Inhibitory Receptors and Autoimmune Arthritis

抑制性受体和自身免疫性关节炎

基本信息

批准号：
9729528
负责人：
AE-KYUNG YI
金额：
$ 33.44万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-13 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9729528
关键词：
Affect Animal Model Antibodies Arthritis Attenuated Autoimmune Process Autoimmunity Biochemical Biological Response Modifiers CD3 Antigens CD4 Positive T Lymphocytes Cell Lineage Cell physiology Cells Cholecalciferol Collagen Collagen Arthritis Cytokine Suppression Cytoplasmic Tail DR1 gene Data Disease Etiology Event FOXP3 gene Flow Cytometry Harvest Histologic Immune Immunization Immunize Immunoglobulins Inflammation Inflammatory Inflammatory Response Interferon Type II Interleukin-1 Receptors Interleukin-10 Interleukin-17 Interleukin-4 Joints Lead Leukocytes Ligands MAP Kinase Gene Measures Mediating Methods Modeling Molecular Monoclonal Antibodies Mus PTPN6 gene Pathway interactions Patients Prevention Production Receptor Cell Receptor Signaling Regulation Reporter Rheumatoid Arthritis Role Severities Signal Pathway Signal Transduction Spleen Stains T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Tyrosine Up-Regulation Vitamin D Vitamin D Analog Work analog attenuation autoimmune arthritis base cytokine delta opioid receptor effective therapy experimental study immunoregulation in vivo leukocyte activation lymph nodes mouse model novel receptor recruit response transcription factor treatment strategy

项目摘要

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by autoimmunity. We propose a novel method for suppressing inflammation by upregulating and activating natural inhibitory receptors called leukocyte associated immunoglobulin-like receptors (LAIR). One of these, LAIR-1 (also called CD305) acts as a negative regulator of immune cell receptor signaling, suggesting that activating LAIR-1 receptors may lead to diminished autoimmune activity and less severe disease in patients with RA. We have further demonstrated that culture with vitamin D increases LAIR-1 on CD4+ T cells. The discovery of a new secosteroidogenic pathway initiated by P450scc that produces vitamin D3 hydroxyderivatives has opened new options in treatment for RA. We predict that upregulating Lair-1 by using new vitamin D3 hydroxyderivatives could lead to attenuation of the severity of arthritis using safer therapies than are currently available. We propose a set of experiments using murine models of autoimmune arthritis. Our central hypothesis is that inflammation can be downregulated by stimulation of the inhibitory receptor LAIR-1 and that vitamin D and its analogs enhance this suppression by upregulating LAIR-1. We also believe that the noncalcemic 20(OH)D3 will be as effective and less toxic than the classical form of vitamin D3 [1,25(OH)2D3]. To understand the mechanisms by which inhibitory receptors attenuate inflammation we propose the following specific aims: Specific Aim 1: To test the hypothesis that activation of the LAIR-1 inhibitory receptor leads to suppression of T cell cytokine production and that the inhibition is enhanced by vitamin D or the noncalcemic 20(OH)D3 analog. Specific Aim 2. Determine whether activation of LAIR-1 will attenuate autoimmune arthritis and whether vitamin D or 20(OH)D3 enhances this effect using two mouse models of arthritis: collagen-induced arthritis (CIA) and the IL-1 receptor antagonist deficiency IL-1Rn-/- spontaneous arthritis model (SAD). Specific Aim 3. To test the hypothesis that upregulation of LAIR-1 leads to suppression of T cell signaling by repressing the canonical T cell pathway and altering T cell cytokine production and that vitamin D or 20(OH)D3 will enhance this effect. Successful completion of these experiments will elucidate the mechanisms whereby treatment with new Vit D analogs leads to upregulation of the inhibitory receptor LAIR-1, ultimately inducing suppression of cytokine secretion and prevention of arthritis.

类风湿关节炎（RA）是一种以自身免疫性为特征的炎症性疾病。我们提出了一种通过上调和激活来抑制炎症的新方法天然抑制受体称为白细胞相关免疫球蛋白样受体（巢穴）。其中之一是Lair-1（也称为CD305）充当负调节剂免疫细胞受体信号传导，表明激活Lair-1受体可能导致 RA患者的自身免疫性活性减少和较低的严重疾病。我们有进一步证明，维生素D的培养会增加CD4+ T细胞上的Lair-1。这发现由P450SCC启动的新的肠spotoidation途径维生素D3羟基衍生物为RA治疗开辟了新的选择。我们预测通过使用新的维生素D3羟基衍生物来上调Lair-1可能会导致使用比目前可用的更安全的关节炎严重程度的衰减。我们建议使用自身免疫性关节炎的鼠模型提出一组实验。我们的中心假设是通过刺激可以下调炎症抑制性受体Lair-1和维生素D及其类似物增强了这一点通过上调巢穴1来抑制。我们也相信非钙的 20（OH）D3将比维生素D3的经典形式有效且毒性更低 [1,25（OH）2d3]。了解抑制受体减弱的机制炎症我们提出以下特定目的：特定目的1：测试假设Lair-1抑制受体的激活导致T细胞的抑制细胞因子的产生，并通过维生素D或非钙血症增强了抑制作用 20（OH）D3模拟。具体目标2。确定lair-1的激活是否会减弱自身免疫性关节炎以及维生素D还是20（OH）D3增强了这种效果使用两个小鼠关节炎模型：胶原蛋白诱导的关节炎（CIA）和IL-1 受体拮抗剂缺乏IL-1RN - / - 自发性关节炎模型（SAD）。具体的目的3。检验巢穴1导致T细胞抑制的假设通过抑制规范T细胞途径并改变T细胞因子来传导生产和维生素D或20（OH）D3将增强这种效果。成功的这些实验的完成将阐明与治疗的机制新的vit d类似物导致抑制受体lair-1的上调诱导细胞因子分泌和预防关节炎的抑制。