Neuropeptides as Mediators of Th2-type Immunity

描述（由申请人提供）：中枢神经系统和免疫系统之间的双向通信是通过共同的配体和受体介导的，即细胞因子、激素和神经肽。有充分的证据表明，神经肽VlP和PACAP通过对巨噬细胞的作用来影响先天免疫。然而，VlP/PACAP在树突状细胞（DC）和小胶质细胞的成熟和活性中的作用尚不清楚，树突状细胞和小胶质细胞是外周和中枢神经系统先天免疫和抗原呈递的主要参与者。尽管树突状细胞和小胶质细胞对病原体的消除至关重要，但不受限制的激活会导致组织破坏。有许多例子表明dc与自身免疫性疾病有关，如SLE、RA、MS、胰岛素缺乏型糖尿病。dc和小胶质细胞刺激和再激活T细胞，促进促炎Th1效应物的产生和积累。内源性药物，如抗炎细胞因子、糖皮质激素、前列腺素，通过使抗原呈递细胞失活和促进Th2免疫来限制免疫反应。本研究的核心假设是，VlP和PACAP抑制dc和小胶质细胞的先天免疫反应，阻止促炎细胞因子和趋化因子（CK）的产生，降低它们激活T细胞的能力，并使效应T细胞偏向Th2反应。Specific Aim I主要关注VlP/PACAP对dc的影响，包括特异性细胞因子和CK的产生、CK受体的表达和dc的定向迁移、刺激/共刺激分子的表达和T细胞活化。特异性Aim II在两种小胶质细胞激活模型中解决了类似的问题，LPS刺激主要诱导先天免疫反应，GM-CSF治疗导致类似dc的小胶质细胞。在特异性目的ii中，我们评估了VlP/PACAP作为诱导dc和小胶质细胞促进Th2效应积累和反应的药物。这些研究将有助于更好地理解神经肽的生理相关性，特别是在建立和维持免疫偏差方面，并有助于未来开发适当的受体激动剂，以限制先天炎症反应，并逆转外周和中枢神经系统自身免疫性疾病中主要的Th1反应。

DESCRIPTION (provided by applicant): Bi-directional communications between the CNS and the immune system are mediated through common ligands and receptors, i.e. cytokines, hormones, and neuropeptides. There is ample evidence that the neuropeptides VlP and PACAP affect innate immunity through their effect on macrophages. However, the role of VlP/PACAP in the maturation and activity of dendritic cells (DC) and microglia, major participants in innate immunity and antigen presentation in the periphery and CNS, is not known. Although DCs and microglia are essential for pathogen elimination, unrestrained activation leads to tissue destruction. There are numerous examples of DCs involvement in autoimmune diseases, such as SLE, RA, MS, insulin-deficient diabetes. DCs and microglia stimulate and reactivate T cells, and promote the generation and accumulation of pro-inflammatory Th1 effectors. Endogenous agents such as anti-inflammatory cytokines, glucocorticoids, prostaglandins, limit the immune response by deactivating the antigen presenting cells, and promoting Th2 immunity. The central hypothesis in this proposal is that VlP and PACAP inhibit the innate immune response of DCs and microglia, preventing pro-inflammatory cytokine and chemokine (CK) production, reduce their capacity to activate T cells, and bias effector T cells towards Th2 responses. Specific Aim I is focused on the effects of VlP/PACAP on DCs, including production of specific cytokines and CK, expression of CK receptors and directed migration of DCs, expression of stimulatory/costimulatory molecules and T cell activation. Specific Aim II addresses similar questions in two models of microglial activation, LPS stimulation that induces primarily an innate immune response, and GM-CSF treatment resulting in DC-resembling microglia. In Specific Aim Ill we evaluate VlP/PACAP as agents that induce DCs and microglia to promote the Th2 effector accumulation and response. These studies will contribute to a better understanding of the physiological relevance of neuropeptides, particularly in establishing and maintaining immune deviation, and to the future development of appropriate receptor agonists with the capacity to limit innate inflammatory responses, and to reverse the predominant Th1 response in autoimmune diseases in the periphery and the CNS.