PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Integrin alpha4”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources
PubMed1995

A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis.

In experimental allergic encephalomyelitis (EAE), circulating leukocytes enter the central nervous system (CNS) producing inflammation, myelin damage and paralysis. Prevention of leukocyte infiltration by an antibody against alpha 4 integrin suppressed clinical and pathological features of EAE in the guinea pig. Rapid clearance of leukocytes from the CNS and reversal of clinical findings were observed when anti-alpha 4 treatment was administered during active disease. Clinical improvement was accompanied by a marked decrease in abnormal pathological findings, including demyelination. Therefore anti-alpha 4 is an effective treatment of EAE and may be similarly useful in the treatment of autoimmune diseases such as multiple sclerosis.

Animals↗
PubMed1994

Xenotransplantation: an examination of the adhesive interactions between human lymphocytes and porcine renal epithelial cells.

Specific adhesion molecules stabilize the binding between lymphocytes and antigen bearing cells; this intercellular adhesion is vital to both the affector and effector phases of an immune response. It is not known whether adhesion molecules and their counter-receptors can form the cross-species interactions that will facilitate human T cell recognition of xenogeneic porcine target cells. In this report it is demonstrated that a higher proportion of mitogen-activated than of resting human lymphocytes adhere to cultured porcine renal epithelial cells. Furthermore, antibody blocking experiments demonstrated that at least part of this cell-cell binding is stabilized by the human adhesion molecules LFA-1 (lymphocyte function-associated antigen-1) and the alpha 4-containing integrins. It is possible that this capacity for cross-species adhesion will play a role during the cell-mediated rejection of clinical porcine xenografts.

Animals↗
PubMed2005

Adhesion molecules in inflammatory bowel disease: therapeutic implications for gut inflammation.

Mucosal endothelium has become one of the major areas of investigation in gut inflammation. It is now well recognised that it plays an active role in the pathogenesis of both forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis, since endothelial cells regulate mucosal immune homeostasis, acting as "gatekeepers", controlling leukocyte accumulation in the interstitial compartment. This process is mediated by leukocyte-endothelial adhesion molecules. This paper reviews the major molecules that mediate leukocyte-endothelial interactions, and summarises the results of the most recent clinical trials targeting adhesion molecules in inflammatory bowel disease.

Animals↗
PubMed2005

Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells.

Normal bone marrow (BM) contains T cells whose function and origin are poorly understood. We observed that CD8+ T cells in BM consist chiefly of CCR7+ L-selectin+ central memory cells (TCMs). Adoptively transferred TCMs accumulated more efficiently in the BM than naive and effector T cells. Intravital microscopy (IVM) showed that TCMs roll efficiently in BM microvessels via L-, P-, and E-selectin, whereas firm arrest required the VCAM-1/alpha4beta1 pathway. alpha4beta1 integrin activation did not depend on pertussis toxin (PTX)-sensitive Galphai proteins but was reduced by anti-CXCL12. In contrast, TCM diapedesis did not require CXCL12 but was blocked by PTX. After extravasation, TCMs displayed agile movement within BM cavities, remained viable, and mounted potent antigen-specific recall responses for at least two months. Thus, the BM functions as a major reservoir for TCMs by providing specific recruitment signals that act in sequence to mediate the constitutive recruitment of TCMs from the blood.

Adoptive Transfer↗
PubMed2005

Short-term homing assay reveals a critical role for lymphocyte function-associated antigen-1 in the hepatic recruitment of lymphocytes in graft-versus-host disease.

BACKGROUND/AIMS: The liver is a major target organ of graft versus host disease (GvHD) with massive infiltration of alloreactive lymphocytes resulting in hepatitis and hepatocyte injury. Although adhesive mechanisms have been implicated in the biology of GvHD hepatitis, the identity of homing receptors involved in the initial recruitment of cells from the blood is not known. METHODS: We have developed a short-term homing assay in a model of murine GvHD. Splenocytes from donors at an active stage of GvHD were injected intravenously into adoptive recipients also undergoing GvHD. The recruitment of cells to the liver was assessed 6h after cell transfer. RESULTS: Activated donor CD8 and CD4 lymphocytes expressed lymphocyte function antigen-1 (LFA-1), alpha4-integrins, and P-selectin binding ligands, and localized more efficiently than naïve T cells. Immunoneutralization of LFA-1 reduced the recruitment of CD8 and CD4 lymphocytes to the liver by more than 60%. Anti-LFA-1 antibody also markedly reduced infiltration of lymphocytes in periportal areas and protected against hepatocellular damage. CONCLUSIONS: We demonstrate a critical role of LFA-1 in the recruitment of activated lymphocytes to the liver and in immune-cell mediated hepatitis. LFA-1 may be an effective therapeutic target for protecting the liver following bone marrow transplantation.

Animals↗
PubMed2001

Patterns of integrin expression in a human mandibular explant model of osteoblast differentiation.

Cell-matrix interaction is crucial in regulating osteoblast differentiation and function. These interactions are themselves regulated, at least in part, by integrins. Although there are some data from mammalian models, few studies have compared integrin expression at different stages of the osteoblast lineage. Here, primary human mandibular osteoblast cultures were grown in the presence of epidermal growth factor (EGF), giving a proliferative, less differentiated phenotype, or of vitamin D(3) and hydrocortisone (D+Hc), giving a more differentiated phenotype. These cultures were compared with those of cells prepared in the absence of EGF or D+Hc by fluorescence-activated cell sorter using a panel of monoclonal antibodies to specific integrin heterodimers. To provide in vivo correlation, the same panel of antibodies was used to stain fresh-frozen, undemineralised sections of human mandibular bone. Under baseline conditions the alpha(3), alpha(5), alpha(v), alpha(v)beta(3), beta(3) and beta(1) integrin subunits were expressed strongly by the cells, with low-level expression of the alpha(1), alpha(2) and alpha(4) subunits. In the presence of EGF there was increased alpha(2) expression. With D+Hc, alpha(3) and alpha(5) expression was elevated. Immunohistochemical analysis demonstrated alpha(2), alpha(3), alpha(5), alpha(v)beta(3), beta(1) and beta(3) subunits in cells of the osteoblast lineage; alpha(2) staining was restricted to cells close to the bone surface whilst alpha(v)beta(3) and beta(3) were most frequently localised in the osteocytes. The results provide evidence that cells at successive stages of the osteoblast lineage show different patterns of integrin expression. These integrins may be important in cell-matrix interactions leading to osteoblast differentiation.

Antibodies, Monoclonal↗
PubMed2000

Use of integrins to date the endometrium.

OBJECTIVE: To compare traditional histologic dating criteria of the endometrium with immunohistochemical criteria based on epithelial integrin expression during the menstrual cycle. DESIGN: Prospective clinical study. SETTING: An academic teaching hospital. PATIENT(S): Fertile and infertile women undergoing endometrial biopsy. MAIN OUTCOME MEASURE(S): Immunohistochemical staining intensity and distribution (HSCORE) of three integrins and traditional histologic endometrial dating. RESULT(S): In 1,501 endometrial specimens, phase assignment-based integrin staining was 95% and 85% concordant with histology for the proliferative and early secretory phase, respectively, but only 54% and 49% concordant for the middle and late secretory phase, respectively. The greatest disagreement occurred during the midluteal phase. Of 1,090 patients who underwent sampling 6-10 days after detection of a urinary LH surge (corresponding to cycle days 20-24), multiple logistic regression analysis revealed that endometriosis was positively correlated and male factor infertility was negatively correlated with absent beta3 integrin subunit expression. Diagnosis and absent epithelial alpha4beta1 expression were not related. Patient age was not correlated with the incidence of abnormalities in integrin expression. CONCLUSION(S): Traditional histologic dating of the endometrium has remained the gold standard for nearly 50 years. Although the use of marker proteins provides additional information and may reflect endometrial function or receptivity, such markers cannot yet replace traditional methods of endometrial assessment.

Adolescent↗
PubMed2002

Emergency contraception with mifepristone and levonorgestrel: mechanism of action.

OBJECTIVE: To study the effect of mifepristone and levonorgestrel on ovarian function and endometrial development in doses effective as emergency contraception. METHODS: Twelve fertile women were treated with either 10 mg of mifepristone as a single dose (n = 6) or two doses of 0.75 mg of levonorgestrel, 12 hours apart (n = 6) before and after ovulation. An endometrial biopsy performed during the implantation period was analyzed for endometrial maturation and expression of markers of endometrial receptivity. The markers tested for were integrin alpha4 and beta3, cyclooxygenase-1 and -2, progesterone receptors, Dolichos biflorus agglutinin lectin binding, and pinopodes. Urinary excretion of luteinizing hormone, estrone, and pregnanediol were also determined. RESULTS: Treatment with mifepristone and levonorgestrel before ovulation inhibited the luteinizing hormone surge showing no significant differences between the means of luteinizing hormone measurements. When mifepristone was administered in the early luteal phase, downregulation of progesterone receptors was inhibited in five of six women. No significant alteration was found in any of the remaining markers of endometrial receptivity. CONCLUSION: The mode of action of emergency contraception with mifepristone or levonorgestrel is primarily due to inhibition of ovulation rather than inhibition of implantation.

Adult↗
PubMed1997

Immunolocalization of integrins in the normal lung and in pulmonary carcinomas.

Cryosections of normal adult lung (n = 7) and pulmonary epithelial tumors, including squamous (n = 8), adeno (n = 8), bronchioloalveolar (n = 5), and large cell (n = 4) carcinomas (SCC, ACC, BAC, LCC), carcinoids (Cd, n = 7), and neuroendocrine carcinomas (NEC) of variable grades (n = 14) were immunostained by the avidin-biotin peroxidase (ABC) method with monoclonal antibodies to the alpha1-6 and alpha(v) and the beta1-4 integrin subunits. Normal adult alveolar septae showed variably intense immunoreactivity for alpha1,3,6 and beta1, whereas reactions for alpha5 and alpha(v) were weaker and uneven; the remaining integrin subunits were not detected. Bronchial and bronchiolar epithelium showed variably intense staining for alpha2.3,6,v and beta1,4. Reactions were often, though not invariably, basally polarized. SCC, ADC, and LCC showed variably intense reactions for alpha2.3,6,v and beta1,4. BAC were strongly and uniformly stained for alpha1.3 and beta1. In Cd, alpha1,2,3,v and beta1 reactions were noted, whereas in NEC, weak alpha1,3 and beta1 staining was detected with only traces of alpha6 and alpha(v). We conclude that alveolar epithelial cells do not express the hemidesmosome-associated, laminin-binding integrin alpha6beta4 of the bronchial epithelium but rather the alpha1beta1 and alpha3beta1, collagen IV, and laminin receptors, respectively. SCC, ADC, and sampled LCC express an integrin repertory qualitatively similar to that of the bronchial epithelium. Distinct from the latter, the integrin repertory of BAC parallels that of the alveolar epithelium by its strong expression of the multipotential alpha1beta1 and alpha3beta1 integrins. NEC tumors do not display the laminin receptors alpha6beta4 and alpha6beta1 shown by SCC and ADC but express instead alpha1beta1, a collagen IV-laminin receptor rarely found in epithelial neoplasms except for BAC. In NEC tumors, integrins, especially alpha2, decrease with dedifferentiation. Notably distinct from epithelial mesotheliomas, the major fibronectin-binding integrin alpha5beta1 was not found in any type of lung carcinoma.

Adenocarcinoma↗
PubMed1997

Regulation of alpha 4 integrin-mediated adhesion of human eosinophils to fibronectin and vascular cell adhesion molecule-1.

BACKGROUND: Eosinophils selectively accumulate at sites of allergic inflammation. Their recruitment is dependent on both the expression and functional activity of cell adhesion molecules. How the functional activity of cell adhesion molecules on eosinophils is regulated is poorly understood. OBJECTIVE: Our objective was to examine the functional activity of alpha 4 integrins on human eosinophils and its regulation by various agents. METHODS: Function of alpha 4 integrins on human eosinophils was examined by testing adhesion to immobilized fibronection and vascular cell adhesion molecule-1 (VCAM-1) in the presence or absence of a monoclonal antibody (mAb) (8A2) that activates beta 1 integrin function. RESULTS: Spontaneous eosinophil adhesion to VCAM-1 was enhanced by 8A2, but adhesion to fibronectin could only be detected in the presence of 8A2. Concentrations of 8A2 that were approximately 100-fold less than saturating induced maximal eosinophil adhesion. Adhesion to VCAM-1 in the presence of 8A2 was effectively inhibited by alpha 4 and beta 1 integrin mAbs: beta 7 mAb had partial inhibitory activity. Connecting segment-1 peptide and alpha 4 mAb blocked 8A2-dependent fibronectin binding: beta 1, beta 2, and beta 7 integrin mAbs had partial inhibitory activity. Eosinophils obtained from bronchoalveolar lavage fluids and blood eosinophils stimulated with IL-5, platelet-activating factor, or RANTES displayed increased beta 2 integrin-dependent, not alpha 4 integrin-dependent, attachment. Spontaneous adhesion of eosinophils to VCAM-1 was significantly reduced by the tyrosine kinase inhibitor tyrphostin B46 (inhibitory concentration of 50% approximately equal to 20 mumol/L); this effect was reversed by 8A2. CONCLUSIONS: The functional activity of integrins on eosinophils can be positively and negatively regulated. Altered integrin avidity may influence eosinophil recruitment in vivo.

Antibodies, Monoclonal↗
PubMed1998

Expression of adhesion and Fcgamma-receptors on canine blood eosinophils and neutrophils studied by anti-human monoclonal antibodies.

Commercially available anti-human monoclonal antibodies were tested as markers of adhesion receptors and Fcgamma-receptors on canine neutrophils and eosinophils. Purified populations of eosinophils and neutrophils were incubated with selected monoclonal antibodies and binding was measured by flow cytometry. Most of the anti-human monoclonal antibodies used in this study crossreacted with canine granulocytes and many showed expression similar to that of human granulocytes. The results suggest that the adhesion and Fcgamma-receptors are well conserved among species. Canine eosinophils and neutrophils were simultaneously purified by a two-layer Percoll density gradient centrifugation. The purity of the neutrophil fraction was > or = 97% after lysis of the erythrocytes. In the eosinophil fraction, 27-92% were eosinophils (mean 60%). After purification, the neutrophils and eosinophils were incubated with selected monoclonal antibodies and analysed by flow cytometry. Human anti-CD11b and CD18 antibodies bound intensely to both canine eosinophils and neutrophils. Canine neutrophils did label with anti-CD29, but eosinophils did not. Anti-CD49d bound weakly to both eosinophils and neutrophils. Both anti-CD16 and anti-CD32antibodies labelled neutrophils, but not eosinophils. There was no binding of anti-CD9 to canine neutrophils and the binding of anti-CD9 to canine eosinophils varied between dogs.

Animals↗
PubMed2003

Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow.

Our laboratory has characterized a population of stromal cells obtained from adipose tissue termed processed lipoaspirate cells (PLAs). PLAs, like bone-marrow derived mesenchymal stem cells (BM-MSCs), have the capacity to differentiate along the adipogenic, osteogenic, chondrogenic, and myogenic lineages, In order to better characterize these two multi-lineage populations, we examined the surface phenotype of both bone marrow and adipose tissue-derived cells from five patients undergoing surgery. PLA and BM-MSC cells were isolated, subcultivated, and evaluated for cell surface marker expression using flow cytometry. PLA and BM-MSC cells both expressed CD13, CD29, CD44, CD90, CD105, SH-3, and STRO-1. Differences in expression were noted for cell adhesion molecules CD49d (Integrin alpha4), CD54 (ICAM-1), CD34, and CD106 (VCAM-1). While markedly similar, the surface phenotypes of PLA and BM-MSC cells are distinct for several cell adhesion molecules implicated in hematopoietic stem cell homing, mobilization, and proliferation.

Adipose Tissue↗
PubMed2000

VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis.

Effects on adhesion molecules of immune cells might contribute to the mode of action of interferon-beta (IFN-beta) in multiple sclerosis (MS). We have serially monitored the cell surface expression of integrins CD49d (VLA-4) and CD11a (LFA-1) on fresh T lymphocyte subpopulations from 5 MS patients monthly for 2 months prior to treatment and for 3 months on treatment with IFN-beta1b. In parallel, we assessed inflammatory disease activity by monthly contrast-enhanced magnetic resonance imaging (MRI). IFN-beta treatment specifically downregulated CD49d expression on CD8+ and CD4+/CD45RO+ 'memory' T lymphocytes and differentially modulated the proportion of CD4+, CD8+ and CD27+ T cells. These effects may play an important role in the reduction of central nervous system cell trafficking and inflammation in MS.

Adjuvants, Immunologic↗
PubMedDate not supplied

The effect of dithiothreitol on VLA-4 detection in peripheral blood and induced sputum cells.

BACKGROUND: Induced sputum has been shown to be a reliable technique for investigating airway inflammation non-invasively. Flow cytometry could provide useful information in this area. However, the viscosity of the sample entails the use of a mucolytic agent. Dithiothreitol (DDT) is the most frequently used agent although it could affect detection of different inflammatory markers. METHODS: To measure the effect of DDT on the detection of certain adhesion molecules in eosinophils and lymphocytes, sputum was induced from seven non-smoking asthmatic and non-asthmatic subjects treated with 0.1 M DDT. The samples were analyzed by flow cytometry. Whole blood samples from the same subjects were also processed with DTT and analyzed by flow cytometry. RESULTS: Very late activated antigen-4 (VLA-4) levels on eosinophils in intracellular and surface staining were much lower than expected. VLA-4 on lymphocytes was also altered but less so than on eosinophils. VLA-4 levels were also decreased on blood cells after DTT treatment. No abnormalities were found in the detection of CD29 on eosinophils and the beta7-chain in lymphocytes. CONCLUSIONS: Flow cytometry could be used as a complementary method to induced sputum in the investigation of airway inflammation. However, DTT could interfere with the detection of some inflammatory markers, as is the case with VLA-4.

Adult↗
PubMed2003

Endometrial integrin expression in the early luteal phase in natural and stimulated cycles for in vitro fertilization.

OBJECTIVE: To investigate the effect of ovarian stimulation on integrin expression in the early luteal phase. STUDY DESIGN: Seven endometrial biopsies were taken 2 days after the oocyte retrieval from stimulated cycles for IVF and 23 from natural cycles, 2 days after ovulation. RESULT: Endometrium was in-phase in 22/23 and 7/7 biopsies from the natural and stimulated cycles, respectively. Integrins alpha(1) and alpha(4) were simultaneously positive in 43.4% from the natural and in all (100%) the stimulated cycles (P<0.03). On the day of the endometrial biopsy, progesterone serum values were higher in the stimulated cycles (55.2+/-9.5 microg/l versus 8.5+/-3.8 microg/l) (P<0.001). HSCORE value was significantly higher in stimulated cycles for both integrins. CONCLUSION: Endometrial integrin expression is more consistently present in the early luteal phase in stimulated cycles than in natural cycles and this may be related to the higher serum progesterone concentration and/or the more advanced endometrial histological features.

Adult↗
PubMed2001

Identification of a novel heparin-binding site in the alternatively spliced IIICS region of fibronectin: roles of integrins and proteoglycans in cell adhesion to fibronectin splice variants.

The extracellular matrix molecule fibronectin (FN) is a glycoprotein whose major functional property is to support cell adhesion. FN contains at least two distinct cell-binding domains: the central cell-binding domain and the HepII/IIICS region. The HepII region comprises type III repeats 12-14 and contains proteoglycan-binding sites, while the alternatively spliced IIICS segment possesses the major alpha4beta1 integrin-binding sites. Both cell surface proteoglycans and integrins are important for mediating the adhesion of cells to this region of FN. By comparing heparin binding to different recombinant splice variants of the HepII/IIICS region, evidence was obtained for the existence of a novel heparin-binding site in the centre of the IIICS. Site-directed mutagenesis of basic amino acid sequences in this region reduced heparin binding to recombinant HepII/IIICS proteins and, in conjunction with mutations in the HepII region, caused a synergistic loss of activity. Using the H/120 variant of FN, which contains type III repeats 12-15 and the full-length IIICS region, and the H/95 variant of FN, which contains type III repeats 12-15 but lacks the high affinity integrin-binding LDV sequence, the relative roles played by cell-surface proteoglycans and integrins in mediating cell adhesion have been investigated. This was achieved by studying the effects of anti-integrin antibodies and exogenous heparin on A375 melanoma cell attachment to the wild-type and three different mutants of H/120 and H/95 in which the potential proteoglycan-binding sites were partially or completely removed. A375 cell adhesion to H/120 and its mutants was found to involve the co-operative action of both integrin and cell-surface proteoglycan binding, although integrin made a dominant contribution. Anti-integrin antibodies and exogenous heparin were capable of inhibiting melanoma cell adhesion to H/95 and in this case adhesion was due primarily to cell-surface proteoglycan and not integrin binding.

Alternative Splicing↗
PubMed2001

Immunotherapy of multiple sclerosis: the end of the beginning.

Currently available medicines approved for use in Europe and North America reduce the relapse rate in relapsing/remitting multiple sclerosis by about 30%. These medications may be no more efficacious than intermittent use of corticosteroids at the time of relapse. New directions for therapy of multiple sclerosis include blockade of alpha4 integrin, the use of altered peptide ligands, inhibition of Th1 cytokines, and DNA vaccination.

Animals↗