Inhibitory Receptors and Autoimmune Arthritis

风湿性关节炎（RA）是一种以自身免疫为特征的炎症性疾病。 我们提出了一种新的方法，通过上调和激活 称为白细胞相关免疫球蛋白样受体的天然抑制性受体 （LAIR）。其中之一，LAIR-1（也称为CD 305）作为一种负调节因子， 免疫细胞受体信号传导，表明激活LAIR-1受体可能导致 减少自身免疫活性和较轻的疾病与RA患者。我们有 进一步证明了用维生素D培养增加了CD 4 + T细胞上的LAIR-1。的 发现了一种由P450 SCC启动的新的开环类固醇生成途径， 维生素D3羟基衍生物为治疗RA开辟了新的选择。我们预测 通过使用新的维生素D3羟基衍生物上调Lair-1可能导致 使用比目前可用的更安全的疗法减轻关节炎的严重程度。 我们提出了一套实验使用小鼠模型的自身免疫性关节炎。我们 中心假设是炎症可以通过刺激 抑制性受体LAIR-1和维生素D及其类似物增强了这种作用 通过上调LAIR-1抑制。我们还认为， 20（OH）D3将与维生素D3的经典形式一样有效且毒性更小 [1，25（OH）2D3]。为了了解抑制性受体减弱 我们提出以下具体目标：具体目标1：测试 LAIR-1抑制性受体激活导致T细胞抑制的假设 细胞因子的产生，维生素D或非钙离子能增强抑制作用。 20（OH）D3类似物。具体目标2。确定LAIR-1的激活是否会 减轻自身免疫性关节炎，维生素D或20（OH）D3是否增强了这种作用 使用两种关节炎小鼠模型：胶原诱导的关节炎（CIA）和IL-1 受体拮抗剂缺乏IL-1 Rn-/-自发性关节炎模型（SAD）。具体 目标3：为了验证LAIR-1的上调导致T细胞增殖抑制的假设， 通过抑制经典T细胞通路和改变T细胞细胞因子来进行信号传导 维生素D或20（OH）D3将增强这种效果。成功 这些实验的完成将阐明用 新的维生素D类似物导致抑制性受体LAIR-1的上调，最终 诱导抑制细胞因子分泌和预防关节炎。

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.