Elucidating the Mechanisms of Arthritic Flare and Developing Treatments

阐明关节炎发作的机制并开发治疗方法

• 批准号: 10673109
• 负责人: Edward M. Schwarz
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673109
• 关键词: Acute; Adherence; Adoptive Transfer; Adult; Affect; Affective; Animals; Anti-Tumor Necrosis Factor Therapy; Apoptotic; Arthritis; Autoimmune Diseases; B cell therapy; B-Lymphocytes; Biological Markers; Biological Response Modifier Therapy; Blood Vessels; Bromodeoxyuridine; Cell Maintenance; Cells; Characteristics; Chronic; Clinical; Data; Defect; Diagnosis; Disease; Etiology; Failure; Flare; Frequencies; Functional disorder; Funding; Genetic; Grant; Growth; Hand; Homeostasis; ITGAM gene; Image; Immune response; In Vitro; Indocyanine Green; Inflammation; Inflammatory; Inflammatory Arthritis; Investigation; Ipsilateral; Joints; Knee; Label; LoxP-flanked allele; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphocyte; Macrophage; Maintenance; Mediating; Messenger RNA; Morbidity - disease rate; Mus; Muscle Cells; Muscle satellite cell; Myeloid Cells; Nature; Near-infrared optical imaging; Outcome; PDGFB gene; PDGFRB gene; PIK3CG gene; Pain; Pathway interactions; Patients; Peer Review; Pharmaceutical Preparations; Phase; Placebos; Population; Publications; Recovery; Recovery of Function; Recurrent disease; Refractory; Refractory Disease; Rheumatoid Arthritis; Role; Secondary to; Signal Transduction; Signs and Symptoms; Sinus; Swelling; Synovitis; TNF gene; Testing; Tissues; aggressive therapy; anti-CD20; arthropathies; cell injury; clinically significant; collagen antibody induced arthritis; draining lymph node; early onset; experience; functional genomics; hand therapy; human disease; imaging biomarker; improved; in vivo; insight; joint inflammation; loss of function; lymph flow; lymph nodes; lymphatic drainage; lymphatic dysfunction; lymphatic vessel; mortality; mouse model; multidisciplinary; new therapeutic target; novel; prevent; progenitor; recruit; repaired; targeted treatment; theories; translational research program; treatment response

Abstract Rheumatoid arthritis (RA) is a destructive inflammatory joint disease associated with increased morbidity and mortality. While biologic therapies have improved treatment response, unmet clinical needs remain due to the refractory nature of RA, and recurrent disease flares despite aggressive treatment. In the prior funding periods, we developed a multidisciplinary translational research program that combined longitudinal near infrared (NIR) imaging of indocyanine green (ICG) with targeted therapies to elucidate how TNF, B cells and lymphatics converge to trigger arthritic flare in murine models and RA patients. Specifically, we found that prior to RA signs and symptoms, there is an increase in lymphatic vessel (LV) contraction frequency to enhance the efflux of CD11b+ myeloid cells from the affected joints, which ultimately gets overwhelmed at early onset. RA disease proceeds with expansion of joint draining lymph nodes from an influx of unactivated-polyclonal CD23+/CD21hi/CD1d hi B cells in inflamed nodes (Bin) and lymph, until a sudden loss of LV contractions is observed along the ipsilateral axis, which results in lymph node collapse and Bin clogging of the sinuses. Interestingly, knee synovitis following popliteal lymph node (PLN) collapse in TNF-Tg mice is ameliorated by anti- CD20 B cell depletion therapy (BCDT), which restores passive but not active lymph flow. Most recently, we demonstrated that loss of LV contractions in TNF-Tg mice is secondary to activated macrophage adherence to the lymphatic endothelial cells (LEC), and subsequent LEC and lymphatic muscle cell (LMC) damage from chronic inflammation. Remarkably, this major defect can be corrected with anti- TNF therapy that ameliorates the inflammatory-erosive arthritis, and restores LEC-LMC integrity. To further understand the role of lymphatics in arthritic flare, we propose three Specific Aims. In Aim 1 we will demonstrate perivascular LMC progenitor incorporation into PLVs during growth and flare in WT growing mice (homeostasis), and TNF-Tg mice with Expanding vs. Collapsed PLN treated with anti- TNF or placebo. We will also confirm their LMC progenitor potential in adoptive transfer studies in vitro and in vivo. In Aim 2 we will demonstrate the role of PDGF signaling in LMC during the Expanding and Collapsed phases of arthritic progression via functional genomic studies, and genetic loss of function in the setting of acute collagen antibody-induced arthritis and chronic TNF-induced arthritis in mice. To correlate these animal studies with human disease, in Aim 3 we will complete a clinical pilot of RA patients receiving anti-TNF therapy for hand flare, to formally demonstrate the utility of NIR-ICG imaging as a biomarker of LV recovery, and its correlation with response to therapy. Completion of these Specific Aims will substantiate our paradigm-shifting hypothesis of RA flare, and may provide novel insights into refractory disease that can be diagnosed by assessing efferent lymphatics.

抽象的 类风湿关节炎（RA）是与增加有关的破坏性炎症性关节疾病 发病率和死亡率。虽然生物疗法改善了治疗反应，但未完成临床 由于RA的难治性和复发性疾病耀斑的目的地，需求仍然存在 治疗。在以前的资金期间，我们制定了一个多学科翻译研究计划 与靶标的纵向近红外（NIR）成像合并的纵向成像 阐明TNF，B细胞和淋巴细胞如何触发鼠类中的Artritic耀斑的疗法 模型和RA患者。具体来说，我们发现在RA标志和符号之前，有一个 增加淋巴管（LV）收缩频率以增强CD11b+髓样细胞的外排 从受影响的关节中，最终在早期发病时就会不知所措。 RA疾病进行 从未激活的聚会CD23+/CD21HI/CD1D HI的影响的关节排水淋巴结扩展 B细胞发炎的淋巴结（bin）和淋巴，直到观察到LV收缩突然损失 同侧轴，导致淋巴结塌陷和鼻窦堵塞。有趣的是， 在TNF-TG小鼠中popliteal淋巴结（PLN）塌陷后膝盖滑膜炎通过抗抗衡来改善 CD20 B细胞部署疗法（BCDT），它恢复被动但没有活性淋巴流量。最近， 我们证明了TNF-TG小鼠中LV收缩的损失继发于激活的巨噬细胞 遵守淋巴内皮细胞（LEC）以及随后的LEC和淋巴肌肉细胞 （LMC）慢性炎症损害。值得注意的是，该主要缺陷可以通过抗 TNF治疗可改善炎症性渗透性关节炎并恢复LEC-LMC完整性。到 我们提出了三个特定的目标，进一步了解淋巴染在关节炎耀斑中的作用。在目标1中我们 将证明在生长和耀斑期间掺入PLV中的血管周围LMC祖细胞 生长的小鼠（体内平衡）和TNF-TG小鼠，抗抗PLN的肿胀 TNF或安慰剂。我们还将在体外确认其在自适应转移研究中的LMC祖细胞潜力 和体内。在AIM 2中，我们将证明PDGF信号在LMC中的作用 并通过功能基因组研究和遗传丧失的关节性进展崩溃的阶段 在急性胶原抗体诱导的关节炎和慢性TNF诱导关节炎的情况下的功能 老鼠。为了将这些动物研究与人类疾病相关，在AIM 3中，我们将完成临床飞行员 在接受抗TNF治疗的RA患者中，正式证明了NIR-ICG的实用性 成像是LV恢复的生物标志物，及其与治疗反应的相关性。完成 这些具体目标将证实我们的RA耀斑范式假设，并可能提供 对难治性疾病的新见解，可以通过评估有效的淋巴管来诊断。

项目成果

The role of bone marrow edema and lymphangiogenesis in inflammatory-erosive arthritis.

骨髓水肿和淋巴管生成在炎性糜烂性关节炎中的作用。

• DOI: 10.1007/978-1-4419-1050-9_1
• 发表时间: 2010
• 期刊: Advances in experimental medicine and biology
• 作者: Schwarz,EdwardM;Proulx,StevenT;Ritchlin,ChristopherT;Boyce,BrendanF;Xing,Lianping
• 通讯作者: Xing,Lianping

Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis.

• DOI: 10.1038/nrrheum.2017.205
• 发表时间: 2018-03
• 期刊: Nature reviews. Rheumatology
• 作者: Bouta EM;Bell RD;Rahimi H;Xing L;Wood RW;Bingham CO 3rd;Ritchlin CT;Schwarz EM
• 通讯作者: Schwarz EM

Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice.

• DOI: 10.1186/s13075-016-0963-8
• 发表时间: 2016-03-12
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Liang Q;Ju Y;Chen Y;Wang W;Li J;Zhang L;Xu H;Wood RW;Schwarz EM;Boyce BF;Wang Y;Xing L
• 通讯作者: Xing L

Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

• DOI: 10.1002/art.41309
• 发表时间: 2020-10
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Bell RD;White RJ;Garcia-Hernandez ML;Wu E;Rahimi H;Marangoni RG;Slattery P;Duemmel S;Nuzzo M;Huertas N;Yee M;O'Reilly MA;Morrell C;Ritchlin CT;Schwarz EM;Korman BD
• 通讯作者: Korman BD

Single-cell transcriptomics of popliteal lymphatic vessels and peripheral veins reveals altered lymphatic muscle and immune cell populations in the TNF-Tg arthritis model.

• DOI: 10.1186/s13075-022-02730-z
• 发表时间: 2022-03-07
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Kenney HM;Wu CL;Loiselle AE;Xing L;Ritchlin CT;Schwarz EM
• 通讯作者: Schwarz EM