NKT cell-mediated modulation of autoimmune diabetes

NKT 细胞介导的自身免疫性糖尿病调节

• 批准号: 7036034
• 负责人: MARIKA MC FALCONE
• 金额: $ 10.8万
• 依托单位: FONDAZONE CENT/SAN RAFFAELE/DEL MONTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036034
• 关键词: CD1 molecule; NOD mouse; T cell receptor; T lymphocyte; autoimmunity; cell cell interaction; cytokine; dendritic cells; disease /disorder etiology; flow cytometry; gene environment interaction; gene expression; gene expression profiling; genetically modified animals; immune tolerance /unresponsiveness; immunosuppression; insulin dependent diabetes mellitus; leukocyte activation /transformation; lymph nodes; microarray technology; natural killer cells; pancreatic islets; pathologic process; phenotype

DESCRIPTION (provided by applicant): Self-reactive T cells that escape negative selection in the thymus are potentially activated in the course of common infections. In order to avoid autoimmune diseases, the immune system developed several mechanisms to limit adaptive immune responses, including self-reactive ones, to the clearance of pathogens. Natural Killer (NK) T cells play a key role for regulation of adaptive immunity and are able to avert autoimmune disease in pre-clinical models. It is yet to be determined how NKT cells counter-regulate the pathogenesis of autoimmune diseases such as Type 1 Diabetes (T1D). Knowledge of mechanisms underlying NKT cell-mediated regulation could be instrumental to design new therapy to restore islet tolerance and preserve residual beta cell mass in T1D patients. Most of the difficulties so far encountered by studying those mechanisms could be due to activation and analysis of systemic NKT cells that may not be directly involved in prevention of the autoimmune process. We developed transgenic insCDId NOD mice that express the NKT cell restriction molecule, CD1d, within the pancreatic islets. In our transgenic model, CD1d expression induced local NKT cell activation and modulatory mechanisms that prevented autoimmune diabetes. We will take advantage of our unique transgenic model to analyze mechanisms by which NKT cells alter immunity within pancreatic tissues to perturb diabetogenesis. Specifically, we will address the following questions: Aim 1: Is a specific cytokine phenotype of NKT cells required for protection from autoimmune diabetes? We will analyze whether NKT cells, recruited to the site of autoimmunity by CD1d expression, carry a specific cytokine profile. Aim 2: Is the cytokine/chemokine microenvironment altered by activation of NKT cells within pancreatic islets? We will assess whether NKT cells locally alter the cytokine/chemokine profile towards a protective type that limits the inflammatory lymphocyte infiltration and favor recruitment of immune cells with regulatory function. Aim 3: Do NKT cells down regulate islet-reactive T cell responses by modulating dendritic cell (DC) function? We will address whether regulatory NKT cells modulate maturation state and tolerogenic function of DC. Aim 4: Do NKT cells favor recruitment of regulatory T cells such as Tr1 and CD4+CD25+ cells? We will test whether NKT cells, by acting on DC or the cytokine/chemokine environment, promote recruitment of T cell subsets able to suppress self-reactive T cells.

描述（由申请人提供）：在常见感染过程中可能会激活避免胸腺阴性选择的自反应性T细胞。为了避免自身免疫性疾病，免疫系统开发了多种机制，以将适应性免疫反应（包括自我反应性）限制为病原体的清除。天然杀手（NK）T细胞在调节适应性免疫方面起关键作用，并能够在临床前模型中避免自身免疫性疾病。 NKT细胞如何应对自身免疫性疾病（例如1型糖尿病（T1D））的发病机理尚未确定。了解NKT细胞介导的调节的机制知识可能对设计新疗法来恢复胰岛耐受性并保留T1D患者中残留的β细胞量。迄今为止，通过研究这些机制遇到的大多数困难可能是由于对可能与预防自身免疫性过程无直接涉及的全身性NKT细胞的分析所致。我们开发了胰岛中表达NKT细胞限制分子CD1D的转基因INSCDID小鼠。在我们的转基因模型中，CD1D表达诱导了预防自身免疫性糖尿病的局部NKT细胞激活和调节机制。我们将利用我们独特的转基因模型来分析NKT细胞改变胰腺组织内免疫的机制，以扰动糖尿病发生。具体来说，我们将解决以下问题：目标1：保护免受自身免疫性糖尿病所需的NKT细胞的特定细胞因子表型？我们将分析通过CD1D表达招募到自身免疫部位的NKT细胞是否具有特定的细胞因子谱。目标2：胰岛中NKT细胞的激活改变了细胞因子/趋化因子微环境？我们将评估NKT细胞是否在局部将细胞因子/趋化因子谱转换为一种保护性类型，该保护类型限制了炎症性淋巴细胞浸润并有利于具有调节功能的免疫细胞募集。 AIM 3：NKT细胞是否通过调节树突细胞（DC）功能来调节胰岛反应性T细胞反应？我们将解决调节性NKT细胞是否调节DC的成熟状态和耐受功能。目标4：NKT细胞是否有利于募集调节性T细胞（例如TR1和CD4+ CD25+细胞）？我们将通过作用于DC或细胞因子/趋化因子环境来测试NKT细胞是否促进能够抑制自反应性T细胞的T细胞亚群的募集。