Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adhesion measurements between CD8 and 48 point mutants of HLA-A2.1 show that the CD8 alpha-chain binds to the alpha 3 domain of HLA-A2.1. Three clusters of alpha 3 residues contribute to the binding, with an exposed, negatively charged loop (residues 223-229) playing a dominant role. CD8 binding correlates with cytotoxic T-cell recognition and sensitivity to inhibition by anti-CD8 antibodies. Impaired alloreactive T-cell recognition of an HLA-A2.1 mutant with reduced affinity for CD8 is not restored by functional CD8 binding sites on an antigenically irrelevant class I molecule. Therefore, complexes of CD8 and the T-cell receptor bound to the same class I major histocompatibility complex molecule seem to be necessary for T-cell activation.
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PMID:A binding site for the T-cell co-receptor CD8 on the alpha 3 domain of HLA-A2. 210 37

Adhesion of lymphocytes to vascular endothelium is the first event in the passage of lymphocytes into a chronic inflammatory reaction. To investigate molecular mechanisms of T-EC adhesion, monoclonal antibodies (Mab) against T cell surface antigens have been tested for inhibition of binding. Baseline and phorbol ester-stimulated adhesion were strongly inhibited by either Mab 60.3 (reactive with the beta-chain of the LFA-1, OKM1, and p150,95 molecules) or by Mab TS 1/22 (specific for the alpha-chain of LFA-1). Although the increased binding of phorbol ester-stimulated lymphocytes was inhibited by anti-LFA-1 antibody, there was no increased expression of LFA-1 on phorbol ester-stimulated T cells, as determined by FACS analysis. Maximal inhibition of unstimulated and phorbol ester-stimulated T-EC adhesion was seen at Mab concentrations of 1 microgram/ml. In contrast, LPS- and IL 1-enhanced T-EC adhesion were only weakly inhibited by these antibodies. Mab 60.3 and TS 1/22 did not stain either unstimulated EC or LPS- or IL 1-stimulated EC, as measured by FACS analysis; moreover, preincubation of EC alone with these antibodies did not lead to inhibition of T-EC binding. Adhesion was not affected by Mab against the sheep erythrocyte receptor (LFA-2), a nonpolymorphic HLA class 1 framework antigen, or against LFA-3, the alpha-chain of OKM1, or the alpha-chain of p150,95. These results suggest that the mechanism of binding of lymphocytes to unstimulated endothelium differs from that to stimulated endothelium. LFA-1 appears to be an important adhesion-related molecule for binding to unstimulated endothelium. However, the increased lymphocyte adhesion to IL 1- or LPS-stimulated EC observed in these experiments appears to be relatively independent of LFA-1. The increased adhesion to stimulated EC could be due either to an increase in the avidity or the density of the EC receptor molecules ordinarily involved in unstimulated T-EC binding or to the formation of alternative receptors on the stimulated EC that are not present on unstimulated cells.
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PMID:T lymphocyte adhesion to endothelial cells: mechanisms demonstrated by anti-LFA-1 monoclonal antibodies. 242 77

The specific binding of human polymorphonuclear leukocytes (PMN) to antibody-coated target cells was characterized by flow cytometry. PMN were labeled with phycoerythrin-E (PE) via a granulocyte-specific monoclonal antibody (leu-M1) and mixed with fluorescein isothiocyanate-labeled K562 tumor cells sensitized with rabbit antiserum. Specific conjugates were formed as analyzed by two-color fluorescence in a flow cytometer. The formation of stable conjugates was dependent on initiation of contact, temperature, time, and antiserum concentration. Studies with inhibitors implicate that microfilaments, but not microtubules, Ca2+, Mg2+, or energy-dependent processes were a prerequisite for binding of PMN to the antibody-coated target cells. No conjugates were formed when uncoated target cells were used or when the experiment was performed in the presence of protein A, indicating that binding was specifically mediated through Fc receptors (FcR). Monoclonal antibodies against the FcRII and FcRIII were used to address the role of these receptors in conjugation. One of the two anti-FcRIII antibodies and an anti-FcRII antibody effectively prevented conjugation. A monoclonal antibody directed against the common beta-chain of the adhesion molecule family and a combination of antibodies against the alpha-chain of LFA-1 and Mo-1 also blocked conjugation when target cells were sensitized under suboptimal conditions. The antibody against the beta-chain also diminished killing of antibody-coated K562, as measured by chromium release when included in the cytotoxicity assay. These results indicate that flow cytometry permits accurate quantitation and characterization of the binding between PMN and antibody-coated target cells, which in principle, can be prevented by monoclonal antibodies against surface receptors. Binding is primarily established by both the FcRII and FcRIII. Adhesion-associated molecules on the PMN surface contribute to optimal binding.
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PMID:Quantitation of conjugate formation between human polymorphonuclear leukocytes and antibody-coated target cells by flow cytometry: the role of Fc receptor and LFA-1 antigen. 268 90

Platelet adhesion has been measured to type-I monomeric collagen, collagen fibres, alpha 1(I) and alpha 2(I) chains and the chain fragments alpha 1(I)CB3, alpha 1(I)CB6, alpha 1(I)CB7 and alpha 1(I)CB8, and alpha 2(I)CB3,5 and alpha 2(I)CB4. Little if any adhesion occurred to any denatured species at 37 degrees C, demonstrating the importance of the collagen helix. However, on coating at 4 degrees C to promote helix formation, and assaying at room temperature to avoid denaturation, adhesion was observed to both alpha-chain types and all fragments, the exact level of which depended on the identity of the species in question. Adhesion was strongly Mg(2+)-dependent. Antibodies against the integrin alpha 2 beta 1 partially inhibited adhesion to alpha-chains and all fragments except alpha 1(I)CB6, indicating a wide distribution of alpha 2 beta 1-binding sites in the collagen molecule. 'Activation-dependent' adhesion to monomeric collagen, totally secondary to alpha 2 beta 1-mediated adhesion, involved at least two mechanisms, one mediated by integrin alpha IIb beta 3 and insensitive to prostaglandin E1, the other inhibitable by prostaglandin E1 but independent of integrin alpha IIb beta 3. alpha IIb beta 3-mediated adhesion to fragments was, at least in part, independent of the alpha 2 beta 1-mediated adhesion. Adhesion to fibres was largely bivalent-cation-independent with only minor involvement of integrin alpha 2 beta 1. Some alpha IIb beta 3-mediated adhesion occurred but was independent of any alpha 2 beta 1-initiated adhesion. Total 'activation-dependent' adhesion to fibres was less than to monomeric collagen. Affinity chromatography revealed bivalent-cation-independent binding to fibres of three main platelet surface proteins, 90, 150 and 190 kDa in size.
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PMID:Conformation-dependent platelet adhesion to collagen involving integrin alpha 2 beta 1-mediated and other mechanisms: multiple alpha 2 beta 1-recognition sites in collagen type I. 751 71

Expression of adhesion molecules on endothelial cells (EC) can be up-regulated or induced by cytokines. The aim of the present study was to investigate the effect of IL-4 on both the expression of adhesion molecules on EC and monocyte adhesion to EC. Flow cytometric analysis showed that VCAM-1 expression on EC was up-regulated after stimulation with IL-4 for 24 h, whereas the expression of E-selectin (formerly called endothelial leucocyte adhesion molecule-1 (ELAM-1)) was not enhanced, and that of intercellular adhesion molecule-1 (ICAM-1) only slightly. The adhesion of monocytes to EC increased to maximum values upon stimulation of EC with IL-4 for 24 h. Coating of monocytes with MoAb against the integrin beta 2-subunit (CD18) significantly inhibited their adhesion to IL-4-stimulated EC; maximal inhibition was found when monocytes were coated with anti-CD18 MoAb in combination with MoAb against CD49d (the alpha-chain of VLA-4), whereas no inhibition was found when monocytes were coated only with MoAb against CD49d. Monocyte adhesion was not significantly inhibited when IL-4-stimulated EC were coated with MoAbs against ICAM-1 or VCAM-1 alone or in combination. Adhesion of monocytes was inhibited to a greater extent when in addition to coating of monocytes with MoAb against CD18 the EC were coated with MoAb against VCAM-1. From these results we conclude that monocytes bind to IL-4-stimulated EC via interaction of CD11/CD18 molecules on the monocytes with an as yet unknown endothelial ligand, and interaction of VLA-4 on monocytes with VCAM-1 on EC.
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PMID:Increased adhesion of human monocytes to IL-4-stimulated human venous endothelial cells via CD11/CD18, and very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1)-dependent mechanisms. 768 78

The ligation between leucocyte-Function-Associated Molecule 1 (LFA-1) and Intercellular Adhesion Molecules (ICAM) is thought to be an important component in the stimulatory interaction between antigen-presenting cells (APC) and T cells. Similar to antigenic stimulation, T-cell stimulation with pokeweed mitogen (PWM) is highly dependent on monocytes as accessory cells. This is partly a consequence of the requirement for mitogen presentation by the monocytes. The study described here addressed the question of whether LFA-1 ligation by accessory cells influences the activation of T cells with PWM. To avoid multiple costimulatory interactions between T cells and monocytes, experiments were performed with purified T cells, which were stimulated with PWM bound on autologous red blood cells (PWM-RBC). Binding on the RBC substituted partly for PWM presentation by the monocytes. Anti-LFA-1 MoAbs were presented in the immobilized form in order to mimick LFA-1 ligation by cell-bound ICAM. Three out of three different MoAbs against the beta-chain of the LFA-1 molecule (CD18) and two out of three MoAbs against the alpha-chain (CD11a) had an enhancing effect on T-cell proliferation. Proliferation was increased further by simultaneous addition of interleukin (IL)-1 beta and IL-6. Ligation of the LFA-1 molecule was found to enhance IL-2 production and tumour necrosis factor-alpha (TNF-alpha) production. The results suggest that interaction of LFA-1 with ICAM on the monocytes contributes to the accessory signal activity of monocytes in T-cell activation with PWM.
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PMID:Ligation of leukocyte function-associated (LFA) molecule-1 provides an accessory signal for T-cell activation with pokeweed mitogen. 790 4

Adhesion molecules (AM) are cell surface proteins which interact with ligands and mediate cell-cell bindings. Possibly, the AM are involved in the spermatozoal adhesion to oocytes. Human spermatozoa showed several adhesion molecules on their surface: the alpha chains of the beta 1-integrins VLA alpha 4 (CDw 49d), VLA alpha 5 (CDw 49e) and VLA alpha 6 (CDw 49f), the beta-chain of beta 2-integrins (CD 18) and the matrix proteins laminin and fibronectin. Semen samples with severe teratozoospermia were characterized by a significantly lower percentage (P < 0.01) of spermatozoa with VLA alpha 4, VLA alpha 5 and laminin. VLA alpha 5 (the alpha-chain of the fibronectin receptor) showed the most significant difference between the "normal" and teratozoospermic semen sample groups. This phenomenon could contribute to the explanation of a lower fertilizing capacity of teratozoospermic semen samples.
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PMID:Semen samples with teratozoospermia show a lower percentage of spermatozoa with detectable adhesion molecules (AM). 827 Mar 77

Adhesion and signaling by integrins require their dynamic association with nonintegrin membrane proteins. One such protein, the glycolipid-anchored urokinase receptor (uPAR), associates with and modifies the function of the beta(2)-integrin Mac-1 (CD11b/CD18). In this study, a critical non-I-domain binding site for uPAR on CD11b (M25; residues 424-440) is identified by homology with a phage display peptide known to bind uPAR. Recombinant soluble uPAR and cells expressing uPAR bound to immobilized M25, binding being promoted by urokinase and blocked by soluble M25, but not a scrambled control or homologous peptides from other beta(2)-associated alpha-chains. Mac-1, but not a mutated Mac-1 in which M25 was replaced with the homologous sequence of CD11c, co-precipitated with uPAR. In the beta-propeller model of alpha-chain folding, M25 spans an exposed loop on the ligand-binding, upper surface of alphaM, identifying uPAR as an atypical alphaM ligand. Although not blocking ligand binding to Mac-1, M25 (25-100 microM) inhibited leukocyte adhesion to fibrinogen, vitronectin, and cytokine-stimulated endothelial cells. M25 also blocked the association of uPAR with beta(1)-integrins and impaired beta(1)-integrin-dependent spreading and migration of human vascular smooth muscle cells on fibronectin and collagen. These observations indicate that uPAR associates with integrins directly and that disruption of this association broadly impairs integrin function, suggesting a novel strategy for regulation of integrins in the settings of inflammation and tumor progression.
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PMID:Identification of a urokinase receptor-integrin interaction site. Promiscuous regulator of integrin function. 1074 8

Apoptotic cells are regarded as inert bodies that turn off intracellular processes and functional capabilities. The objective was to study adhesion by eosinophils in relation to the apoptotic process. Eosinophils were cultured for up to 72 h. The living cells were separated from the apoptotic cells, and their adhesion to transfected cell lines expressing vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin and laminin was measured. To relate the functional studies with cell structure, the surface receptor expression of beta1- and beta2-integrins was investigated by flow cytometry. Apoptotic eosinophils evidenced an increased expression of the alpha-chain of the laminin receptor and CD49f and an increased ability to adhere to a laminin-coated surface. Adhesion to the endothelial cell adhesion receptors E-selectin, VCAM-1 and ICAM-1 was absent in apoptotic eosinophils and was paralleled by a low expression of CD11b, CD29, CD49d and CD66b. The specifically increased adhesion to laminin and expression of the laminin receptor alpha-chain is a unique feature of apoptotic eosinophils. When an eosinophil goes into apoptosis, it still possesses the ability to interact with its environment. Our results point to new ideas as to how the apoptotic eosinophil behaves in apoptosis.
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PMID:Enhanced adhesion to laminin by apoptotic eosinophils. 1450 6

The generation of drug conjugates for safe and effective tumor targeting requires binding proteins tolerant to functionalization by rational engineering. Here, we show that Designed Ankyrin Repeat Proteins (DARPins), a novel class of binding proteins not derived from antibodies, can be used as building blocks for facile orthogonal assembly of bioconjugates for tumor targeting with tailored properties. DARPin Ec1, which targets the Epithelial Cell Adhesion Molecule (EpCAM), was genetically modified with a C-terminal cysteine for conjugation of the small molecule cytotoxin monomethylauristatin F (MMAF). In addition, it was N-terminally functionalized by metabolic introduction of the non-natural amino acid azidohomoalanine to enable linkage of site-specifically dibenzocyclooctyne-modified mouse serum albumin (MSA) for half-life extension using Cu(I)-free click chemistry. The conjugate MSA-Ec1-MMAF was assembled to obtain high yields of a pure and stable drug conjugate as confirmed by various analytical methods and in functional assays. The orthogonality of the assembly led to a defined reaction product and preserved the functional properties of all modules, including EpCAM-specific binding and internalization, FcRn binding mediated by MSA, and cytotoxic potency. Linkage of MMAF to the DARPin increased receptor-specific uptake of the drug while decreasing nonspecific uptake, and further coupling of the conjugate to MSA enhanced this effect. In mice, albumin conjugation increased the serum half-life from 11 min to 17.4 h, resulting in a more than 22-fold increase in the area-under-the-curve (AUC). Our data demonstrate the promise of the DARPin format for facile modular assembly of drug conjugates with improved pharmacokinetic performance for tumor targeting.
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PMID:Orthogonal assembly of a designed ankyrin repeat protein-cytotoxin conjugate with a clickable serum albumin module for half-life extension. 2416 70


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