The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells.
The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells.
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DOI：
10.1186/ar3400
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发表时间：
2011-07-13
影响因子：
4.9
通讯作者：
Buggy JJ
中科院分区：
文献类型：
--
作者：
Chang BY;Huang MM;Francesco M;Chen J;Sokolove J;Magadala P;Robinson WH;Buggy JJ
目的是确定布鲁顿酪氨酸激酶（Btk）选择性抑制剂PCI-32765（目前在淋巴瘤试验的I/II期研究中）在基于关节炎和免疫复合物（IC）的动物模型中的作用，并描述潜在的细胞机制。在一系列鼠IC疾病模型中给予PCI-32765，包括胶原诱导的关节炎（CIA）、胶原抗体诱导的关节炎（CAIA）、逆转被动过敏反应（RPA）和被动皮肤过敏反应（PCA）。治疗后检查每个模型的临床和病理特征。PCI-32765随后在使用与关节炎发病机制相关的免疫细胞的测定中进行检查，并且其中Btk被认为发挥功能性作用。这些包括B细胞中的增殖和钙动员、单核细胞/巨噬细胞中的细胞因子和趋化因子产生、肥大细胞的脱粒及其随后的细胞因子/趋化因子产生。PCI-32765在治疗性CIA模型中以2.6 mg/kg/天的ED 50剂量依赖性和有效地逆转关节炎炎症。PCI-32765还预防CAIA模型中的临床关节炎。在这两种模型中，单核细胞和巨噬细胞向滑膜中的浸润被完全抑制，重要的是，关节的骨和软骨完整性得以保留。PCI-32765在Arthus和PCA测定中减少炎症。在体外，PCI-32765抑制BCR激活的原代B细胞增殖（IC 50 = 8 nM）。FcγR刺激后，PCI-32765抑制原代单核细胞中TNFα、IL-1β和IL-6的产生（IC 50分别为2.6、0.5、3.9 nM）。在FcεRI刺激培养的人肥大细胞后，PCI-32765抑制组胺、PGD 2、TNF-α、IL-8和MCP-1的释放。PCI-32765在CIA和不依赖于来自B细胞的自身抗体产生的IC模型中有效。因此，PCI-32765不仅靶向B淋巴细胞，而且靶向单核细胞、巨噬细胞和肥大细胞，它们是关节炎中重要的表达Btk的效应细胞。
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. 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/chemokine production. PCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED50 of 2.6 mg/kg/day. PCI-32765 also prevented clinical arthritis in CAIA models. In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved. PCI-32765 reduced inflammation in the Arthus and PCA assays. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC50 = 8 nM). Following FcγR stimulation, PCI-32765 inhibited TNFα, IL-1β and IL-6 production in primary monocytes (IC50 = 2.6, 0.5, 3.9 nM, respectively). Following FcεRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD2, TNF-α, IL-8 and MCP-1. PCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells. Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells, which are important Btk-expressing effector cells in arthritis.
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影响因子：
2.3
作者：
Lindstrom, Tamsin M.;Robinson, William H.
通讯作者：
Robinson, William H.
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
影响因子：
6.1
作者：
Lappalainen, J.;Lindstedt, K. A.;Kovanen, P. T.
通讯作者：
Kovanen, P. T.
影响因子：
20.3
作者：
Mangla, A;Khare, A;Rath, S
通讯作者：
Rath, S
用重组巨噬细胞刺激因子培养的人类单核细胞的抗体依赖性抗肿瘤细胞毒性。同位素释放分析未检测到有效抗体介导的抗体细胞毒性。
影响因子：
15.3
作者：
MUNN, DH;CHEUNG, NKV
通讯作者：
CHEUNG, NKV