elective coronary artery bypass surgery. The patients were randomly assigned to receive either normothermic (n = 19, rectal temperature: 35.9 +/- 0.1 degrees C, mean +/- SE) or hypothermic (n = 19, 29.2 +/- 0.5 degrees C) CPB. The cellular response to the extracorporeal circulation was significantly delayed in the hypothermic group with a later onset of neutrophilia and a later increase in plasma elastase levels during bypass. Lung function deteriorated significantly after CPB as assessed by respiratory index, alveolar-arterial oxygen gradient, and intrapulmonary shunt, independent of bypass temperature. There was a positive correlation between peak elastase concentrations and postoperative respiratory index as well as intrapulmonary shunt (R2 = 0.5, p = 0.002 and R2 = 0.45, p = 0.003, respectively). Besides peak plasma elastase levels, multiple regression revealed no significant influence of other independent factors on postoperative lung dysfunction in our patients.
Body Temperature↗
Neutrophil activation in response to immune complex-bearing endothelial cells depends on the functional cooperation of Fc gamma RII (CD32) and Fc gamma RIII (CD16).
Leukoclastic vasculitis is thought to be initiated by deposition of immune complexes (ICs) in the vascular wall. To study the neutrophil response in a related in vitro model, we primed human umbilical vein endothelial cell (HUVEC) monolayers with antibodies against human fibronectin. The resulting respiratory burst to the immobilized ICs depended on the antibody concentration used to prime the monolayers and included a marked release of primary and secondary granule constituents. On IC-bearing HUVEC monolayers, but not on ICs directly bound to tissue culture dishes, blocking monoclonal antibodies (mAbs) to crystallizable fragment-gamma receptor II (Fc gamma RII) and Fc gamma RIII markedly inhibited the respiratory burst and the release of elastase. However, on both surfaces the neutrophil response was strongly inhibited by mAbs against CD18. Regardless of whether we used neutrophils from a patient with severe paroxysmal nocturnal hemoglobinuria (PNH) lacking the Fc gamma RIII, or whether the Fc gamma RII-mediated signal transduction was blocked by pertussis toxin, the respiratory burst to the IC-bearing HUVECs was essentially unchanged. With PNH neutrophils, the respiratory burst was predominantly blocked by an anti-Fc gamma RII mAb. In contrast, the response of pertussis toxin treated neutrophils was strongly inhibited by a mAb against Fc gamma RIII. Together these data indicate that the answer of neutrophils to ICs immobilized at the endothelial barrier depends on the cooperative function of both low-affinity Fc gamma Rs.
CD18 Antigens↗
Differences in the regulation of specific glycosylation in the pathogenesis of paroxysmal nocturnal hemoglobinuria and the Tn-syndrome.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder that resembles in several aspects the Tn-syndrome, in which bone marrow-derived cells are deficient in mucin-type beta 1,3 galactosyltransferase (beta 1,3Gal-T) due to the persistent repression of an intact allele. In the present study, we have investigated phytohemagglutinin (PHA)-activated T cells from the peripheral blood of an individual with the well-established clinical diagnosis of PNH. Only 10% of T cells were deficient in surface expression of the glycosylphosphatidylinositol (GPI)-linked CD48 antigen; in contrast, 95% of the patient's polymorphonuclear leukocytes harbored the defect. The cell-surface density of CD48 on unaffected T cells from this patient was two- to three-fold higher when compared to PHA-activated normal donor T cells. CD48-negative T cells were cloned and shown to belong to the CD4+ or the CD8+ antigenic subset. To test for the possibility that in PNH, as in Tn syndrome, gene repression may be responsible for the deficiency, CD48- T cell clones were treated with 5-azacytidine (5-azaC) and sodium n-butyrate (NaB). While such treatment reproducibly led to reexpression of a sialylated CD43 epitope on affected Tn-syndrome T cell clones, these drugs failed to induce reexpression of CD48 on affected PNH T cell clones. Our data suggest that despite many similarities, different pathogenetic mechanisms are responsible for PNH and Tn-syndrome. These CD48- T cell clones are the first to be described and may be useful to define the PNH lesion at a biochemical and genetic level.
Adult↗
Chemotaxins inhibit neutrophil adherence to and transmigration across cytokine-activated endothelium: correlation to the expression of L-selectin.
Non-activated neutrophils strongly adhere to cytokine-activated human umbilical vein endothelial cells (HUVE). However, activation of neutrophils by different chemotactic mediators led to potent inhibition of this endothelial-dependent interaction. For different formylated peptides, concentrations leading to maximal adherence inhibition coincided with those known for inducing maximal chemotactic migration of neutrophils. In terms of maximal adherence inhibition, a rank list was found in the order of N-formyl-Met-Leu-Phe > C5adesArg > interleukin-8 > C5a > or = leukotriene B4, whereas platelet-activating factor, and lipopolysaccharide showed no inhibition. This rank order was congruent to that of down-regulation of neutrophil L-selectin detected by the monoclonal antibody Leu-8. Moreover, the dose-dependent increase of neutrophil adherence inhibition corresponded to the loss of L-selectin expression. Concentrations higher than that required for maximal inhibition led to a dose-dependent decrease of inhibition, which was accompanied by increasing expression of neutrophil CD11/CD18. In contrast to the capacity of non-activated neutrophils to migrate across interleukin-1-activated HUVE monolayers, transmigration was significantly impaired after chemotactic activation.
Antigens, CD↗
Repeated continuous administration of low doses of intravenous iron in anemic patients with active rheumatoid arthritis.
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Anemia↗
Interleukin-4 induces tissue eosinophilia in mice: correlation with its in vitro capacity to stimulate the endothelial cell-dependent selective transmigration of human eosinophils.
Interleukin-4 (IL-4) has been shown to play a crucial role in the pathogenesis of allergic disease. In this study, intraperitoneal administration of IL-4 in mice led to selective accumulation of eosinophils, and intradermal injection induced marked eosinophil infiltration. However, IL-4 had no detectable effect on neutrophil accumulation. Preincubation of mouse IL-4 with the neutralizing mAb 11B11 abolished this peritoneal and dermal eosinophilia. These in vivo data correlate with the in vitro capacity of IL-4 to specifically promote the selective transendothelial migration of eosinophils. Supernatants of antigen-stimulated T cell clones derived from hypersensitized individuals induced significant eosinophil transmigration that was inhibited by the neutralizing mAb 8F12 against human IL-4. These experiments impressively demonstrate a link between specific antigenic recognition and the selective recruitment of eosinophils by the endothelial barrier. Furthermore, data are presented supporting our previous evidence that eosinophils need initial priming to transmigrate across IL-4-activated monolayers. Whereas freshly isolated eosinophils from nonallergic individuals failed to transmigrate, the eosinophils from a group of patients with allergic asthma showed spontaneous layer penetration. These data further support the evidence that eosinophils from allergic patients undergo in vivo priming and are functionally different with respect to their capacity to transmigrate.
Animals↗
IL-4 controls the selective endothelium-driven transmigration of eosinophils from allergic individuals.
The mechanism leading to selective accumulation of eosinophils in allergic inflamed tissue is still unknown. In this article, transendothelial migration of circulating eosinophils from normal and allergic individuals is characterized by means of human umbilical vein endothelial cells cultivated on extracellular matrix from human fibroblasts. IL-4 pretreatment of these vascular constructs induced adherence and impressive layer penetration of eosinophils but not of neutrophils. For layer penetration, blood eosinophils from nonallergic donors needed in vitro priming by granulocyte/macrophage-CSF, IL-3, or IL-5. In contrast, freshly isolated blood eosinophils from a group of patients with atopic dermatitis spontaneously penetrated IL-4-activated vascular constructs. The here described selective pathway of eosinophil transmigration was 1) specifically induced by IL-4; 2) inhibited by the IL-4 specific, neutralizing mAb 8F12; and 3) dependent upon endothelial mRNA synthesis. Both eosinophil adherence and transmigration were present at an IL-4 concentration of 1 U/ml. The effect of endothelial preincubation with IL-4 culminated at 16 h and persisted up to 48 h. A linear increase of subendothelial accumulating eosinophils was observed within 2 h, reaching almost 100% after 4 h of coincubation. From inhibition experiments using different mAb, we conclude that the integrins CD11a/CD18, CD11b/CD18, and very late Ag-4 (CDw49d/CD29) are involved in this selective pathway of eosinophil transmigration. Taken together, this study demonstrates a novel mechanism which allows in vitro or in vivo primed eosinophils to leave the vascular compartment without influencing emigration of neutrophils.
Adult↗
Migration of primed human eosinophils across cytokine-activated endothelial cell monolayers.
Eosinophils are known to adhere to cytokine-activated endothelium. Whereas transendothelial migration for neutrophils is an inevitable consequence of this endothelial-dependent adherence, this has not yet been shown for eosinophils. By means of human umbilical vein endothelial cells (HUVE) grown to confluence on microporous filters as an in vitro model of leukocytic migration across postcapillary venules, we have characterized the conditions leading to endothelium-driven transmigration of blood eosinophils from normals and from patients with allergic asthma. Freshly isolated eosinophils from nonallergic donors adhered to interleukin-1 (IL-1) and tumor necrosis factor-activated HUVE, but did not penetrate these monolayers. In contrast, eosinophils from allergic asthma patients showed an increased adherence and transmigration capacity. This increased functional competence was not caused by a difference in density phenotype, because the eosinophils from both groups showed a comparable density distribution over discontinuous Percoll gradients. Moreover, no difference existed within one group among eosinophils harvested from the Percoll density bands 1.080, 1.085, and 1.090 g/mL in terms of transendothelial migration. In vitro cultivation of freshly isolated eosinophils from nonallergic individuals in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 induced a stepwise decrease of the density distribution over such gradients. In contrast, eosinophils from patients with allergic asthma directly shifted to a final density of 1.075 g/mL within 24 hours of culture. Notwithstanding the kinetics of density changes, eosinophils from nonallergic donors already expressed the capacity to transmigrate IL-1-activated HUVE monolayers 20 hours after cultivation with different combinations of GM-CSF, IL-3, and IL-5. Inhibition studies with monoclonal antibodies showed that endothelium-driven transmigration of eosinophils predominantly implicates CD11/CD18 structures on the eosinophil surface, whereas no significant inhibition was found with the anti-VLA-4 monoclonal antibody HP2/1. From cytofluorometric studies, we conclude that spontaneous transmigration of eosinophils from allergic asthma patients is not accompanied by quantitative upregulation of these antigens. Taken together, these results allow the conclusion that blood eosinophils from allergic asthma patients have undergone in vivo priming, mimicked in vitro by cytokines such as GM-CSF, IL-3, and IL-5, leading to induction of the capacity to migrate across cytokine-activated HUVE monolayers.
Asthma↗
Density separation of human red blood cells on self forming Percoll gradients: correlation with cell age.
Human red blood cells were density separated on self-forming Percoll gradients. Redistribution of density fractionated red blood cells was studied by recentrifugation on self-forming Percoll gradients. A protocol that avoids centrifugation of red cells prior to removal of white cells and introduces EDTA before red cell pelleting completely avoided redistribution. Dense red cells separated according to this method were senescent on the basis of a biochemical and a physical criterion: the increase in the band 4.1a:4.1b ratio (Mueller, T., Jackson, C.W., Dockter, M.E. and Morrison, M. (1987) J. Clin. Invest. 79, 492-499) and the loss of maximum deformability. Characterization also included the relative content of two surface proteins (complement receptor 1, CR1 (Ripoche, J. and Sim, R.B. (1986) Biochem. J. 235, 815-821); decay accelerating factor, DAF) on density fractionated red cells. Unlike cytoplasmic proteins, these proteins face similar conditions, whether located on circulating reticulocytes or aging red cells. Both components were lost linearly within experimental errors with cell density and were lower by 60 and 40% in dense than light cells, respectively.
Blood Proteins↗
TNF-specific deactivation of granulocytes in vivo: a possible mechanism of self-protection.
Granulocytes (PMN) have recently been shown to be specifically deactivated towards tumor necrosis factor (TNF) by preexposure to TNF itself and to other stimuli such as endotoxin and complement C5a in vitro. When TNF (200 micrograms/m2) was infused to a male volunteer, we found ex vivo an almost complete TNF-specific deactivation of PMN adhesion (57 +/- 3* vs 6 +/- 2%**), of exocytosis of secondary granules (37 +/- 1* vs 7 +/- 1%**) and of the respiratory burst as measured by hexose monophosphate shunt activation (74 +/- 1* vs 12 +/- 3** nM/10(7) PMN/45 min). Furthermore, up- and down-regulation, respectively, of the PMN surface adhesion molecules Mac-1 and LAM-1 became TNF-resistant. Similar to the results obtained in vitro, deactivation correlated with a decrease in the number of cellular TNF receptors. In PMN of 4 patients exposed to activated complement during hemodialysis, a state of TNF-specific cross-deactivation could also be demonstrated.
Adult↗
Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia.
Early studies suggested that the risk of haemorrhagic complications become unacceptable when platelet counts drop below 20 x 10(9)/l. Because there are insufficient data to define 20 x 10(9)/l as the threshold for prophylactic platelet transfusions, the practicability of a more restrictive transfusion policy has been assessed prospectively in 102 consecutive patients being treated for acute leukaemia. Besides platelet count, the transfusion protocol took into consideration factors such as presence of bleeding, fever, coagulation disorders, and intention to do therapeutic procedures. 31 major bleeding episodes occurred on 1.9% of the study days when platelet counts were 10 x 10(9)/l or less and on 0.07% of study days when counts were 10-20 x 10(9)/l. The findings indicate that the threshold for prophylactic transfusions can safely be set at 5 x 10(9)/l in patients without fever or bleeding manifestations and at 10 x 10(9)/l in patients with such signs. For patients with coagulation disorders or anatomical lesions, or for those on heparin, the threshold should be at least 20 x 10(9)/l. Such a restrictive platelet transfusion policy, which is applicable not only to thrombocytopenia associated with acute leukaemia but also to other forms of hypoproliferative thrombocytopenia, reduces exposure of such patients to blood donors and results in substantial health-care savings.
Adolescent↗
Transient pure red cell aplasia caused by antilymphoblast globulin after cadaveric renal transplantation.
Transient pure red cell aplasia (PRCA) in three consecutive patients receiving ATG for management of kidney graft rejection prompted a systematic study of the effects on erythropoiesis of the ATG preparation used at our institution. We found that 90% of patients treated with rabbit anti-T lymphoblast globulin developed reticulocytopenia (less than 17,000 reticulocytes/mm3), with complete disappearance of reticulocytes in 65% of patients and increased requirement for red cell transfusion. PRCA, with selective aplasia of erythroblasts was confirmed by bone marrow aspiration in 4 patients volunteering for aspiration, and by the kinetic of the disappearance of blood reticulocytes in relation to the beginning of ATG treatment. The nadir of thrombocytes and lymphocytes, blood cells directly destroyed by ATG in circulation, followed the start of ATG treatment within 1 to 4 days. In contrast the nadir of reticulocyte counts occurred later, between day 7 and 13 after ATG was begun, reflecting the fact that toxicity was directed against red cell precursors rather than mature circulating cells. In agreement with these clinical findings ALG was found to be cytotoxic in vitro for erythroid precursors. Analogously to autoimmune PRCA caused by autoantibodies to erythroblasts, this type of PRCA could be viewed as "heteroimmune disease."
Adolescent↗