Surgery (RMH) - Research Publications

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Author: HARDER, KENNETH × End date: 2019 ×

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    Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase.
    Odom, S ; Gomez, G ; Kovarova, M ; Furumoto, Y ; Ryan, JJ ; Wright, HV ; Gonzalez-Espinosa, C ; Hibbs, ML ; Harder, KW ; Rivera, J (Rockefeller University Press, 2004-06-07)
    A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn-/- bone marrow-derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn-/- mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn-/- mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcepsilonRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcepsilonRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn-/- mice because both lyn-/- and lyn-/- fyn-/- mice showed high IgE levels. Thus, lyn-/- mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.
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    Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity
    Beavitt, SJE ; Harder, KW ; Kemp, JM ; Jones, J ; Quilici, C ; Casagranda, F ; Lam, E ; Turner, D ; Brennan, S ; Sly, PD ; Tarlinton, DM ; Anderson, GP ; Hibbs, ML (AMER ASSOC IMMUNOLOGISTS, 2005-08-01)
    The etiology of asthma, a chronic inflammatory disorder of the airways, remains obscure, although T cells appear to be central disease mediators. Lyn tyrosine kinase has been implicated as both a facilitator and inhibitor of signaling pathways that play a role in allergic inflammation, although its role in asthma is unclear because Lyn is not expressed in T cells. We show in the present study that Lyn-/- mice develop a severe, persistent inflammatory asthma-like syndrome with lung eosinophilia, mast cell hyperdegranulation, intensified bronchospasm, hyper IgE, and Th2-polarizing dendritic cells. Dendritic cells from Lyn-/- mice have a more immature phenotype, exhibit defective inhibitory signaling pathways, produce less IL-12, and can transfer disease when adoptively transferred into wild-type recipients. Our results show that Lyn regulates the intensity and duration of multiple asthmatic traits and indicate that Lyn is an important negative regulator of Th2 immune responses.