Gene therapy targeting the Th17 / IL-27 system in autoimmune exocrinopathy

针对自身免疫性外分泌病的 Th17/IL-27 系统基因治疗

基本信息

批准号：
7895693
负责人：
AMMON B PECK
金额：
$ 18.31万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2011-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895693
关键词：
Acinar Cell Affect Androgens Animal Model Anxiety Appearance Applications Grants Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Cell Lymphomas B-Lymphocytes Biological Biopsy Bladder CD4 Positive T Lymphocytes Cell physiology Cells Cephalic Chronic Clinic Visits Clinical Connective Tissue Diseases Dementia Dendritic Cells Development Diffuse Disease Disease susceptibility Dry Eye Syndromes Epithelial Equilibrium Estrogens Exhibits Exocrine Glands Family Fatigue Fibromyalgia Fluids and Secretions Functional disorder Future Gastrointestinal tract structure Genes Goals Gonadal Steroid Hormones Helper-Inducer T-Lymphocyte Human Immunology Immunotherapy Impaired cognition In Vitro Infiltration Interleukin-17 Kidney Knowledge Lacrimal gland structure Lead Leukocytes Lung Lymphocyte Memory Loss Mental Depression Mental disorders Methods Molecular Mus Natural Immunity Nature Neuropathy Pathway interactions Patients Peripheral Phase Play Population Quality of life Relative (related person)Reporting Research Role Salivary Salivary Glands Sensory Severity of illness Sialadenitis Signal Transduction Pathway Site Sjogren&apos s Syndrome Skin Staining method Stains Submandibular gland Symptoms Syndrome System T memory cell T-Lymphocyte Time Tissues Vagina Viral Vector Woman Work Xerostomia autoimmune exocrinopathy base cytokine fascinate gene therapy insight interest interleukin-23 macrophage memory CD4 T lymphocyte men mouse model novel prevent public health relevance sexual dimorphism systemic autoimmune disease therapeutic target translational study

项目摘要

DESCRIPTION (provided by applicant): Over the past several years, the TH1/TH2 paradigm forming the basis of T cell immunology has expanded rapidly from the discovery of TH17 cells, a subset of CD4+ T memory cells characterized by their unique ability to secrete IL-17 family cytokines. Most importantly, TH17 cells appear to be intimately involved in innate immunity and autoimmunity. Sjvgren's syndrome (SjS) is an autoimmune disease affecting primarily of the salivary and lacrimal glands characterized by exocrine gland dysfunction. In recent years, NOD and NOD-derived mice have been shown to exhibit a disease that closely parallels SjS, including the loss of fluid secretions concomitant with the appearance of leukocyte infiltrates within the salivary and lacrimal glands. This autoimmune exocrinopathy has been separated into two major phases: first, numerous pathophysiologic changes occur within the exocrine glands independent of any autoimmune attack, and second, a progressive chronic autoimmune response resulting in loss of acinar cell mass and decline in exocrine function. Immunohistochemical staining of submandibular glands from C57BL/6.NOD-Aec1Aec2 mice (as well as salivary gland biopsies from SjS patients) has now shown strong positive staining for both IL-17 and IL-23 within the lymphocytic foci, plus a diffuse, sparsely staining of epithelial tissues. Temporal expressions of IL-17 and IL-23 in submandibular glands of C57BL/6.NOD-Aec1Aec2 mice correlated with expression of ROR3t, the TH17 cell master control gene. At the same time, more recent work has shown that IL-27, the cytokine that down-regulates TH17 activity, is expressed at very low levels in the exocrine glands. These results suggest that the TH17/IL-17/ IL-23 system is not only up-regulated in the exocrine glands of C57BL/6.NOD-Aec1Aec2 mice (and SjS patients) at time of disease, but may contribute to the clinical manifestations of the disease. In this grant application, we propose to study the importance of this TH17/IL-17/ IL-23 - IL-27 interactive system in the development and onset of SjS. To achieve this goal two aims are advanced: (i) define and characterize the IL-23 secreting and CD4+ TH17 memory T cell populations infiltrating the salivary glands during development of SjS- like disease, and (ii) determine a possible regulatory potential of IL-27 on the CD4+ TH17 memory T cell populations for preventing development of SjS using a gene therapy approach in the C57BL/6.NOD-Aec1Aec2 mouse model of SjS. Results from this study are expected to provide insight into the inter-relationship(s) between the LF-associated TH17 / IL-23 system and its regulatory IL-27 system in the development and sustainability of the autoimmune response leading to salivary gland dysfunction. Identification of molecular and cellular mechanisms involved in the development and onset of SjS, focusing specifically on biological changes associated with secretory dysfunction at a molecular level, should point to a variety of new and novel pathways permitting development of immunotherapy. A gene therapy approach directed towards regulating the TH17/IL-17/ IL-23 system through IL-27 would be a highly feasible method if results of the current study provide evidence that TH17 cells play an active role in the development and/or onset of SjS PUBLIC HEALTH RELEVANCE: TH1/TH2 paradigm, forming the basis of T cell immunology for decades, has been challenged by the discovery of TH17 cells, a subset of CD4+ T memory cells characterized by their unique ability to secrete IL-17 family cytokines and apparently involved in autoimmunity. In this grant application, we propose to utilize a gene therapy approach to study the possible role of the TH17/IL-17/ IL-23 - IL-27 interactive system in the development and onset of Sjvgren's syndrome (SjS), an autoimmune disease leading to dry mouth and dry eye syndromes. Identification of molecular and cellular mechanisms involved in the development and onset of SjS, focusing specifically on biological changes regulated by TH17/IL-17/ IL-23 / IL-27 and associated with secretory dysfunction, should point to a variety of new and radical targets permitting development of immunotherapy to treat SjS.

描述（由申请人提供）：在过去的几年里，TH17 细胞是 CD4+ T 记忆细胞的一个子集，其特征在于其独特的分泌 IL 的能力，形成 T 细胞免疫学基础的 TH1/TH2 范例随着 TH17 细胞的发现而迅速扩展。 -17家族细胞因子。最重要的是，TH17 细胞似乎与先天免疫和自身免疫密切相关。干燥综合征（SjS）是一种主要影响唾液腺和泪腺的自身免疫性疾病，其特征是外分泌腺功能障碍。近年来，NOD 和 NOD 衍生小鼠已被证明表现出与 SjS 密切相关的疾病，包括液体分泌物减少，同时出现唾液腺和泪腺内白细胞浸润。这种自身免疫性外分泌病分为两个主要阶段：首先，外分泌腺内发生许多病理生理变化，与任何自身免疫攻击无关；其次，进行性慢性自身免疫反应，导致腺泡细胞质量损失和外分泌功能下降。对 C57BL/6.NOD-Aec1Aec2 小鼠的下颌下腺（以及 SjS 患者的唾液腺活检）进行免疫组织化学染色，现已显示淋巴细胞病灶内 IL-17 和 IL-23 呈强阳性染色，此外还存在弥漫性、稀疏的区域。上皮组织染色。 C57BL/6.NOD-Aec1Aec2 小鼠颌下腺中 IL-17 和 IL-23 的时间表达与 TH17 细胞主控基因 ROR3t 的表达相关。与此同时，最近的研究表明，IL-27（下调 TH17 活性的细胞因子）在外分泌腺中的表达水平非常低。这些结果表明，TH17/IL-17/IL-23 系统不仅在疾病时在 C57BL/6.NOD-Aec1Aec2 小鼠（和 SjS 患者）的外分泌腺中上调，而且可能有助于临床疾病的表现。在本次拨款申请中，我们建议研究 TH17/IL-17/IL-23 - IL-27 交互系统在 SjS 的发展和发病中的重要性。为了实现这一目标，提出了两个目标：(i) 定义和表征 SjS 样疾病发展过程中浸润唾液腺的 IL-23 分泌细胞和 CD4+ TH17 记忆 T 细胞群，以及 (ii) 确定 IL 可能的调节潜力在 C57BL/6.NOD-Aec1Aec2 小鼠模型中使用基因治疗方法对 CD4+ TH17 记忆 T 细胞群进行 -27 预防 SjS 的发展SjS。这项研究的结果有望深入了解 LF 相关的 TH17 / IL-23 系统及其调节性 IL-27 系统在导致唾液腺功能障碍的自身免疫反应的发展和可持续性方面的相互关系。识别 SjS 的发展和发病所涉及的分子和细胞机制，特别关注分子水平上与分泌功能障碍相关的生物学变化，应该指出允许免疫疗法发展的各种新的和新颖的途径。如果当前研究结果证明 TH17 细胞在发育和/或发病中发挥积极作用，那么通过 IL-27 调节 TH17/IL-17/IL-23 系统的基因治疗方法将是一种高度可行的方法。 SjS 公共卫生相关性：TH1/TH2 范式几十年来一直构成 T 细胞免疫学的基础，但由于 TH17 细胞的发现而受到挑战，TH17 细胞是 CD4+ T 记忆细胞的一个子集，其特征在于其独特的分泌 IL-17 家族细胞因子的能力，显然参与自身免疫。在本次拨款申请中，我们建议利用基因治疗方法来研究 TH17/IL-17/IL-23 - IL-27 相互作用系统在干燥综合征 (SjS)（一种自身免疫性疾病）的发展和发病中的可能作用导致口干和干眼综合症。鉴定参与 SjS 发生和发病的分子和细胞机制，特别关注 TH17/IL-17/IL-23/IL-27 调节的生物变化以及与分泌功能障碍相关的分子和细胞机制，应该指出各种新的和根本性的允许开发治疗 SjS 的免疫疗法的目标。