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A number of natural and recombinant human cytokines have been tested for their ability to activate basophil and neutrophil adhesiveness for human umbilical vein endothelial cells in vitro. Coincubation of basophils and endothelial cell monolayers for 10 min with biologically relevant concentrations of rIL-1, natural IL-2, rIL-4, rIL-5, rIL-6, rIL-8, rGM-CSF, and rIFN-gamma had no effect on basophil adhesiveness. In contrast, rIL-3 induced basophil adhesiveness for endothelial cells (optimal at 1 ng/ml: 144 +/- 18% of control adherence (mean +/- SEM); control basophil binding, 13 +/- 3%, n = 9, p less than or equal to 0.05). This increase in adhesiveness was similar in magnitude to that induced by an optimal concentration of a known potent inducer of basophil adhesiveness (1 microM FMLP, 164 +/- 15% of control adherence, n = 9). Under these experimental conditions, the effects of rIL-3 occurred at concentrations of 0.1 to 30 ng/ml, were partially dependent on calcium, and were not accompanied by histamine release. Fixation experiments demonstrated that the effect of rIL-3 was directed against the basophil rather than the endothelial cell. Neither rIL-3 nor the other cytokines tested had any effect on the adherence of 51Cr-labeled neutrophils, even when tested simultaneously on cells from the same donors. Under experimental conditions that permitted histamine release, no correlation was seen between the ability of rIL-3 (0.3 to 300 ng/ml) to induce histamine release or enhance adhesiveness (n = 8). mAb blocking experiments demonstrated a role for both CD11 and CD18 adherence glycoproteins in basophil adherence induced by rIL-3, and indirect immunofluorescence and flow cytometric analysis revealed that rIL-3 treatment led to rapid and sustained increases in cell surface expression of CD11b antigens on basophils but not neutrophils (e.g., after 10 min: 217 +/- 29 vs 91 +/- 11% of control mean fluorescence intensity, p less than 0.05). However, no correlation was seen between the magnitude of changes in CD11b expression and changes in adhesion when tested simultaneously. These results suggest that local production of IL-3 during allergic reactions in vivo may selectively promote basophil activation, adhesion to endothelium, and recruitment to extravascular sites of inflammation.
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PMID:IL-3 augments adhesiveness for endothelium and CD11b expression in human basophils but not neutrophils. 169 10

The anti-inflammatory influence of dapsone may involve suppression of neutrophil chemotaxis to selected attractants, but other actions of the drug are likely also involved. We have discovered that dapsone may suppress migration of neutrophils to extravascular sites through inhibition of adherence functions required for neutrophil recruitment. Neutrophil adherence mediated by integrins (CD11/CD18 or Mac-1 family receptors) was measured in vitro in terms of binding of stimulated cells to albumin-coated wells of microtiter plates, using phorbol myristate acetate (PMA) and N-formylmethionyl-leucyl-phenylalanine (FMLP) as stimuli. Adherence was assessed by staining attached cells with crystal violet dye and measuring the dye concentration at OD590 using an automated plate reader. The role of integrins in this assay was confirmed by the ability of anti-integrin antibody to suppress stimulated neutrophil adherence. The OD590 value for cells adhering to albumin in the absence of stimulus and dapsone averaged 0.2 +/- 0.04 (SEM) over five experiments. In the presence of 0.1 microM PMA or 10(-6) M FMLP, the OD590 values averaged 0.88 +/- 0.1 and 0.75 +/- 0.12, respectively. Dapsone did not affect unstimulated neutrophil adherence but, when present with stimulus, produced a dose-related inhibitory effect on adherence. Fifty percent inhibitory doses were approximately 150 micrograms/ml dapsone for both stimuli. Sulfapyridine reproduced the inhibitory effect of dapsone, but two structurally related compounds, hydrochlorothiazide and furosamide, did not. The observed ability of dapsone to inhibit neutrophil chemotaxis under agarose to FMLP and interleukin-8 may also be explained by interference with integrin-mediated adherence required for motility in this assay system. To consider if dapsone might have a similar inhibitory influence on neutrophil adherence in vivo, we tested the stimulated adherence function of neutrophils isolated from three individuals on dapsone therapy for dermatitis herpetiformis. Stimulated adherence of patients' cells averaged less than 40 percent of the control value. Suppression of leukocyte integrin function may therefore also contribute to the ability of dapsone to inhibit neutrophil infiltration in neutrophilic dermatoses.
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PMID:Dapsone suppresses integrin-mediated neutrophil adherence function. 173 79

Neutrophil accumulation is a hallmark of the inflammatory process. The ability of neutrophils to release lipid mediators, toxic oxygen metabolites, proteolytic enzymes and cationic proteins may contribute to the tissue pathology seen in inflammatory diseases such as inflammatory bowel disease and psoriasis. The first step in the process of neutrophil diapedesis in a gradient of chemoattraction is adhesion to the microvascular endothelium, a phenomenon mediated by the stimulated activation of the neutrophil CD11a-c/CD18 cell surface glycoprotein complex. We assessed the ability of a monoclonal antibody (MoAb) (hybridoma: SP2/0-Ag. 14XBALB/c spleen cells; isotype: murine IgG1) to CD18 that recognizes the beta chain of LFA1(CD11a/CD18), MAC-1(CD11b/CD18) and CD11c/CD18 to effect the neutrophils response to the proinflammatory chemotaxins leukotriene B4 (LTB4) and 12(R)-hydroxy-5,8,11,14-eicosatetraenoic acid [12(R)-HETE] in the mouse dermis. LTB4 and 12(R)-HETE induce a time and concentration dependent infiltration of s when applied intradermally. LTB4 (100 ng) and 12(R)-HETE (50 micrograms) were injected intradermally in CD-mice (18 g body weight) and assessed for chemotactic activity four h later by the dermal levels of myeloperoxidase (MPO), a neutrophil marker enzyme. CD18 MoAb(0.02 mg) was given intravenously 10 min ahead of dermal chemotaxin injection. LTB4 increased (p less than .01) dermal levels of MPO at 4 h, a neutrophil accumulation inhibited (p less than .005) by CD18 MoAb pretreatment (Mean MPO +/- SEM: Vehicle, 0.049 +/- 0.006U vs LTB4, 0.309 +/- 0.033U vs MoAb, 0.137 +/- 0.012U) (n = 12/group).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:CD 18 monoclonal antibody inhibits neutrophil diapedesis in the murine dermis induced by leukotriene B4 and 12(R)-hydroxyeicosatetraenoic acid. 197 85

The glycoprotein complex GPIIb-IIIa of the platelet membrane and CD18 of the monocyte membrane have been established as being the central figure for the adhesion processes of the corresponding cells. The molecular structure of these 2 GPs bears some similarities. It was proposed recently that LFA-1 and Mo-1 (CD18 family) and GPIIb-IIIa might be encoded by the same gene. For this purpose, we studied the expression of Mo-1, Mo-2 (as control) receptors on monocytes and GPIIIa and GPIIb-IIIa on platelets of two GT patients as compared to normal healthy subjects. Monoclonal antibodies anti Mo-1, MO-2, AP-3 and AP-2 were used to measure the expression of the respective antigens by indirect immunofluorescence procedure. The fluorescence of the labelled cells was analysed with an Ortho Cytofluorograph 50-H. The resulting Mean Fluorescence Intensity (MFI) values of AP-2 and AP-3 showed that the patients had a total absence of GPIIb-IIIa antigens. However, Mo-1, as well as those of control Mo-2, in patients (MO-1: 672 and 716; Mo-2: 453 and 637) were similar to that of normal subjects (Mo-1: 735 +/- 74; Mo-2: 585 +/- 35; mean +/- SEM). Therefore, the normal expression of Mo-1 receptors on the monocytes of Glanzmann's thrombasthenia patients suggests different genomic regulations for Mo-1 antigens on the monocyte and GPIIb-IIIa complex on the platelet.
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PMID:Normal expression of the adhesive structure Mo-1 on monocytes from patients with Glanzmann's thrombasthenia. 201 Jul 2

Protamine reversal of heparin anticoagulation can cause catastrophic pulmonary hypertension, systemic hypotension, and hypoxemia. This reaction is thought to be associated with pulmonary sequestration of activated neutrophils. To examine whether this reaction could be prevented by blocking neutrophil activation with NPC 15669 (N-(9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl)-L-leucine), an inhibitor of Mac-1 adhesion molecule up-regulation, we gave 12 piglets a heparin bolus (300 IU/kg i.v.) followed by protamine (3 mg/kg i.v. over 90 sec) 15 min later. Six of the piglets received NPC 15669 (10 mg/kg i.v. bolus, then 6 mg/kg/hr i.v. infusion) 15 min before the heparin bolus. Two minutes after protamine administration, CD18 (beta-subunit of Mac-1) expression measured by immunofluorescence flow cytometry increased 128 +/- 9% (mean +/- SEM) over preprotamine levels in control piglets but remained unchanged in NPC piglets (99 +/- 2%, P < 0.05). Fifteen minutes after protamine, lung myeloperoxidase activity, an index of neutrophil degranulation, was significantly lower in the NPC group (87.83 +/- 10.04 versus 57.23 +/- 2.59 mumol/10 mg; P < 0.005). NPC 15669 also prevented postreversal pulmonary artery hypertension (158 +/- 30, 150 +/- 20, and 140 +/- 13 versus 91 +/- 7, 91 +/- 18, and 85 +/- 9% preprotamine at Minutes 2, 5, and 10; P < 0.05). Systemic arterial pressure, cardiac output, and circulating neutrophil counts were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neutrophil activation mediates protamine-induced pulmonary hypertension. 810 32

The most common cause of intraperitoneal adhesions is previous abdominal surgery. Postoperative adhesion formation results from a fibroproliferative inflammatory reaction that begins with an influx of polymorphonuclear leukocytes (PMNs) into the peritoneal cavity. Adherence of the PMNs to the endothelial cells (EC) is necessary for PMN migration into the tissue in response to a stimulus. Several receptor-counterreceptor pairs of ligands such as CD11/CD18 on the PMN and ICAM-1 (CD54) on EC have been identified. Monoclonal antibody against CD11/CD18 (R15.7) inhibits PMN adherence and migration and consequently protects against PMN-induced tissue injuries. We therefore studied the effect of preventing PMN-EC adherence, using anti-CD18 monoclonal antibody, on postoperative adhesion formation in rabbits. Group 1 was a control receiving physiologic saline, and group 2 received anti-CD18 antibody (R15.7, 2 mg/kg). The treatment was administered iv at the end of surgery and repeated on the first and second postoperative days. Peritoneal adhesions were induced at laparotomy by repairing two peritoneal defects, by oversewing the defect (model 1), and by resuturing the removed parietal peritoneum in its place as an ischemic graft (model 2). Adhesions were evaluated blindly at 10 days after operation by measuring the percentage of the suture line covered with adhesions (model 1) or by a scoring system (model 2). All control animals developed intraperitoneal adhesions and the percentage of the suture line covered with adhesions was 25 +/- 5.9% (mean +/- SEM) and the mean score in model 2 was 0.9 +/- 0.2. Anti-CD18 antibody, R15.7, increased the degree of postoperative adhesion formation in both models, but the results were significant only in model 2. Also, anti-CD18 antibody significantly decreased peritoneal neutrophils from 11.1 x 10(7) +/- 1.8 x 10(7) to 2.2 x 10(7) +/- 0.4 x 10(7) (P < 0.001) on the first postoperative day. It is concluded that inhibition of PMN-EC adherence does influence the postoperative adhesion formation. These results might suggest that PMNs have a role in modulating postoperative adhesion formation.
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PMID:The role of neutrophils in peritoneal adhesion formation. 876 57

To determine the relationship between the expression of leukocyte-specific integrins in the airways and the airway obstruction in smokers, we analyzed hypertonic saline-induced sputum in 33 male subjects, age 64.7 +/- 0.5 yr (mean +/- SEM), with a smoking history of 12 to 94 pack-years, at the end of a 15-yr follow-up study. Average FEV1/VC ratio was 69 +/- 1% at the beginning of the study and 66 +/- 2% at the end of the follow-up period, and annual decline of FEV1 was 20 +/- 3 ml/yr. Fourteen individuals exhibited airway obstruction as assessed by a FEV1/VC ratio lower than 63.3%. Differential leukocyte count was performed on cytospin preparations and the expression of integrin alpha (CD11a, CD11b, CD11c) and beta (CD18) chains was assessed on granulocytes and mononuclear cells by immunocytology. The numbers of neutrophils expressing CD11b and CD18, but not CD11c or CD11a, were increased in the subjects with airway obstruction compared with those without airway obstruction. CD11b- and CD18-positive neutrophils were negatively correlated with FEV1/VC ratio (p < 0.01). No significant correlations were found between CD11a-, CD11b-, CD11c-, CD18-positive mononuclear cells and lung function measurements. In conclusion, our results suggest that leukocyte-specific integrin CD11b/CD18 expressed on sputum polymorphonuclear leukocytes represents a marker for the smokers who develop chronic airway obstruction.
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PMID:Integrin upregulation on sputum neutrophils in smokers with chronic airway obstruction. 891 39

Localized cutaneous leishmaniasis (LCL) in Colombia is caused primarily by Leishmania panamensis, a different species from those reported in Brazil, French Guiana, and Venezuela. Because different parasites may elicit disparate immune responses, the present study was undertaken to establish the leukocyte participation in the immune response against L. panamensis. Epidermal and dermal immune complexes were studied using an avidinbiotin immunoperoxidase technique and specific monoclonal antibodies. In LCL, the epidermis showed keratinocytes expressing intercellular adhesion molecule-1, a universal expression of human leukocyte antigen-DR, and a hyperplasia of CD1a+ Langerhans cells. The dermal granuloma observed had a mean +/- SEM value for the CD4/CD8 ratio of 0.80 +/- 0.06. The expression of the activation molecules CD25 (interleukin-2 receptor) and CD18 (lymphocyte function-associated antigen-1 beta), 10.5% and 38.1% respectively, suggests that many cells are primed and proliferating. Most T cells in the granuloma expressed alpha beta T cell receptor (TCR) (40.3%) whereas only a few (6.7%) expressed gamma delta TCR. The results show that Colombian LCL patients possessed the appropiate activation and accessory signals from immunocompetent cells to trigger the effector phase of the immune response and eventually eliminate the parasite.
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PMID:Immunocytochemical and histopathologic characterization of lesions from patients with localized cutaneous leishmaniasis caused by Leishmania panamensis. 891 90

Neutrophil activation and accumulation as a consequence of cerebral ischemia-reperfusion has been suggested to exacerbate tissue injury. The current study is designed to examine the effect of IB4, a monoclonal antibody directed against the neutrophil adhesion protein, CD18, in a rabbit model of thromboembolic stroke. New Zealand rabbits (3-3.5 kg n=8 each group), were given an autologous clot embolus, delivered to the anterior circulation of the brain via the internal carotid artery. Immediately following thromboembolism, the mean arterial pressure in all animals was reduced to 30 mmHg by controlled exsanguination for a period of 45 min. All animals were mechanically ventilated and following parameters were monitored hourly: arterial blood gases, intracranial pressure, regional cerebral blood flow, hematocrit, and core temperature. Rabbits were given either IB4 (1 mg kg(-1)), or vehicle (1 percent albumin, IV) 30 min following the thromboembolic event. The mean arterial pressure of all animals was restored to the baseline value of 50-60 mmHg for the remainder of the 4-h experiment. Following the thromboembolic event, the intracranial pressure rose in both groups, although this was significantly less in the IB4-treated group, with the final values being 195.9 +/- 38.3 vs. 135.5 +/- 26.0 percent of baseline (mean +/- SEM, p < 0.05). However, regional cerebral blood flow and infarct size (TTC staining) were virtually identical in both groups. It is concluded that blockade of the neutrophil adhesion protein, CD18, may contribute to a reduction in the intracranial pressure following cerebral ischemia and reperfusion, providing further evidence that activated neutrophils may contribute to cerebral edema.
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PMID:IB4, a monoclonal antibody against the CD18 leukocyte adhesion protein, reduces intracranial pressure following thromboembolic stroke in the rabbit. 916 74

The effect of different expansion protocols on the expression levels of CD49dw/CD29 (VLA-4), CD11a/CD18 (LFA-1), CD31 (PECAM-1), CD44, and CD34 was determined after cord blood CD34+ cells were cultured for defined periods with the following: 1) A growth factor mix (GFmix) containing interleukin (IL)-1, IL-3, IL-6, kit ligand (KL), G-CSF, GM-CSF, and erythropoietin (Epo); 2) IL-3 + KL; and 3) HS-5 (a human stromal cell line supernatant) + KL. Before culturing, cord blood CD34+ cells (> 95% purity) were 94 +/- 5% CD31+, 98 +/- 1% CD44+, 66 +/- 29% VLA-4+, and 68 +/- 18% LFA-1+ (mean +/- SEM). Immunophenotyping and morphological examination of pre- and post-cultured cells indicated that GFmix preferentially supported erythroid development, while IL-3+KL and HS-5+KL preferentially supported myeloid development. Similar to what other investigators have reported, there was an absolute increase in CD34+ cell numbers as well as clonogenic precursors with ex vivo expansion. However, the majority of clonogenic precursors post-expansion expressed CD34 antigen at reduced levels. Examination of adhesion molecules indicated that a majority of cells cultured with GFmix expressed PECAM-1 and LFA-1 at undetectable levels, but PECAM-1 and LFA-1 levels remained essentially unchanged when cells were cultured with IL-3+KL and HS-5+KL. Overall VLA-4 expression levels slightly increased and CD44 expression levels were more heterogeneous with ex vivo expansion. Nevertheless, LFA-1, VLA-4, PECAM-1, and CD44 expression levels remained essentially unchanged on cultured progeny retaining a CD34 phenotype, independent of the culture system used. Together these results indicate that differential modulation of adhesion markers occur with different culture conditions, yet adhesion receptor expression levels on progeny cells retaining a CD34 phenotype are essentially maintained independent of the culture conditions. And although there is an absolute increase in CD34+ cells after ex vivo expansion, a majority of clonogenic precursors have reduced levels of CD34 antigen.
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PMID:Differential modulation of adhesion markers with ex vivo expansion of human umbilical CD34+ progenitor cells. 931 Jan 90


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