Neuropeptides and Regulatory T cells

神经肽和调节性 T 细胞

• 批准号: 6926277
• 负责人: Doina Ganea
• 金额: $ 24.82万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 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 2005-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926277
• 关键词: CD4 molecule; autoimmunity; cell cell interaction; cell differentiation; cell growth regulation; cell migration; chemical structure function; dendritic cells; developmental immunology; experimental allergic encephalomyelitis; flow cytometry; genetically modified animals; immune tolerance /unresponsiveness; inflammation; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; neuroimmunomodulation; neuropeptide receptor; neuropeptides; neuroregulation; rheumatoid arthritis; suppressor T lymphocyte; vasoactive intestinal peptide

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外源性或内源性抗原识别异常引起的耐受性破坏引起的。细胞和分子机制的网络在对自身抗原的耐受限度内不断调整免疫应答。最近，调节性T细胞（Treg）被认为在维持耐受性和重建免疫稳态方面至关重要。尽管最近的努力，但是仍然存在许多未回答的问题，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。CNS和免疫系统之间的神经免疫相互作用通过可溶性因子如细胞因子、趋化因子、神经肽和神经递质介导。虽然大量的研究证明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/或活化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）和垂体腺苷酸环化酶激活多肽（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/或活化，Treg然后在实施VIP/PACAP抗炎功能中起重要作用。在前两个具体的目标，我们建议调查的生成和/或激活的Treg VIP/PACAP在体内和体外，VIP/PACAP诱导的Treg的表型，抗原特异性，和抑制机制方面的特征，并评估树突状细胞在VIP/PACAP诱导Treg的作用。在第三个具体目标，我们建议扩展我们的调查到两个模型的Th 1为主的自身免疫性疾病。我们将评估Treg在VIP/PACAP在EAE和胶原诱导的关节炎中的保护作用中的作用，最终目标是为治疗自身免疫性疾病建立新的治疗途径。