Neuropeptides and Regulatory T cells

神经肽和调节性 T 细胞

• 批准号: 7237873
• 负责人: Doina Ganea
• 金额: $ 29.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237873
• 关键词: Address; Affect; Agreement; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Apoptosis; Autoantigens; Autoimmune Diseases; Autoimmunity; Award; Binding; Bone Marrow; Brain; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Collagen Arthritis; Data; Dendritic Cells; Development; Disease; Equilibrium; Experimental Autoimmune Encephalomyelitis; Eye; Funding; Generations; Goals; Grant; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunomodulators; In Vitro; Inflammatory; Investigation; Lymphoid; MeSH Thesaurus; Mediating; Mediator of activation protein; Melanocyte stimulating hormone; Microglia; Modeling; Molecular; Mus; Natural Immunity; Nature; Neurohormones; Neuropeptides; Neurotransmitters; Numbers; Organ; POMC gene; Phenotype; Physiological; Play; Population; Prevalence; Recruitment Activity; Regulation; Reporting; Research; Rheumatoid Arthritis; Role; Septic Shock; Series; Site; Specificity; Staging; Stress; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Thinking; Tissues; Title; Transgenic Organisms; Transplantation; United States National Institutes of Health; Vasoactive Intestinal Peptide; alpha-Melanocyte stimulating hormone; anterior chamber; base; chemokine; concept; cytokine; immune function; in vivo; macrophage; novel therapeutics; pituitary adenylate cyclase activating polypeptide; prevent; protective effect; receptor; reproductive; research study; response; vasoactive intestinal peptide 2 receptor

DESCRIPTION (provided by applicant): Autoimmune diseases are thought to result from breaks in tolerance, brought upon by abnormalities in the recognition of exogenous or endogenous antigens. A network of cellular and molecular mechanisms constantly adjusts the immune response within the limits of tolerance for self-antigens. Recently, regulatory T cells (Treg) have been recognized as essential in maintaining tolerance, and in re-establishing immune homeostasis. In spite of recent efforts, many unanswered questions remain however, particularly regarding the nature of cells/factors/mechanisms that control the generation and/or activity of antigen-specific Treg. Neuroimmune interactions between the CNS and the immune system are mediated through soluble factors such as cytokines, chemokines, neuropeptides, and neurotransmitters. Although a large number of studies attest to the role of neuropeptides as immunomodulators, the question whether they contribute to the generation and/or activation of Treg has not been addressed. We reported previously on the potent anti-inflammatory effect of the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) both in vivo and in vitro. The central hypothesis of this proposal is that VIP and PACAP induce the generation and/or activation of Treg, which then play an essential role in implementing the VIP/PACAP anti-inflammatory functions. In the first two specific aims, we propose to investigate the generation and/or activation of Treg by VIP/PACAP in vivo and in vitro, to characterize the VIP/PACAP-induced Treg in terms of phenotype, antigen-specificity, and mechanisms for suppression, and to evaluate the role of dendritic cells in the induction of Treg by VIP/PACAP. In the third specific aim, we propose to extend our investigation into two models of Th1-dominated autoimmune diseases. We will evaluate the role of Treg in the protective effect of VIP/PACAP in EAE and collagen-induced arthritis, with the ultimate goal of establishing new therapeutic avenues for the treatment of autoimmune diseases.

描述(由申请人提供)：自身免疫性疾病被认为是由于对外源性或内源性抗原的识别异常而导致的耐受性中断。细胞和分子机制的网络在自身抗原的耐受性范围内不断调节免疫反应。最近，调节性T细胞(Treg)被认为在维持耐受和重建免疫稳态方面是必不可少的。然而，尽管最近做出了许多努力，许多问题仍然没有得到解答，特别是关于控制抗原特异性Treg的产生和/或活性的细胞/因子/机制的性质。中枢神经系统和免疫系统之间的神经免疫相互作用是通过细胞因子、趋化因子、神经肽和神经递质等可溶性因子介导的。尽管大量研究证实了神经肽作为免疫调节剂的作用，但它们是否有助于Treg的产生和/或激活的问题尚未得到解决。我们先前报道了神经肽血管活性肠肽(VIP)和垂体腺苷环化酶激活多肽(PACAP)在体内和体外的有效抗炎作用。该建议的中心假设是VIP和PACAP诱导Treg的产生和/或激活，Treg在VIP/PACAP的抗炎功能中发挥重要作用。在前两个特定目标中，我们建议研究VIP/PACAP在体内和体外产生和/或激活Treg，从表型、抗原特异性和抑制机制方面表征VIP/PACAP诱导的Treg，并评价树突状细胞在VIP/PACAP诱导Treg中的作用。在第三个具体目标中，我们建议将我们的研究扩展到Th1主导型自身免疫性疾病的两个模型。我们将评估Treg在VIP/PACAP对EAE和胶原诱导的关节炎的保护作用中的作用，最终目标是建立治疗自身免疫性疾病的新的治疗途径。