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Results for “Integrin alpha4”

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PubMed2006

Ultraviolet B radiation suppresses Langerhans cell migration in the dermis by down-regulation of alpha4 integrin.

BACKGROUND/PURPOSE: Ultraviolet B (UVB) radiation affects the migration and function of epidermal Langerhans cells (LC) and causes immunosuppression of contact hypersensitivity. It is known that LC leaves the epidermis after exposure to UVB. To know the behavior of LC in the dermis after UVB radiation, we studied the effect of UVB radiation on the expression of integrin families on freshly isolated or cultured murine LC. We also examined whether UVB radiation affects the migration of LC to secondary lymphoid tissue chemokine (SLC/6Ckine). METHODS: Integrin expressions of murine LC cultured in epidermal cell suspension were analyzed using flowcytometry. We used murine LC sorted flowcytometrically for binding assay to extracellular matrix and for migration assay to chemokine. Skin explant assay and immnohistochemical staining for 'cords formation' were performed as previously described. RESULTS: Twenty and 40 mJ/cm2 of UVB radiation down-regulated the expression of alpha4 integrin on 24 h-cultured LC, but not that of alpha6, beta1, or beta4 integrin. The number of cultured LC adhered to fibronectin, a ligand for alpha4 integrin, was decreased after UVB irradiation, while that to laminin, a ligand for alpha6 integrin, was not influenced. UVB radiation reduced the number of migrating LC to SLC. Furthermore, skin sheet explant experiments showed that UVB radiation inhibited the 'cords' formation in dermal vessels of the 48 h-cultured skin. CONCLUSIONS: These data suggest that UVB radiation may suppress the migration of LC from the dermis to lymphatic vessels. UVB radiation may downregulate the adherence of LC to dermal fibronectin and migration to SLC, and consequently suppress the migration of LC from the UVB-irradiated dermis to lymphatics.

Animals↗

PubMedDate not supplied

Inhibition of alpha4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-deficient mice.

BACKGROUND: Monocytes/macrophages play a central role in many stages of development of atherosclerotic plaques, including the conversion to an unstable morphology with rupture and fissuring. A better understanding of the mechanism of attachment of monocytes to activated endothelial cells would prove useful in developing strategies aimed at blocking this initial step. Here we describe a novel in vivo model that directly demonstrates homing of macrophages to atherosclerotic plaques. METHODS AND RESULTS: Macrophages were loaded with fluorescent microspheres and injected intravenously into 40-week-old apolipoprotein E-deficient mice. After 48 hours, labeled macrophages were observed adhering to all stages of atherosclerotic plaques from the early fatty streak to mature calcified lesion. The mean number of macrophages adherent to atherosclerotic plaques located in the proximal 1 mm of the aortic root was quantitated by counting serial frozen sections and found to be 143 +/- 17 macrophages per aortic root. Pretreatment of the apolipoprotein E-deficient mice with monoclonal antibodies directed against the alpha-subunit of the alpha4beta1 integrin and against intracellular cell adhesion molecule (ICAM-1) reduced macrophage homing by 75% and 65%, respectively, as compared with isotype-matched controls (P<.05). Pretreatment with a monoclonal antibody directed against E-selectin did not significantly reduce macrophage homing. CONCLUSIONS: These data demonstrate that alpha4 integrin and ICAM-1 play major roles in the recruitment of macrophages to atherosclerotic plaques, whereas E-selectin does not appear to contribute significantly to macrophage recruitment. This model will be useful for studying the mechanism of macrophage recruitment to atherosclerotic plaques and for evaluating the efficacy of inhibitors to adhesion molecules in preventing macrophage recruitment.

Animals↗

PubMed2004

Murine neuronal progenitor cells are preferentially recruited to tumor vasculature via alpha4-integrin and SDF-1alpha-dependent mechanisms.

Recent studies have described neuronal progenitor cell recruitment to tumors in vivo, however, the mechanisms mediating this recruitment are not yet understood. When C17.2 murine neuronal progenitors stably expressing luciferase (C17.2-luc) were adoptively transferred into mice carrying subcutaneous Lewis lung carcinomas they accumulated at 1% injected dose/g of tumor tissue. C17.2-luc demonstrated significantly greater accumulation and transmigration on tumor-derived endothelium (TEC) than on normal endothelium under physiologically relevant flow conditions. Function blocking of alpha4-integrin reduced recruitment of C17.2-luc cells to normal endothelium but not to TEC, however, function blocking of SDF-1alpha reduced overall accumulation of C17.2-luc on TEC and specifically reduced transendothelial migration. Together, these data suggest that recruitment of C17.2-luc cells to TEC is mediated via SDF-1alpha/CXCR4 activation that results in modification of alpha4-integrin and results in improved recruitment of C17.2-luc cells.

Animals↗

PubMed2005

Involvement of alpha4 integrins in maintenance of cardiac sympathetic axons.

Sympathetic neurons extend and maintain axons that innervate the myocardium, and proper innervation is important for cardiac function. However, the molecular basis for axon outgrowth and maintenance is not well understood. We have shown previously that the integrin alpha4beta1 is expressed on developing axons, and the alpha4 function is important for the development of innervation in vivo [Wingerd, K.L., Goodman, N.L., Tresser, J.W., Smail, M.M., Leu, S.T., Rohan, S.J., Pring, J.L., Jackson, D.Y., and Clegg, D.O., 2002. Alpha 4 integrins and vascular cell adhesion molecule-1 play a role in sympathetic innervation of the heart. J. Neurosci. 22,10772-10780]. Here we examine the function of alpha4beta1 integrins in the maintenance of cardiac sympathetic innervation in vitro and in vivo, and investigate integrin expression and function after myocardial infarction and in hypertensive rats. On substrates of vascular cell adhesion molecule-1 (VCAM-1), alpha4beta1 was required for both initial outgrowth and maintenance of neurites in vitro. On fibronectin substrates, initial outgrowth requires only alpha4 integrins, but maintenance requires both alpha4 integrins and RGD-dependent integrins. In vivo, in adult Long Evans rats, inhibition of alpha4 integrins resulted in decreased maintenance of sympathetic fibers innervating the apex of the heart. However, alpha4 integrins were not detected on most sympathetic axons that sprout after myocardial infarction, and alpha4 function was not required for sprouting. Spontaneously hypertensive rats (SHR) have increased numbers of cardiac sympathetic fibers compared to the parental Wistar strain, but many of these lack alpha4 expression, and alpha4 function is not required for maintenance of these fibers in the heart. These results suggest that developing sympathetic axons and sprouting sympathetic axons use different mechanisms of outgrowth, and that maintenance of cardiac sympathetic innervation involves alpha4 integrins in some rat strains.

Adrenergic Fibers↗

PubMed2004

Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis.

Supporting roles of stromal cells in preferential colonization of myeloma cells in bone marrow and development of associated osteoclastic osteolysis through cell-cell interactions have been indicated. Here we examined the effects of a monoclonal antibody to alpha4 integrin (anti-alpha4 Ab) that disrupts myeloma cell-stromal cell interactions mediated via alpha4beta1 integrin and vascular cell adhesion molecule-1 (VCAM-1) on myeloma cell growth in bone marrow and accompanying osteolysis. The anti-alpha4 Ab decreased VCAM-1-stimulated 5TGM1/luc cell growth in culture. The 5TGM1 murine myeloma cells stably transfected with the firefly luciferase (5TGM1/luc) were inoculated from tail vein in bg/xid/nd mice. Preventative administration of the anti-alpha4 Ab suppressed the elevation of serum IgG2b levels, decreased 5TGM1/luc tumor burden with increased apoptosis in bone and spleen, reduced bone destruction with diminished number of osteoclasts, and prolonged survival of 5TGM1/luc-bearing mice. In contrast, therapeutic administration of the antibody failed to show these effects. However, therapeutic administration of the antibody combined with melphalan significantly suppressed serum IgG2b levels and tumor burden in bone. Our results suggest that the interactions with stromal cells via alpha4beta1/VCAM-1 are critical to the development of myeloma and associated osteolysis and that disruption of these interactions using anti-alpha4 Ab is a potential therapeutic approach for myeloma.

Animals↗

PubMed1999

Human eotaxin induces eosinophil extravasation through rat mesenteric venules: role of alpha4 integrins and vascular cell adhesion molecule-1.

Eotaxin is a potent eosinophil-specific CC-chemokine, which has been shown to play a role in the selective induction of eosinophil accumulation in a number of allergic models of inflammation. Many aspects of the mechanism by which eotaxin induces eosinophil accumulation in vivo remain unresolved. In the present study, we investigated the direct effect of synthetic human eotaxin on leucocyte/endothelial cell interactions within rat mesenteric venules, as quantified by intravital microscopy. Topical eotaxin (30 pmol) induced rapid firm adhesion and extravasation of leucocytes within the rat mesentery, the extravasated leucocytes all being eosinophils, as determined by histological analysis. Whilst eotaxin was unable to stimulate the interaction of rat eosinophils with vascular cell adhesion molecule-1 (VCAM-1) under static conditions in vitro, eotaxin-induced responses in vivo were significantly suppressed by anti-alpha4 integrin and anti-VCAM-1 monoclonal antibodies (mAbs). The anti-alpha4 integrin mAb, HP2/1 (3.5 mg/kg), inhibited the eotaxin-induced firm adhesion and extravasation, 60 min postapplication of the chemokine, by 89% and 84%, respectively. In the same set of experiments, the anti-VCAM-1 mAb, 5F10 (3.5 mg/kg), inhibited leucocyte adhesion and extravasation by 61% and 63%, respectively. These results demonstrate that eotaxin-induced migration of eosinophils through rat mesenteric venules in vivo is dependent on an alpha4 integrin/VCAM-1 adhesion pathway, the significance of which may only be evident under flow conditions and/or following the ligation of other adhesion molecules expressed on eosinophils.

Administration, Topical↗

PubMed1997

Regulation of human T lymphocyte coactivation with an alpha4 integrin antagonist peptide.

The cyclic hexapeptide CWLDVC (TBC 772) is an antagonist of alpha4 integrins and a potent inhibitor of lymphocyte interactions with fibronectin, vascular cell adhesion molecule-1, and muscosal vascular addressin cell adhesion molecule-1 (MAdCAM-1). As such, peptide TBC 772 effectively inhibits the activation of freshly isolated human T lymphocytes stimulated with purified vascular cell adhesion molecule-1 coimmobilized with anti-CD3 mAb. The influence of peptide binding on distinct sites of the alpha4beta1 complex was determined by flow cytometry and cellular adhesion assays employing a panel of mAbs. Binding of the alpha4-specific mAb L25 and the beta1-specific mAb 33B6 was not altered by the peptide; however, binding of mAb 19H8, which is specific for a combinatorial epitope of alpha4beta1, was dramatically inhibited. Treatment of lymphocytes with the peptide caused an increase in a ligand-induced epitope on beta1 integrin defined by mAb 15/7. In T cell activation studies using coimmobilized anti-CD3 mAb and the anti-integrin mAbs, the peptide had broader inhibitory activity, suppressing costimulation induced by all the integrin mAbs. The peptide was not generally toxic and was integrin selective in its suppressive activity, as coactivation by ligation of CD3 in conjunction with CD28 or CD26 was not affected. These results suggest that the antagonist peptide CWLDVC can effectively neutralize integrin coactivation systems by a mechanism independent of competitive binding.

Antibodies, Monoclonal↗

PubMed2000

Soluble VCAM-1 binding to alpha4 integrins is cell-type specific and activation dependent and is disrupted during apoptosis in T cells.

Soluble vascular cell adhesion molecule-1 (sVCAM-1) is generated during inflammation and can alter lymphocyte functions. The authors report that the binding of sVCAM-1 to alpha4 integrin-bearing cells is a dynamically regulated, active cellular process. Binding of recombinant sVCAM-1 to alpha4 integrins on peripheral blood mononuclear cells was cell-type specific. Circulating CD16+ NK cells constitutively bound sVCAM-1 with high affinity, whereas a subpopulation of T-lymphocytes, primarily CD45RO+ (memory), bound sVCAM-1 only after phorbol ester stimulation. sVCAM-1 binding to homogenous stable cell lines was also cell-type specific, and required active cellular processes because it was blocked by the inhibition of ATP synthesis and by Fas-induced apoptosis. Indeed, the loss of high-affinity VCAM-1 binding was an early event in apoptosis. Furthermore, an H-Ras/Raf-initiated signaling pathway also suppressed sVCAM-1 binding to alpha4beta1 integrins. Collectively, these results showed that the capacity of alpha4 integrins to bind VCAM-1 is actively regulated and that this regulation may control alpha4 integrin-dependent cellular functions. (Blood. 2000;95:602-609)

Animals↗

PubMed2003

Spatial restriction of alpha4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration.

Integrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from alpha4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient alpha4-mediated migration requires spatial control of alpha4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated alpha4 accumulated along the leading edge. Blocking alpha4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced alpha4-dependent migration and lamellipodial stability. alpha4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-alpha4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated alpha4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with alpha4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding.

Animals↗

PubMed1997

A novel region of the alpha4 integrin subunit with a modulatory role in VLA-4-mediated cell adhesion to fibronectin.

The integrin VLA-4 (alpha4 beta1) is a receptor for fibronectin and vascular cell-adhesion molecule 1 (VCAM-1). Four functionally different epitopes, designated A, B1, B2 and C, have previously been defined on the alpha4 subunit. Using K562 alpha4 mutant transfectants we found that alpha4 amino acids Tyr151, Gln152, Asp153, Tyr154 and Val155 are important for the structure of the epitope B2. Mutations at alpha4 Gln152 substantially impaired the transfectant adhesion to a CS-1-containing fragment of fibronectin (FN-H89), whereas this adhesion was not affected on the other alpha4 mutant transfectants. None of the alpha4 mutations significantly altered the adhesion of the different alpha4 transfectants to VCAM-1. In addition, we have identified residues Gln152, Asp153 and Tyr154 as part of the alpha4 epitope B2 involved in homotypic cell aggregation. The decrease in adhesion to FN-H89 shown by Gln152 alpha4 mutant transfectants was the result of an inefficient binding of FN-H89 by VLA-4 mutated at this residue. Also, mutant VLA-4 displayed an altered reactivity with HUTS-21, an anti-beta1 monoclonal antibody that reacts with functionally active VLA integrins. Adhesion to FN-H89 was not restored unless stimuli that increase the ligand-binding affinity of VLA heterodimers were added, suggesting that cell adhesion was affected in the initial phases. These results indicate that alpha4 Gln152 modulates cell adhesion to FN-H89 by playing important roles in the maintenance and/or the acquisition of an active state of VLA-4, an integrin that is normally expressed on the cell surface in a range of multiple activation states. The location of the alpha4 Gln152 residue on a loop of the upper surface of the proposed beta-propeller structure suggests a close association with potential ligand-binding sites.

Antibodies, Monoclonal↗

PubMed1997

Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.

Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.

Allergens↗

PubMed1998

Angiogenesis induced by tumor necrosis factor-agr; is mediated by alpha4 integrins.

Tumor necrosis factor-alpha (TNF-alpha) and fibroblast growth factor-2 (FGF-2 or bFGF) are potent stimulators of angiogenesis. TNF- alpha, but not FGF-2, can induce the expression of vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells. The soluble form of VCAM-1 has recently been demonstrated to function as an angiogenic mediator. Here we demonstrate that monoclonal antibodies directed against VCAM-1 or its alpha4 integrin counter- receptor inhibited TNF-alpha-induced endothelial cell migration in vitro. Angiogenesis induced in vivo in rat corneas by TNF-alpha was inhibited by a neutralizing antibody directed against the rat alpha4 integrin subunit. A peptide antagonist of the a4 integrins blocked TNF-alpha-induced endothelial cell migration in vitro and angiogenesis in rat corneas in vivo. No inhibition by the antibodies or peptide antagonist was observed either in vitro or in vivo when FGF-2 was used as the stimulus. The peptide antagonist did not inhibit TNF-a binding to its receptor nor did it block the function of alphavbeta3, an integrin previously implicated in TNF-a and FGF- 2 mediated angiogenesis. These results demonstrate that angiogenic processes induced by TNF-alpha are mediated in part by agr;4 integrins possibly by a mechanism involving the induction of soluble VCAM-1.

Journal Article↗

PubMed2000

A role for alpha4-integrin in the pathology following Semliki Forest virus infection.

Migration of cells into the central nervous system (CNS) is a pivotal step in the pathogenesis of immune-mediated diseases such as multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE) and virus-induced demyelinating diseases. Such migration is dependent on expression of adhesion molecules. The expression of adhesion molecules in the CNS was studied in Biozzi ABH mice infected with Semliki Forest virus (SFV) A7(74) - an important demyelinating model of MS. Expression of LFA-1alpha/CD11a, LFA-1beta/CD18 and ICAM-1/CD56 were rapidly elevated and remained high whereas MAC-1, CD44 and VCAM-1/CD106 were less widely expressed. The alpha4-integrin VLA-4/CD49d was more specifically associated with CNS lesions. To identify the importance of VLA-4, CD44, ICAM-1 and MAC-1 in the pathogenesis of SFV infection, monoclonal antibodies that block these adhesion molecules were administered in vivo during infection. Anti-VLA-4 treatment dramatically reduced the cellular infiltrates and demyelination within the CNS but did not affect the clearance of virus while antibodies to CD44, ICAM and MAC-1 antibody treatment had no effect. This study demonstrates that SFV infection induces the expression of adhesion molecules within the CNS and that VLA-4 plays an important role in the development of inflammation and demyelination in the CNS following SFV infection.

Alphavirus Infections↗

PubMed2001

Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats.

BACKGROUND AND PURPOSE: The present study was performed to determine the role of alpha4 (CD49d), a member of the integrin family of adhesion molecules, in ischemic brain pathology. METHODS: Male spontaneously hypertensive rats (SHR) or Sprague-Dawley rats underwent 60-minute middle cerebral artery occlusion (MCAO) followed by 23-hour reperfusion. Animals were injected intravenously with 2.5 mg/kg anti-rat alpha4 antibody (TA-2) or isotype control antibody (anti-human LFA-3 IgG(1), 1E6) 24 hours before MCAO. Infarct volume was quantified by staining of fresh tissue with tetrazolium chloride and myeloperoxidase activity measured in SHR tissue homogenates 24 hours after MCAO. In SHR, mean arterial blood pressure was recorded before and after MCAO in animals treated with TA-2 and 1E6. Fluorescence-activated cell sorting analysis was performed on peripheral blood leukocytes before and after MCAO. RESULTS: TA-2 treatment significantly reduced total infarct volume by 57.7% in normotensive rats (1E6, 84.2+/-11.5 mm(3), n=17; TA-2, 35.7+/-5.9 mm(3), n=16) and 35.5% in hypertensive rats (1E6, 146.6+/-15.5 mm(3), n=15; TA-2, 94.4+/-25.8 mm(3), n=11). In both strains, TA-2 treatment significantly reduced body weight loss and attenuated the hyperthermic response to MCAO. In SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activity. Resting mean arterial blood pressure was unaffected by treatment. Leukocyte counts were elevated in TA-2-treated rats. Fluorescence-activated cell sorting analysis demonstrated the ability of TA-2 to bind to CD3+, CD4+, CD8+, and CD11b+ cells in both naive animals and after MCAO. CONCLUSIONS: These data demonstrate that inhibition of alpha4 integrin can protect the brain against ischemic brain injury and implicate endogenous alpha4 integrin in the pathogenesis of acute brain injury. The mechanism by which alpha4 integrin inhibition offers cerebroprotection is independent of blood pressure modulation and is likely due to inhibition of leukocyte function.

Animals↗

PubMed1998

In vivo treatment with anti-alpha4 integrin suppresses clinical and pathological evidence of Borna disease virus infection.

Borna disease virus (BDV) infection of the rat brain induces a severe T-lymphocyte mediated inflammatory response that parallels the course of clinical Borna disease. In other models of CNS inflammation, the recruitment of T-lymphocytes from the circulation to sites of inflammation is believed to be directed, in part, by the cellular adhesion molecules alpha4 beta1 integrin (expressed on T-lymphocytes) and its ligand VCAM-1 (expressed on blood brain barrier endothelium). Since BDV-specific T-lymphocytes are known to express the alpha4 beta1 integrin, we examined the effect of in vivo treatment with an anti-alpha4 integrin monoclonal antibody (GG5/3) on the development of BDV-specific encephalitis and Borna disease. Here, we report that the inhibition of alpha4 integrin provided significant clinical benefit in slowing the progression of Borna disease. Antibody treatment greatly reduced the immune cell infiltrates in the CNS of BDV-infected animals, but we found that this inhibition of the immune response did not result in enhanced viral levels.

Animals↗

PubMed2002

Steroids modulate the expression of alpha4 integrin in mouse blastocysts and uterus during implantation.

Blastocyst implantation and successful establishment of pregnancy require delicate interactions between the embryo and the maternal uterine milieu, which are controlled at the embryo-maternal interface by the coordinated interplay of a variety of growth factors, cytokines, hormones, and cell adhesion molecules expressed by both the decidualized endometrium and the trophoblast cells. Proper implantation of the embryo is solely dependent on the initial endometrial receptivity and the preparation of the blastocyst to glue itself to the uterine wall. Both these events are considered to be mediated by cell adhesion molecules and integrins expressed by the blastocyst as well by as the maternal endometrium. Integrin expression by the blastocyst and the uterus is a dynamic process. However, reports on the expression and the hormonal modulation of integrins and their role in blastocyst activation and uterine receptivity during implantation are meager. The present study investigates the expression and hormonal regulation of alpha4beta1 integrin by steroid hormones in the blastocyst and the receptive uterus using an in vivo, delayed-implantation mouse model system. The dormant and activated blastocysts as well as the uteri were recovered from ovariectomized mice after progesterone-alone and progesterone-plus-estrogen therapy, respectively. Immunolocalization of protein expression of alpha4 and beta1 integrin subunits indicate that steroids modulate the expression of alpha4beta1 integrin receptor in the mouse blastocyst as well as the uterus and that a differential expression is observed with exposure to progesterone and estrogen. Intrauterine blocking of alpha4 integrin by specific antibody resulted in implantation failure in normal as well as in delayed-implantation mice. Based on our data, we propose here, to our knowledge for the first time, that alpha4beta1 integrin, which is responsible for binding to fibronectin and vascular cell adhesion molecule-1, is induced by estradiol and is down-regulated by progesterone in mice during implantation. Furthermore, the results also indicate the direct role of alpha4 integrin in the process of implantation.

Animals↗

PubMed2005

Hyaluronate receptor (CD44) and integrin alpha4 (CD49d) are up-regulated on T cells during MS relapses.

A longitudinal study of peripheral blood T cell adhesion molecule expression was performed in 24 relapsing-remitting MS patients. There were 15 relapses in 11 patients during 15 months of observation. In comparison with remission, expression of hyaluronate receptor (CD44) was highly significant, and expression of integrin alpha4 (CD49d, VLA-4) significantly up-regulated during relapses. CD44 and CD49d are putative activity markers and CD44 a potential novel therapeutic target in MS.

Adjuvants, Immunologic↗

PubMed1997

Roles of adhesion molecules ICAM-1 and alpha4 integrin in antigen-induced changes in microvascular permeability associated with lung inflammation in sensitized brown Norway rats.

Increased microvascular permeability and mucosal edema are pathological features of airway inflammation in asthma. In this study, we investigated the characteristics of the edema response occurring in a model of antigen-induced lung inflammation in sensitized brown Norway rats and examined the effects of monoclonal antibodies (mAbs) to adhesion molecules on this response. Ovalbumin (OA) challenge-induced increases in lung permeability were determined by the leakage of 125I-labeled bovine serum albumin (BSA) into the extravascular tissues of the lungs 24 h after challenge in animals intravenously injected (prechallenge) with this tracer. Inflammatory cell infiltration into the alveolar space was determined by bronchoalveolar lavage (BAL). Mean extravascular plasma volume in the lung increased 233% as compared with control (P < 0.005) at 24 h and increased to 517% by 72 h. The 24-h edema response was completely inhibited by two oral doses (0.1 mg/kg) of dexamethasone 1 h before, and 7 h after, challenge. Intraperitoneal administration of the anti-rat ICAM-1 mAb 1A29, or anti-rat alpha4 integrin mAb TA-2 (2 mg/kg at 12 and 1 h before, and 7 h after, antigen challenge), significantly suppressed eosinophil infiltration into the alveolar space without inhibiting the enhanced microvascular leakage and lung edema. Determination of plasma antibody concentrations by ELISA of mouse IgG1 indicated that sufficient concentrations of the appropriate mAb were present to block alpha4- or ICAM-1-dependent adhesion. The results suggest that increases in microvascular permeability and plasma leakage occurred independently of eosinophil accumulation.

Animals↗