the bruton tyrosine kinase inhibitor pci-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells布鲁顿酪氨酸激酶抑制剂的pci - 32765改善自身免疫性关节炎多效应细胞的抑制作用.pdf

The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells Chang et al. Chang et al. Arthritis Research Therapy 2011, 13:R115 /content/13/4/R115 (13 July 2011) Chang et al. Arthritis Research Therapy 2011, 13:R115 /content/13/4/R115 RESEARCH ARTICLE Open Access The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells 1* 1 1 1 2,3 1 Betty Y Chang , Min Mei Huang , Michelle Francesco , Jun Chen , Jeremy Sokolove , Padmaja Magadala , William H Robinson2,3 and Joseph J Buggy1 Abstract Introduction: The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms. Methods: PCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA). Clinical and pathologic features characteristic of each model were examined following treatment. PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role. These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemoki