Neuropeptides as Mediators of Th2-type Immunity

描述（由申请人提供）：CNS和免疫系统之间的双向通信通过共同的配体和受体（即细胞因子、激素和神经肽）介导。有充分的证据表明，神经肽VIP和PACAP通过它们对巨噬细胞的作用来影响先天免疫。然而，VIP/PACAP在树突状细胞（DC）和小胶质细胞（外周和CNS中先天免疫和抗原呈递的主要参与者）的成熟和活性中的作用尚不清楚。虽然DC和小胶质细胞对于病原体消除是必不可少的，但无限制的激活导致组织破坏。有许多DC参与自身免疫性疾病的例子，例如SLE、RA、MS、胰岛素缺乏型糖尿病。DC和小胶质细胞刺激和重新激活T细胞，并促进促炎性Th 1效应物的产生和积累。内源性试剂如抗炎性细胞因子、糖皮质激素、甘草素通过使抗原呈递细胞失活和促进Th 2免疫来限制免疫应答。该提议中的中心假设是VIP和PACAP抑制DC和小胶质细胞的先天免疫应答，防止促炎细胞因子和趋化因子（CK）产生，降低它们活化T细胞的能力，并使效应T细胞偏向Th 2应答。具体目的I主要研究VIP/PACAP对DCs的影响，包括特异性细胞因子和CK的产生、CK受体的表达和DCs的定向迁移、刺激/共刺激分子的表达和T细胞活化。具体目标II解决了小胶质细胞活化的两种模型中的类似问题，LPS刺激主要诱导先天性免疫应答，以及GM-CSF治疗导致DC样小胶质细胞。在Specific Aim III中，我们评估了VIP/PACAP作为诱导DC和小胶质细胞促进Th 2效应物积累和应答的试剂。这些研究将有助于更好地了解神经肽的生理相关性，特别是在建立和维持免疫偏差，并在未来发展适当的受体激动剂的能力，以限制先天性炎症反应，并扭转占主导地位的Th 1反应在外周和中枢神经系统的自身免疫性疾病。

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.