Inhibitory Receptors and Autoimmune Arthritis

抑制性受体和自身免疫性关节炎

• 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
• 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

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 天然抑制性受体称为白细胞相关免疫球蛋白样受体 (巢穴)。其中，LAIR-1(也称为CD305)是一种负调控因子。 免疫细胞受体信号，提示激活LAIR-1受体可能导致 RA患者自身免疫活性减弱，病情较轻。我们有 进一步证明，维生素D的培养增加了CD4+T细胞表面LAIR-1的表达。这个 P450scc启动的一条新的促性腺激素生成途径的发现 维生素D3羟基衍生物为RA的治疗开辟了新的选择。我们预测 使用新的维生素D3羟基衍生物上调LAIR-1可能导致 使用比目前可用的更安全的疗法来减轻关节炎的严重性。 我们提出了一系列使用自身免疫性关节炎小鼠模型的实验。我们的 中心假说是炎症可以通过刺激 抑制受体LAIR-1和维生素D及其类似物增强了这一点 上调LAIR-1的抑制作用。我们还认为非钙血症性疾病 20(OH)D3将与经典形式的维生素D3一样有效，毒性更低 [1，25(OH)2D3]。了解抑制性受体衰减的机制 炎症我们提出以下具体目标：具体目标1：检测 激活LAIR-1抑制受体导致T细胞抑制的假说 细胞因子的产生以及维生素D或非钙剂对抑制作用的增强 20(OH)D3类似物。具体目标2.确定激活LAIR-1是否将 减轻自身免疫性关节炎以及维生素D或20(OH)D3是否增强这一作用 使用两种关节炎小鼠模型：胶原性关节炎(CIA)和IL-1 受体拮抗剂缺乏IL-1Rn-/-自发性关节炎模型(SAD)。特定的 目的3.验证LAIR-1上调导致T细胞抑制的假说 抑制规范T细胞途径和改变T细胞细胞因子的信号转导 而维生素D或20(OH)D3会增强这一效果。成功 这些实验的完成将阐明治疗的机制 新的维生素D类似物最终导致抑制性受体LAIR-1的上调 抑制细胞因子分泌，预防关节炎。