Chitosan IFNgamma-pDNA Nanosphere Therapy and Immunopathology of Allergic Asthma

壳聚糖 IFNγ-pDNA 纳米球治疗过敏性哮喘的免疫病理学

• 批准号: 6725650
• 负责人: Shyam S Mohapatra
• 金额: $ 29万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-25 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6725650
• 关键词: T lymphocyte; allergens; antigen presentation; asthma; biotechnology; bronchial mucus; bronchomotion; chitin; diagnostic respiratory lavage; eosinophil; gene expression; gene therapy; genetically modified animals; goblet cells; immunopathology; immunotherapy; inhalation drug administration; interferon gamma; laboratory mouse; microcapsule; nanotechnology; nonhuman therapy evaluation; respiratory disease /disorder therapy; respiratory hypersensitivity; transfection /expression vector

DESCRIPTION (provided by applicant): With an intent to develop effective prophylaxis or treatment of allergic diseases including allergic asthma, our goal is to examine the safety and efficacy of chitosan IFN-gamma-pDNA nanosphere (CIN) Therapy and the cellular and molecular mechanisms underlying its effectiveness in a mouse model of asthma. Deviation of immune response to allergens from a pathogenic T helper-2 type response to T helper-1 type may provide a practical approach to modifying the course of disease. Administration of IFN-gamma, and IL-12 DNA plasmids significantly decreased airway inflammation and airway hyperresponsiveness in a mouse model of grass allergic asthma. In addition, Adenoviral-mediated IFN-gamma, gene transfer effectively reversed established asthma in BALB/c mouse model. While these studies aid in the mechanistic understanding of IFN-gamma, action in the lung, acute inflammation and immunogenicity to virus remains the major obstacle for the application of viral-mediated gene transfer for treating human asthma. We therefore developed a non-viral strategy that involves the development of chitosan nanospheres containing IFN-gamma, pDNA (CIN), intranasally (i.n.) delivered to the lung, as a strategy for asthma treatment. Our working hypothesis is that i.n. CIN therapy provides for effective prophylaxis or treatment of asthma by inducing changes in expression of cytokine and chemokine genes which result in altered antigen presentation, decreased migration of effector cells into the lung, and apoptosis of inflammatory cells, leading to a global decrease in inflammation and airway remodeling. The specific aims of this research program are as follows: Aim #1. Evaluate chitosan-IFN-gamma-pDNA nanospheres (CIN) as a prophylactic or a therapeutic modality for allergic disease in BALB/c mice. We plan to evaluate the role of CIN in prophylaxis/therapy of allergic asthma in BALB/c mice with respect to magnitude of acute inflammation, duration of protection from asthma and its potential in a chronic asthma model. We will analyze different asthma phenotypes, such as immune deviation of allergic response revealed by a change in T-cell cytokine secretion and antibody response profiles, the airway hyperreactivity and eosinophils in broncho-alveolar lavage, and lung pathology. Aim #2. Elucidate the cellular/molecular mechanism of CIN-induced immunomodulation. We plan to examine the role of T cells, CIN modulation of specific T cell response in the lung including apoptosis of Th2 cells and modulation of the number and activity of dendritic cells in the lung. Aim #3. Elucidate the anti-inflammatory mechanism of CIN-induced protection. We plan to examine the genes, which mediate the effects of CIN, whether CIN affects airway inflammation and airway remodeling in lungs of mice, and whether CIN induces apoptosis of mucus producing goblet cells. It is anticipated that the results of these studies will contribute significantly to our knowledge of asthma and CIN therapy may provide a major breakthrough in management of asthma.

描述（由申请人提供）：目的是开发有效的预防或对包括过敏性哮喘在内的过敏性疾病的治疗，我们的目标是检查壳聚糖IFN-Gamma-PDNA纳米球（CIN）疗法的安全性和功效，以及细胞和细胞和分子机制在Asthma的小鼠模型中的有效性。 对过敏原的免疫反应偏离致病性T辅助-2对T辅助-1类型的反应的偏离可能会提供一种修改疾病进程的实用方法。在草过敏性哮喘的小鼠模型中，IFN-GAMMA和IL-12 DNA质粒的给药显着降低了气道炎症和气道高反应性。 此外，腺病毒介导的IFN-gamma，基因转移有效地逆转了BALB/C小鼠模型中已建立的哮喘。尽管这些研究有助于对IFN-gamma的机械理解，但肺部的作用，对病毒的急性炎症和免疫原性仍然是应用病毒介导的基因转移用于治疗人哮喘的主要障碍。因此，我们制定了一种非病毒策略，该策略涉及含有IFN-GAMMA，PDNA（CIN）的壳聚糖纳米球的发展，鼻内（I.N.）作为哮喘治疗的策略。我们的工作假设是I.N. CIN治疗通过诱导细胞因子和趋化因子基因表达的变化来提供有效的预防或治疗哮喘，从而导致抗原呈递改变，效应细胞迁移到肺中的迁移以及炎症细胞的细胞凋亡，从而导致炎症和气动重新塑造的全球降低。该研究计划的具体目的如下：目标＃1。评估BALB/C小鼠的壳聚糖-IFN-Gamma-PDNA纳米球（CIN）作为预防性或治疗方式。我们计划评估CIN在BALB/C小鼠中预防/治疗过敏性哮喘的作用，就急性炎症的幅度，保护哮喘的保护持续时间以及其在慢性哮喘模型中的潜力。我们将分析不同的哮喘表型，例如T细胞因子分泌的变化和抗体反应曲线的变化，在支气管 - 肺泡灌洗中的气道高反应性和嗜酸性粒细胞显示出过敏反应的免疫偏差，以及肺病病理。目标＃2。阐明CIN诱导的免疫调节的细胞/分子机制。我们计划检查T细胞的作用，CIN调节特异性T细胞反应在肺中，包括Th2细胞的凋亡以及对肺中树突状细胞的数量和活性的调节。目标＃3。阐明了CIN引起的保护的抗炎机制。我们计划检查介导CIN影响的基因，CIN是否影响小鼠肺中的气道炎症和气道重塑，以及CIN是否诱导产生杯状细胞的粘液凋亡。预计这些研究的结果将对我们对哮喘和CIN治疗的了解产生重大贡献，这可能会在哮喘管理管理方面有一个重大突破。