Mast cells are positioned in the asthmatic airways so that they are able to respond to the inhaled environment. During active disease, the cells are primed to secrete an array of preformed and newly generated inflammatory mediators including histamine, neutral proteases and heparin sulphate, prostaglandins and cysteinyl leukotrienes as well as an array of cytokines and chemokines that are involved in leucocyte recruitment and activation. These cells are a potent source of mediators in both allergen‐ and exercise‐induced asthma and possibly in asthma provoked by other stimuli such as adenosine and inhaled air pollutants. The important role played by mast cells in maintaining airway dysfunction in asthma is underpinned by the efficacy of mediator inhibitors, such as those interfering with the release or action of the leukotrienes, agents that inhibit mast cell activation such as sodium cromoglycate and the recently studied E‐20 humanized monoclonal antibody that binds to and removes IgE. The recent discovery of novel inhibitory pathways involving inhibitory motifs (ITIMS) on critical cell surface signalling molecules has opened up new possibilities for preventing mast cell activation. Future research will focus on more effective ways for inhibiting the mast cell's contribution to asthma and understanding what role this unique cell has in the pathogenesis of airway wall remodelling.

1998-06-01·Journal of Clinical Investigation1区 · 医学

Leukocyte Adhesion Deficiency Type II is a generalized defect of de novo GDP-fucose biosynthesis. Endothelial cell fucosylation is not required for neutrophil rolling on human nonlymphoid endothelium.

1区 · 医学

Article

作者: Naomi Lannir ; Carol J. Cornejo ; Barbara R. Schwartz ; Hans D. Ochs ; Robert K. Winn ; John M. Harlan ; William Way ; Ruth Gershoni-Baruch ; Aly Karsan ; Amos Etzioni

Leukocyte Adhesion Deficiency Type II (LAD II) is a recently described syndrome and the two patients with this defect lack fucosylated glycoconjugates. These glycoconjugates include the selectin ligand, sialyl LewisX, and various fucosylated blood group antigens. To date, the molecular anomaly in these patients has not been identified. We localized the defect in LAD II to the de novo pathway of GDP-fucose biosynthesis, by inducing cell-surface expression of fucosylated glycoconjugates after exposure of lymphoblastoid cell lines from the LAD II patients to exogenous fucose. This defect is not restricted to hematopoietic cells, since similar findings were elicited in both human umbilical vein endothelial cells (HUVEC) and fibroblasts derived from an affected abortus. We have used these LAD II endothelial cells to examine the consequence of fucosylation of endothelial cells on the rolling of normal neutrophils in an in vitro assay. Neutrophil rolling on LPS-treated normal and LAD II HUVEC was inhibited by an E-selectin monoclonal antibody at both high and low shear rates. LAD II HUVEC lacking fucosylated glycoproteins supported leukocyte rolling to a similar degree as normal HUVEC or LAD II cells that were fucose-fed. At low shear rates, an L-selectin antibody inhibited neutrophil rolling to a similar degree whether the LAD II cells had been fucose-fed or not. These findings suggest that fucosylation of nonlymphoid endothelial cells does not play a major role in neutrophil rolling and that fucose is not a critical moiety on the L-selectin ligand(s) on endothelial cells of the systemic vasculature.

1995-11-01·Journal of Clinical Immunology2区 · 医学

Modulation of adhesion molecules by cytokinesin vivo using human/severe combined immunodeficient (SCID) mouse chimeras

2区 · 医学

Article

作者: Horng Chin Yan ; John Williams ; Melpo Christofidou-Solomidou ; Istvan Juhasz ; Joseph M. Pilewski ; Steven M. Albelda ; George F. Murphy

Endothelial cell-leukocyte interactions involve multiple cell adhesion molecules acting in a programmed and sequential manner to create a leukocyte-endothelial cell adhesion cascade. To understand this process fully, in vivo models are needed. To accomplish this, we have transplanted pieces of normal human tissues onto immunodeficient mice to create chimeric animals. In one model, human skin is grafted and closely resembles normal skin histologically. The grafts retain their human vasculature and show low baseline expression of E-selectin, vascular cell adhesion molecule-1, and intercellular cell adhesion molecule-1. After intradermal injection of human cytokines, these cell adhesion molecules are markedly upregulated and an active inflammatory reaction ensues, with migration of murine leukocytes. Intravenous injection of an anti-human E-selectin antibody completely inhibits leukocyte accumulation induced by tumor necrosis factor-alpha but only partially inhibits leukotriene B4-induced inflammation. In a second model, human bronchus was successfully transplanted heterotopically into severe combined immunodeficient mice. Injection of tumor necrosis factor induced upregulation of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 in the submucosal microvessels, with slightly different kinetics than in the skin. In conclusion, human-severe combined immunodeficient chimeric mice represent a useful model system to study the regulation and function of human cell adhesion molecules in an in vivo setting.

100 项与 E-selectin targeting humanized antibody(Lifearc) 相关的药物交易

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