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Publications (9)119.62 Total impact

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    ABSTRACT: alpha 4 beta 1 integrin (VLA-4) appears to be unique among the leukocyte integrins in that it can initiate the adhesion of circulating lymphocytes without cellular activation. It is not known how lymphocytes or other cell types maintain constitutive levels of alpha 4 beta 1 integrin activity. The current report describes a monoclonal antibody, 15/7, that recognizes a high affinity or ligand-occupied conformation of beta 1 integrin. Studies with 15/7 revealed that alpha 4 beta 1 integrin-dependent adhesion of leukocytic cell lines is mediated by a population of low affinity receptors that is conformationally responsive to ligand; the 15/7 epitope could be induced by nanomolar concentrations of soluble VCAM-1 or by micromolar concentrations of a peptide derived from the type III connecting segment domain of fibronectin (as ligands for alpha 4 beta 1 integrin). The same receptors were also responsive to adhesion activating reagents, such as Mn2+, activating anti-beta 1 integrin antibodies, and phorbol myristate acetate, which induced the 15/7 epitope directly and/or decreased the concentration of ligand required for epitope induction. In addition to the responsive receptor pool, cells expressed a second population of alpha 4 beta 1 integrin that was conformationally restrained, failing to respond to ligand or to any of the activating reagents. The relative size of the responsive and inactive receptor pools, as well as the affinity of the responsive receptors, represented a stable phenotype of different cell types and played important roles in defining the cells' adhesive capacity and ligand specificity. Similar receptor populations were measured on lymphocyte subsets in whole blood. These studies provide insight into how cells maintain different constitutive levels of alpha 4 beta 1 integrin activity, and how the activity of beta 1 integrin can be modulated by activators of cell adhesion.
    Journal of Biological Chemistry 01/1996; 270(48):28740-50. DOI:10.1074/jbc.270.48.28740 · 4.60 Impact Factor
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    ABSTRACT: 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.
    Journal of Neuroimmunology 05/1995; 58(1):1-10. DOI:10.1016/0165-5728(94)00165-K · 2.79 Impact Factor
  • Journal of Neuroimmunology 03/1993; 43(1-2):218-218. DOI:10.1016/0165-5728(93)90146-P · 2.79 Impact Factor
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory condition of the central nervous system with similarities to multiple sclerosis. In both diseases, circulating leukocytes penetrate the blood-brain barrier and damage myelin, resulting in impaired nerve conduction and paralysis. We sought to identify the adhesion receptors that mediate the attachment of circulating leukocytes to inflamed brain endothelium in EAE, because this interaction is the first step in leukocyte entry into the central nervous system. Using an in vitro adhesion assay on tissue sections, we found that lymphocytes and monocytes bound selectively to inflamed EAE brain vessels. Binding was inhibited by antibodies against the integrin molecule alpha 4 beta 1, but not by antibodies against numerous other adhesion receptors. When tested in vivo, anti-alpha 4 integrin effectively prevented the accumulation of leukocytes in the central nervous system and the development of EAE. Thus, therapies designed to interfere with alpha 4 beta 1 integrin may be useful in treating inflammatory diseases of the central nervous system, such as multiple sclerosis.
    Nature 04/1992; 356(6364):63-6. DOI:10.1038/356063a0 · 42.35 Impact Factor
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    ABSTRACT: Endothelial cells that make up brain capillaries and constitute the blood-brain barrier become different from peripheral endothelial cells in response to inductive factors found in the nervous system. We have established a cell culture model of the blood-brain barrier by treating brain endothelial cells with a combination of astrocyte-conditioned medium and agents that elevate intracellular cAMP. These cells form high resistance tight junctions and exhibit low rates of paracellular leakage and fluid-phase endocytosis. They also undergo a dramatic structural reorganization as they form tight junctions. Results from these studies suggest modes of manipulating the permeability of the blood-brain barrier, potentially providing the basis for increasing the penetration of drugs into the central nervous system.
    The Journal of Cell Biology 01/1992; 115(6):1725-35. · 9.69 Impact Factor
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    ABSTRACT: EXPERIMENTAL autoimmune encephalomyelitis (EAE) is an inflammatory condition of the central nervous system with similarities to multiple sclerosis1,2. In both diseases, circulating leukocytes penetrate the blood-brain barrier and damage myelin, resulting in impaired nerve conduction and paralysis3-5. We sought to identify the adhesion receptors that mediate the attachment of circulating leukocytes to inflamed brain endothelium in EAE, because this interaction is the first step in leukocyte entry into the central nervous system. Using an in vitro adhesion assay on tissue sections, we found that lymphocytes and monocytes bound selectively to inflamed EAE brain vessels. Binding was inhibited by antibodies against the integrin molecule alpha4betal, but not by antibodies against numerous other adhesion receptors. When tested in vivo, anti-alpha4 integrin effectively prevented the accumulation of leukocytes in the central nervous system and the development of EAE. Thus, therapies designed to interfere with alpha4betal integrin may be useful in treating inflammatory diseases of the central nervous system, such as multiple sclerosis.
    Nature 01/1992; 356:63-66. · 42.35 Impact Factor
  • Annals of the New York Academy of Sciences 02/1991; 633:420-5. DOI:10.1111/j.1749-6632.1991.tb15631.x · 4.31 Impact Factor
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    ABSTRACT: By taking advantage of the extensive homology found in the cytoplasmic domains of several cloned cadherin molecules, we were able to identify two species of cadherins in bovine aortic endothelial cells using the polymerase chain reaction (PCR). The two species of PCR products were subsequently used as DNA probes to isolate the corresponding cDNA clones from bovine adrenal microvascular endothelial cells. Sequence comparison with other characterized cadherin molecules indicates that the major cDNA species encodes a cadherin molecule highly homologous to chicken and mouse N-cadherins, while the minor species is most homologous to mouse and human P-cadherins. Northern blot analysis with the corresponding cDNA probe showed a wide distribution of bovine N-cadherin among non-neuronal, as well as neuronal tissues, while P-cadherin was most abundant in kidney among all the bovine tissues tested, but was undetectable in placenta.
    The EMBO Journal 10/1990; 9(9):2701-8. · 10.75 Impact Factor
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    ABSTRACT: Endothelialcellsthatmake up braincapil- lariesand constitutetheblood-brainbarrierbecome differentfrom peripheralendothelialcellsinresponse to inductivefactorsfound inthenervoussystem.We have establisheda cellculturemodel oftheblood- brainbarrierby treatingbrainendothelialcellswith a combinationofastrocyte-conditioned medium and agentsthatelevateintracellular cAMP Thesecellsform