CpG-mediated dampening of the effector phase of arthritis

CpG 介导的关节炎效应期抑制

• 批准号: 7666942
• 负责人: DIANE J MATHIS
• 金额: $ 54.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7666942
• 关键词: Alleles; Antibodies; Antigen-Antibody Complex; Arthritis; B-Lymphocytes; Back; Binding; Blood Vessels; CXCR4 gene; Characteristics; Clinical; Clinical Trials; Complement; Complement Activation; Data; Dendritic Cells; Deposition; Development; Disease; Down-Regulation; Elements; Employee Strikes; Etiology; Event; Extravasation; Fc Receptor; Gene Expression; Genes; Genetic; Genetic Phenomena; Health; Human; Inflammatory; Injection of therapeutic agent; Interferon Type II; Interferons; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-2; Interleukins; Joints; K/BxN model; Lesion; Leukocytes; Maps; Mediating; Molecular; Molecular Profiling; Mouse Strains; Mus; Natural Killer Cells; Nucleotides; Pain; Pathogenesis; Patients; Pattern; Performance; Phase; Phenotype; Play; Prevention; Preventive; Production; Recombinants; Resistance; Rheumatoid Arthritis; Role; Serum; Signal Transduction; System; TLR9 gene; Testing; Therapeutic; Toll-like receptors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Waxes; cell type; cytokine; disability; human TNF protein; macrophage; mast cell; migration; mouse model; neutrophil; novel; pathogen; receptor expression; research study

Rheumatoid arthritis (RA) is an important health problem, causing significant pain, disability and financial burden. Unfortunately, its etiology and pathogenesis remain enigmatic, restricting the rational choice of therapeutic strategies. Appreciation of a crucial role for B cells and the antibodies they produce has waxed and waned over the years but, of late, these players have moved back into the limelight, primarily because of the recent positive clinical results using anti-CD20. The K/BxN mouse model of inflammatory arthritis highlights the role of B cells and antibodies. Particularly convenient is an adaptation wherein transfer of serum from arthritic mice into normal recipients rapidly, robustly and repeatedly induces arthritis. Preliminary data indicate that engagement of Toll-like receptors (TLRs) by pathogen-associated molecule patterns can have a striking positive or negative impact on K/BxN serum-transferred arthritis. In particular, injection of certain CpG-containing oligodeoxynucleotides (ODNs) in either a preventive or therapeutic mode inhibits arthritis development or progression. This is an early effect, exerting its impact between the characteristic opening of the vasculature and initiation of the inflammatory cascade signaled by immune complex deposition, complement activation and leukocyte invasion. It requires interleukin-12p35, interferon (IFN)-gamma and TLR9, and also appears to depend on both natural killer and dendritic cells. The CpG-mediated inhibitory effect is mimicked by systemic injection of IFN-gamma. It operates in the prototypical C57BI/6 strain, but not in the Balb/c. Here we propose to explore the cellular and molecular mechanisms underlying CpG-promoted protection from K/BxN serum-transferred arthritis, and to dissect genetic influences on them. More specifically, we aim to: Determine how ODN1668 promotes IFN-gamma production, Elucidate events downstream of IFN-gamma production, Determine why Balb/c mice resist the inhibitory effect of ODN1668. An encouraging performance by recombinant human IFN-gamma in several small clinical trials on RA patients in the 1980s and 1990s suggests that results from the studies proposed may have validity in the human system, despite some known differences in TLR expression and downstream elements.

类风湿关节炎（RA）是一个重要的健康问题，导致严重的疼痛，残疾和财务状况 负担。不幸的是，它的病因和发病机理仍然神秘，限制了合理的选择 治疗策略。对B细胞的关键作用及其产生的抗体的欣赏已有上蜡 这些年来逐渐减弱，但最近，这些球员已经回到了众人瞩目的焦点，主要是因为 使用抗CD20的最近阳性临床结果。炎症性关节炎的K/BXN小鼠模型 突出了B细胞和抗体的作用。特别方便的是适应 关节炎小鼠的血清迅速，健壮和反复诱导关节炎。 初步数据表明，与病原体相关的分子的收费样受体（TLR）的参与 模式可能会对K/BXN血清转移关节炎产生巨大的阳性或负面影响。尤其， 在预防或治疗中注入某些含有CPG的寡脱氧核苷酸（ODN） 模式抑制关节炎的发育或进展。这是一种早期效果，在 脉管系统的特征开放和免疫信号的炎症级联 复杂的沉积，补体激活和白细胞侵袭。它需要interleukin-12p35， 干扰素（IFN）-gamma和TLR9，并且似乎还取决于天然杀手和树突状细胞。这 CPG介导的抑制作用通过全身注射IFN-GAMMA模仿。它在原型中运行 C57BI/6应变，但在BALB/c中没有。在这里，我们建议探索细胞和分子机制 基本的CPG促进的保护免受K/BXN血清转移关节炎的保护，并剖析遗传 影响它们。更具体地说，我们的目标是：确定ODN1668如何促进IFN-Gamma的产生， 阐明IFN-gamma产生下游的事件，确定为什么BALB/C小鼠抵抗ODN1668的抑制作用。在1980年代和1990年代对RA患者的几项小型临床试验中，重组人IFN-Gamma的令人鼓舞的表现表明，提出的研究的结果可能具有人类的有效性 系统，尽管TLR表达和下游元素有一些已知差异。