Neuropeptides and Regulatory T cells

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中断引起的。细胞和分子机制的网络在自身抗原耐受的限度内不断调整免疫反应。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中至关重要。尽管最近做出了努力，但仍有许多未解决的问题，特别是关于控制抗原特异性Treg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可溶性因子介导的，如细胞因子、趋化因子、神经肽和神经递质。尽管大量的研究证明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。我们之前报道了血管活性肠肽（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。本研究的核心假设是VIP和PACAP诱导Treg的产生和/或激活，Treg在VIP/PACAP抗炎功能的实现中发挥重要作用。在前两个具体目标中，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，并评估树突状细胞在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两种以th1为主的自身免疫性疾病模型。我们将评估Treg在VIP/PACAP对EAE和胶原性关节炎的保护作用中的作用，最终目的是为自身免疫性疾病的治疗建立新的治疗途径。

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.