Mechanisms of Tolerance Induction by Immunostimulatory *

描述（由申请人提供）：给予免疫刺激寡核苷酸序列（ISS-ODN，也称为CpG-ODN）抑制实验性哮喘。这种保护作用是短暂的，持续几周。我们最近发现，ISS-ODN诱导高水平的肺吲哚胺2,3-双加氧酶（IDO），这是色氨酸（Trp）代谢的关键酶。我们的初步数据表明，IDO可能通过以器官特异性方式（即肺特异性）通过色氨酸剥夺诱导抗原（即过敏原）刺激的Th2细胞凋亡，从而预防实验性哮喘。根据我们的观察，并与该RFA的探索性相一致，特别是确定已知生物制剂诱导和/或维持免疫耐受的机制，我们将两个具体目标（SA）放在一起。因此，在SA-1中，我们假设短暂耐受性的诱导是由于抗原特异性肺Th2细胞的耗竭和稳态增殖，随着时间的推移补充这个群体，解释了哮喘表型的重新出现。最近发表的数据表明，表达IDO的抗原呈递细胞（APCs）介导T细胞反应的调节作用，并支持T调节性细胞（Treg）的发育。因此，在SA-2中，我们假设，在慢性ova激发小鼠反复服用ISS的条件下，抗原特异性和长期耐受性是继发于Treg细胞的产生和它们在肺部的募集。我们将在一系列体内实验中验证这些假设，使用(1)采用基于移植物的方法，将体外分化的、OVA特异性的转基因Th2细胞转移到wt小鼠和(2)OVA/明淀粉致敏小鼠。本研究结果将通过为ISS-ODN诱导免疫耐受提供分子/生化基础，为控制免疫耐受提供新的见解。此外，这些结果将有助于优化ISS-ODN在未来临床试验中对变应性哮喘患者的治疗效果。

DESCRIPTION (provided by applicant): The administration of immunostimulatory oligonucleotide sequences (ISS-ODN, also known as CpG-ODN) inhibits experimental asthma. This protective effect is transient and lasts for a few weeks. We recently identified that ISS-ODN induces high levels of pulmonary indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism. Our preliminary data suggest that IDO may protect against experimental asthma by inducing apoptosis of antigen (i.e., allergen) stimulated Th2 cells via Trp deprivation in an organ-specific fashion (i.e., lung specific). Based on our observation and aligned with the exploratory nature of this RFA--specifically the identification of mechanisms by which known biological agents induce and/or maintain immune tolerance--we have put together two specific aims (SA). Thus, in SA-1 we hypothesize that the induction of transient tolerance is due to the depletion of antigen-specific pulmonary Th2 cells and that homeostatic proliferation, which replenishes this population with time, accounts for the re-emergence of the asthmatic phenotype. Recent published data indicate that IDO expressing antigen presenting cells (APCs) mediate a regulatory role on T cell responses and support the development of T regulatory (Treg) cells. Thus, in SA-2 we hypothesize that under the conditions of repeated ISS administration to chronically OVA-challenged mice an antigen specific and a long-term tolerance is developed secondary to the generation of Treg cells and their recruitment into the lungs. We will validate these hypotheses in a series of experiments in vivo using (1) an adoptive transfer-based approach of in-vitro differentiated, OVA-specific, transgenic Th2 cells to wt mice and (2) OVA/alum sensitized mice. The results of the proposed studies will offer new insight into controlling immune tolerance by providing the molecular/biochemical basis for tolerance induction by ISS-ODN. Furthermore, these results will help to optimize the therapeutic effects of ISS-ODN in coming clinical trials in patients with allergic asthma.