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Results for “Integrin alpha4”

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PubMed1999

alpha4 integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice.

We investigated the roles of eosinophil infiltration and activation induced by the eosinophil-selective chemokine eotaxin, and of the expression of eosinophil alpha4 and beta2 integrins in causing bronchial hyperresponsiveness (BHR) in interleukin (IL)-5 CBA/Ca transgenic mice. These mice did not show BHR, despite the presence of some eosinophils in the lungs. Intratracheal mouse recombinant eotaxin (3 micrograms) did not induce BHR in wild-type mice. In IL-5 transgenic mice, eotaxin (3 and 5 micrograms) increased responsiveness at 24 h and increased eosinophils in bronchoalveolar lavage (BAL) fluid by 9.4- and 14-fold by 24 h, respectively, together with augmentation of eosinophil peroxidase activity and eosinophil infiltration in the airway submucosa. Using flow cytometry, the expression of alpha4, CD11b, and CD18 was upregulated in BAL, but not in blood, eosinophils. A rat anti-alpha4 antibody inhibited eotaxin-induced BHR and eosinophil migration and activation, but an anti-CD11b antibody had no significant effects on BHR. A combination of both antibodies was more effective. IL-5 and eotaxin synergize in the induction of BHR and airway eosinophilia, effects that are dependent on the induction of eosinophil alpha4 integrin. Expression of BHR depends on the recruitment and activation of eosinophils.

Animals↗

PubMed1999

Cooperative role for activated alpha4 beta1 integrin and chondroitin sulfate proteoglycans in cell adhesion to the heparin III domain of fibronectin. Identification of a novel heparin and cell binding sequence in repeat III5.

We recently reported that the heparin (Hep) III domain of fibronectin contains the H2 cell adhesion site in repeat III5 which binds activated alpha4 integrins. We have now further characterized the heparin and cell binding activities of this domain. A recombinant fragment containing repeats III4-III5 (FN-III4-5) induced Jurkat cell adhesion upon integrin activation with Mn2+ or TS2/16 monoclonal antibody (anti-beta1). Adhesion of Mn2+-treated cells to FN-III4-5 or FN-III5 fragments was inhibited by chondroitinase ABC and ACII but not by the anti-alpha4 monoclonal antibody HP2/1. In contrast, HP2/1 completely blocked adhesion of TS2/16-treated cells while chondroitinase had a partial (FN-III4-5) or minor (FN-III5) effect. Thus, the role of each receptor depended on the stimulus used to activate alpha4 beta1. The combination of HP2/1 and chondroitinase at dilutions which did not inhibit when used individually abolished adhesion of Mn2+ or TS2/16-treated cells to both fragments, indicating a cooperative effect between alpha4beta1 and chondroitin sulfate proteoglycans (CSPG). Furthermore, we have identified a 20-amino acid sequence in III5 (HBP/III5) which binds heparin and induces cell adhesion via CSPG exclusively. Although soluble HBP/III5 was a poor inhibitor, when combined with H2, it abolished adhesion to FN-III4-5 and FN-III5 fragments. These results establish that adhesion to the Hep III domain involves the cooperation of activated alpha4 beta1 and CSPG and show that HBP/III5 is a novel heparin and CSPG-binding site contributing to cell adhesion to this domain.

Amino Acid Sequence↗

PubMed2005

Therapeutic targeting of alpha 4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?

Inhibition of leukocyte trafficking via alpha4-integrin antibody blockade has recently become a validated therapeutic approach for several inflammatory diseases, including multiple sclerosis, ulcerative colitis and Crohn's disease. In the midst of this recent success, 3 patients receiving chronic treatment with the anti-alpha4 antagonist natalizumab (Tysabri) for the treatment of multiple sclerosis or Crohn's disease, developed JC-virus related progressive multifocal leukoencephalopathy (PML). These unforeseen consequences suggest that long term blockade of alpha4-integrins might prevent trafficking of non-pathogenic lymphocytes that are essential for viral immunosurveillance. In the current issue of the European Journal of Immunology Bjursten and colleagues report that long term treatment with anti-alpha4-integrin antibodies results in exacerbation of the murine model of colitis induced by the targeted deletion of the heterotrimeric G protein subunit Galphai2. In order to properly evaluate the efficacy and safety of anti-alpha4-integrin therapy, the relationship between these observations in an immunologically altered animal model and human clinical disease needs to be carefully measured.

Animals↗

PubMed1997

Bone marrow fibroblast exposure to the inflammatory cytokines tumor necrosis factor-alpha and interferon-gamma increases adhesion of acute myeloid leukemia cells and alters the adhesive mechanism.

Human acute myeloid leukemia (AML) cells adhere to bone marrow fibroblasts (BMF) and extracellular matrix proteins including fibronectin. Adhesion is increased when fibroblast monolayers are exposed to tumor necrosis factor-alpha (TNF) alone and in combination with interferon-gamma (IFN) or interleukin-4 (IL-4). The combination of TNF and IFN caused enhanced AML cell adhesion to treated BMFs, from a mean of 25.0 +/- 4.1% to 36.3 +/- 5.4% (p = 0.0007). Enhanced binding was partially a result of upregulated vascular cell adhesion molecule-1 expression on BMFs. Intercellular adhesion molecule-1 was also upregulated, but did not appear to play a role in the increased binding to cytokine-stimulated BMFs. In contrast to observed adhesion to resting BMFs, AML cells binding to TNF/IFN-stimulated BMFs rely more heavily on the VLA-4 alpha chain (CD49d). In some cases, alpha4 integrin chain antibody was more effective than beta1 antibody in blocking binding, suggesting that a non-beta1 alpha4 integrin, possibly alpha4 beta7, on AML cells may act as a stromal ligand. The addition of alpha4 antibody to beta1 and beta2 antibodies significantly increased the inhibition of AML cells to stimulated BMFs. The myeloid cytokines granulocyte colony stimulating factor, granulocyte-monocyte colony stimulating factor, interleukin-3 and stem cell factor enhanced the adhesion of AML blast cells to BMFs in some cases. The phorbol ester PMA, however, consistently upregulated AML cell-binding to BMFs, the increase being mediated entirely via beta1 and beta2 integrins without altering AML cell integrin expression. Binding of AML cells to marrow stroma can be enhanced by influences on leukemic cell or stroma. Enhanced binding under these conditions occurs via different pathways, illustrating the heterogeneity of mechanisms underlying leukemic cell retention within the bone marrow stroma.

Acute Disease↗

PubMed2005

Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands.

Group A rotaviruses are major intestinal pathogens that express potential alpha4beta1 and alpha4beta7 integrin ligand sequences Leu-Asp-Val and Leu-Asp-Ile in their outer capsid protein VP7, and Ile-Asp-Ala in their spike protein VP4. Monkey rotavirus SA11 can use recombinant alpha4beta1 as a cellular receptor. In this study a new potential alpha4beta1, alpha4beta7 and alpha9beta1 integrin ligand sequence, Tyr-Gly-Leu, was identified in VP4. It was shown that several human and monkey rotaviruses bound alpha4beta1 and alpha4beta7, but not alpha9beta1. Binding to alpha4beta1 mediated the infectivity and growth of monkey rotaviruses, and binding to alpha4beta7 mediated their infectivity. A porcine rotavirus interacted with alpha4 integrins at a post-binding stage to facilitate infection. Activation of alpha4beta1 increased rotavirus infectivity. Cellular treatment with peptides containing the alpha4 integrin ligand sequences Tyr-Gly-Leu and Ile-Asp-Ala eliminated virus binding to alpha4 integrins and infectivity. In contrast, rotavirus recognition of alpha4 integrins was unaffected by a peptide containing the sequence Leu-Asp-Val or by a mutation in the VP7 Leu-Asp-Val sequence. VP4 involvement in rotavirus recognition of alpha4beta1 was demonstrated with rotavirus reassortants. Swapping and point mutagenesis of alpha4 surface loops showed that rotaviruses required the same alpha4 residues and domains for binding as the natural alpha4 integrin ligands: mucosal addressin cell adhesion molecule-1, fibronectin and vascular cell adhesion molecule-1. Several rotaviruses are able to use alpha4beta7 and alpha4beta1 for cell binding or entry, through the recognition of the same alpha4-subunit domains as natural alpha4 ligands.

Animals↗

PubMed2002

Alpha 4 integrin antagonists.

The accumulation of leukocytes in various organs contributes to the pathogenesis of a number of human autoimmune diseases such as asthma, rheumatoid arthritis, Crohn s disease, ulcerative colitis, hepatitis C, and multiple sclerosis. The inflammatory processes leading to tissue damage and disease are mediated in part by the alpha4 integrins, alpha4beta1 and alpha4beta7, expressed on the leukocyte cell surface. These glycoprotein receptors modulate cell adhesion via interaction with their primary ligands, vascular cell adhesion molecule (VCAM) and mucosal addressin cell adhesion molecule (MAdCAM), expressed in the affected tissue. Upon binding, the combined integrin/CAM interactions at the cell surface result in firm adhesion of the leukocyte to the vessel wall followed by entry into the affected tissue. Elevated cell adhesion molecule (CAM) expression in various organs has been linked with several autoimmune diseases. Monoclonal antibodies specific for alpha4 integrins or their CAM ligands can moderate inflammation in animal models suggesting such inhibitors may be useful for treating human inflammatory diseases. The alpha4 integrins have become well validated drug targets for pharmaceutical companies and numerous publications describing alpha4 integrin antagonists have recently appeared. This article discusses the rationale for targeting alpha4 integrins for the treatment of autoimmune disorders and reviews some currently known antagonists. The methods used to identify lead molecules and the progress of selected antagonists toward becoming new drugs will is also discussed. (131 references).

Animals↗

PubMed2003

Alpha 4 integrin increases anoikis of human osteosarcoma cells.

Cell motility, growth, and proliferation are regulated by adhesion to the extracellular matrix. Detachment of adherent cells from extracellular matrix results in induction of apoptosis ("anoikis"). Transformed cells often show an anchorage-independent growth that enables them to acquire a motile, invasive phenotype. This phenotype has been associated with the altered expression and function of the integrin family of transmembrane proteins that mediate cell adhesion to the extracellular matrix. Although alpha4 integrin is normally expressed on leukocyte subpopulations, a number of metastatic melanomas and sarcomas express it as well. In this study, we demonstrated the expression of alpha4 integrins on the human osteosarcoma cell line SAOS and on metastatic osteosarcoma lesions from the lung and pericardium. We further demonstrated that alpha4 integrin is coupled to the beta1 subunit by biochemical analysis and by using a mAb directed against a combinatorial epitope unique to the alpha4beta1 molecule. SAOS cells undergo anoikis when adherence is denied. Anoikis involved the activation of caspase 3 and the release of cytochrome c from mitochondria. Treatment of non-adherent SAOS with an anti-alpha4 mAb increased anoikis while anti-beta1 integrin mAbs did not alter anoikis, thus indicating a novel function for the alpha4 subunit in the control of cell death. Since integrins can control cell migration, proliferation, and apoptosis these results demonstrate a potential role for alpha4 integrin during multiple aspects of osteosarcoma metastasis.

Anoikis↗

PubMed1999

Roles of integrins and CD44 on the adhesion and migration of fetal liver cells to the fetal thymus.

Adhesion and migration of mouse fetal liver (FL) cells to the thymus were investigated using cells from green fluorescent protein transgenic (GFP+) mice. FL cells from GFP+ embryos at 12 gestational days (E12) of mice were incubated with 2'-deoxyguanosine-treated fetal thymus lobe (from E14) by thymic repopulation (hanging drop) culture methods. GFP+ cells were observed in the thymus lobe at the end of the repopulation culture period. A large part of the infiltrated cells expressed CD44 until day 2 of culture on a permeable membrane, then lost the expression. CD25 expression was observed from day 1 to day 4. Around day 8, GFP+ cells became both CD4+ and CD8+. The results support the early observation of the sequential expression of CD44, CD25, and CD4/8 during the early stages of thymocyte development. When anti-CD44 mAb was added at the beginning of the repopulation culture period, GFP+ FL cells adhered to the surface of the thymus lobe but did not migrate into the thymus. Pretreatment of the thymus with hyaluronidase or hyaluronate produced results similar to the results of anti-CD44 treatment. On the other hand, the addition of anti-integrin alpha4 mAb inhibited adhesion to the thymus, and almost no GFP+ cells were seen on the surface of the thymus lobe. The data suggest that integrin alpha4 and CD44 play different roles, i.e., integrin alpha4 is required for the adhesion of FL cells to the thymus lobe and CD44 is required for the migration of the cells into the thymus.

Animals↗

PubMed2007

Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab.

BACKGROUND: Natalizumab, a humanized monoclonal IgG(4) antibody to alpha4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied. METHODS: Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score > or = 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment. RESULTS: Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (-37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug-drug interactions were noted. CONCLUSIONS: The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone.

Adult↗

PubMed2001

Transcending conventional therapies: the role of biologic and other novel therapies.

Biologic and other novel therapies targeted to specific pathogenic processes offer the potential for improved treatment outcomes in patients with Crohn's disease and alteration of the course of the disease. Therapies targeted to tumor necrosis factor alpha (TNF-alpha) include anti-TNF-alpha monoclonal antibodies (infliximab and CDP-571), TNF-binding neutralizing fusion proteins (etanercept), and TNF-alpha production inhibitors (thalidomide). In placebo-controlled trials, infliximab has rapidly induced clinical response and remission in patients with moderately to severely active Crohn's disease refractory to conventional therapy and patients with fistulizing Crohn's disease, with minimal toxicity; retreatment with infliximab in patients who experienced an initial response maintained their clinical improvement. Clinical experience suggests that infliximab may also be effective when administered as corticosteroid-sparing therapy. Infliximab is the only anti-TNF-alpha therapy currently available in clinical practice for the treatment of active Crohn's disease. Controlled trials of the investigational anti-TNF-alpha agent CDP-571 show benefit for induction of clinical improvement and steroid-sparing, but further investigation is needed. A pilot study of etanercept suggested a beneficial effect, but its efficacy was not confirmed in a controlled trial. In open-label trials, thalidomide has demonstrated efficacy in patients with refractory Crohn's disease; however, the therapeutic potential of thalidomide may be severely limited by the high incidence of drug-induced side effects. Other novel agents, including anti-alpha4 integrin antibodies, interleukin (IL)-10 and IL-11, and the immunomodulators tacrolimus and mycophenolate mofetil have been evaluated as treatment in patients with severely active or fistulizing Crohn's disease in open-label and controlled trials, with varied results reported to date. The development of these new therapies is an exciting advance that promises to improve the management of Crohn's disease and expand current knowledge of underlying pathophysiologic mechanisms.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Enhancement of metastatic activity of colon cancer as influenced by expression of cell surface antigens.

BACKGROUND: Cell surface antigens are contributory factors toward metastatic activity. There have been no detailed studies on changes in cell surface antigens of colon cancer cell lines. To control life-threatening metastasis, it is necessary to evaluate what types of changes in cell surface antigens exert an influence on metastatic activity. MATERIALS AND METHODS: In vivo selection was performed using the human colon cancer-derived cell line KM12SM to obtain variants of metastatic activity. A murine spleen injection-liver metastasis procedure reflecting the latter half of the metastatic process was adopted and repeated four times. Flow cytometric analyses were carried out to detect expression of antigens: Lewis a (Lea), Lewis x (Lex), sialyl Lewis a (sLea), sialyl Lewis x (sLex), E-cadherin, CD44v6, integrin alpha2 (CD49b), integrin alpha3 (CD49c), integrin alpha4 (CD49d), integrin alpha5 (CD49e), and integrin beta1 (CD29). RESULTS: In vivo selection produced variants with higher metastatic activity. In the original line KM12SM, sLea, E-cadherin, CD49b, CD49c, or CD29 were positive in more than 40% of the cells. After selection, the percentage of cells positive for Lea, sLea, and all examined integrins significantly increased. Lex, sLex, and CD44v6 increased slightly, while E-cadherin decreased slightly. CONCLUSIONS: In vivo selection and flow cytometric analysis revealed that Lea, sLea, CD49b, CD49c, and CD29 appear to be involved in the increase of metastatic activity. The changes of integrin expression in this study suggest that integrins collaborate in the promotion of adhesion to an extracellular matrix.

Animals↗

PubMed2004

Reduction in adhesiveness to extracellular matrix components, modulation of adhesion molecules and in vivo migration of murine macrophages infected with Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite, able to disseminate into deep tissues and cross biological barriers, reaching immunoprivileged sites such as the brain and retina. In order to investigate whether the parasite uses leukocyte trafficking to disseminate throughout the host, the adhesive potential to extracellular matrix components, the expression of adhesion molecules and the in vivo migration of murine macrophages infected with RH strain of T. gondii were investigated. Cellular adhesion to fibronectin, laminin and collagen IV decreased after 24 h of T. gondii infection. However, the decrease in adhesion of infected macrophages observed at early infection was reversed after 48 h. Moreover, decreased adhesion was dependent on active penetration, since heat-killed parasites were unable to reproduce it. Expression of integrins alphaL, alpha4 and alpha5 chains was downmodulated early postinfection, but a progressive regain of expression was observed after 12 h of infection. Expression of beta2, alphav and alpha4 integrins by peritoneal macrophages at late infection was also gradually reestablished. The assessment of in vivo migration of infected macrophages labeled with the fluorescent dye 5-chloromethylfluorescein diacetate showed a 48-h delay in migration to cervical lymph nodes when compared to LPS pre-stimulated macrophages. Furthermore, cells that migrate to distal lymph nodes were loaded with live parasites. Taken together, these results provide insights about T. gondii escape from the host immune response, placing the macrophage as a "Trojan horse", contributing to parasite dissemination and access to immunoprivileged sites.

Animals↗

PubMed2000

Intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and regulated on activation normal T cell expressed and secreted are expressed by human breast carcinoma cells and support eosinophil adhesion and activation.

Eosinophils are usually associated with parasitic and allergic diseases; however, eosinophilia is also observed in several types of human tumors, including breast carcinomas. In this study we examined several human breast carcinoma cell lines for adhesion molecule expression and the ability to bind and activate eosinophils. MDA-MB-435S and MDA-MB-468 cells constitutively expressed both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and this expression was enhanced by treatment with tumor necrosis factor-alpha (TNF-alpha). BT-20 and SK-BR-3 cells only expressed ICAM-1 or VCAM-1 after stimulation with TNF-alpha. Eosinophils constitutively bound to MDA-MB-435S cells, but not to BT-20 cells. Stimulation with TNF-alpha slightly enhanced eosinophil adhesion to MDA-MB-435S cells and dramatically increased adhesion to BT-20 cells. Greater than 80% of eosinophil adhesion to these cell lines was blocked with an anti-alpha4-integrin monoclonal antibody. Both MDA-MB-435S and BT-20 cells also released eosinophil activator(s). Supernatants from TNF-alpha-treated, but not control-treated, cell lines increased eosinophil adhesion to fibronectin and increased eosinophil transmigration across fibronectin-coated transwell plates. Enzyme-linked immunosorbent assays showed that TNF-alpha-stimulated breast carcinoma cells released the chemokine regulated on activation, T cell expressed and secreted (RANTES). Addition of an anti-RANTES antibody to breast carcinoma cell supernatants partially blocked eosinophil activation suggesting that RANTES in these supernatants was participating in eosinophil activation. These data show that TNF-alpha-stimulated breast carcinoma cells express mediators that can both bind and activate eosinophils, suggesting a mechanism for eosinophil localization to breast carcinoma sites.

Antigens, CD↗

PubMed1999

Tumor necrosis factor-alpha stimulates attachment of small cell lung carcinoma to endothelial cells.

Tumor cell attachment to endothelial cells (ECs) is an important step in the metastasis of small cell lung carcinoma (SCLC). Tumor necrosis factor-alpha (TNF-alpha) stimulation of ECs increases the attachment of some malignant cell types to ECs by affecting the expression of cell adhesion molecules (CAMs). Similarly, the inhibition of EC protein kinase C (PKC) and tyrosine kinase (TK) pathways modulates TNF-alpha-mediated effects on CAM expression. We hypothesized that TNF-alpha would increase SCLC attachment to ECs by affecting CAM expression through activation of PKC and TK pathways. To test this hypothesis, human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-alpha (0 to 500 U/mL) for variable time periods (1 to 24 hours), and the attachment of H82 cells (an SCLC cell line) to the HUVECs was quantified. TNF-alpha stimulation of the HUVECs increased H82 attachment from 28.1% +/- 1.6% to 48.8% +/- 1.7% (P < .05). Preincubation of HUVECs with the PKC inhibitors bis-indolylmaleimide (BIN) or calphostin C or the TK inhibitors genistein or herbimycin A (HMA) blocked the TNF-alpha-induced increase in H82 cell attachment. The addition of antibodies to vitronectin (Vn) or beta1-integrin to TNF-alpha-activated HUVECs before the addition of the H82 cells also significantly decreased H82 attachment, whereas the addition of antibodies to E-selectin, P-selectin, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), neural cell adhesion molecule (NCAM), sialyl-Lewis(x), fibronectin (Fn), alpha(v)-integrin, alpha3-integrin, alpha4-integrin, or alpha5-integrin had no effect on SCLC attachment. In summary, the TNF-alpha-mediated increase in SCLC attachment to ECs appears to be mediated by the activation of EC PKC and TK pathways as well as through effects on the function or expression of EC Vn and beta1 integrin.

Carcinoma, Small Cell↗

PubMed1998

Priming and induction of eosinophil trafficking in guinea-pig cutaneous inflammation by tumour necrosis factor alpha.

Tissue eosinophilia is a hallmark of allergic and parasitic diseases. Priming mechanisms may play an important role in mediating the process of eosinophil accumulation in these conditions. We have previously shown that blockade of tumour necrosis factor alpha (TNFalpha) inhibited the capacity of lipopolysaccharide to prime skin sites for chemoattractant-induced eosinophil recruitment. The present study was carried out to investigate the capacity of TNFalpha to prime an inflammatory site for enhanced eosinophil accumulation. Initial experiments investigated the capacity of TNFalpha itself to induce eosinophil accumulation. Intradermal injection of murine TNFalpha (10-300 ng per site) in the guinea-pig induced significant accumulation of 111In-eosinophils. Kinetic studies showed the response to be delayed in onset and inhibited by cycloheximide, consistent with a dependency on protein synthesis. Trafficking of 111In-eosinophils to sites treated for 2 h with TNFalpha (10-100 ng per site) was inhibited by monoclonal antibodies (mAbs) against beta2 or alpha4 integrins. Intradermal injection of a low dose (3 ng) of TNFalpha (which by itself had no significant effect on eosinophil trafficking) prior to chemoattractants or antigen in sensitized skin sites, induced significant priming of eosinophil accumulation. Recruitment of both 111In-eosinophils and endogenous eosinophils was enhanced. Trafficking to TNFalpha-primed responses was dependent on protein synthesis and beta2 integrins. In contrast, the alpha4 integrin mAb failed to inhibit the TNFalpha primed response. Thus, TNFalpha can induce and also prime eosinophil recruitment in guinea-pig skin. Our results provide further evidence that this cytokine may be an important mediator of allergic- or parasite-induced eosinophilic inflammation.

Animals↗

PubMed2006

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.).

Adolescent↗

PubMed2006

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).

Adolescent↗

PubMed1999

Structural aspects of the association of FcepsilonRI with detergent-resistant membranes.

We recently showed that aggregation of the high affinity IgE receptor on mast cells, FcepsilonRI, causes this immunoreceptor to associate rapidly with specialized regions of the plasma membrane, where it is phosphorylated by the tyrosine kinase Lyn. In this study, we further characterize the detergent sensitivity of this association on rat basophilic leukemia-2H3 mast cells, and we compare the capacity of structural variants of FcepsilonRI and other receptors to undergo this association. We show that this interaction is not mediated by the beta subunit of the receptor or the cytoplasmic tail of the gamma subunit, both of which are involved in signaling. Using chimeric receptor constructs, we found that the extracellular segment of the FcepsilonRI alpha subunit was not sufficient to mediate this association, implicating FcepsilonRI alpha and/or gamma transmembrane segments. To determine the specificity of this interaction, we compared the association of several other receptors. Interleukin-1 type I receptors on Chinese hamster ovary cells and alpha4 integrins on rat basophilic leukemia cells showed little or no association with isolated membrane domains, both before and after aggregation on the cells. In contrast, interleukin-2 receptor alpha (Tac) on Chinese hamster ovary cells exhibited aggregation-dependent membrane domain association similar to FcepsilonRI. These results provide insights into the structural basis and selectivity of lipid-mediated interactions between certain transmembrane receptors and detergent-resistant membranes.

Animals↗