Tolerance-programming biomaterial-based Intranasal ASIT for the treatment of autoimmunity

基于耐受编程生物材料的鼻内 ASIT 用于治疗自身免疫性疾病

• 批准号: 10295511
• 负责人: David Scott Wilson
• 金额: $ 49.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295511
• 关键词: Allergens; Allergic; Allergic Disease; American; Animal Model; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Binding; Biocompatible Materials; Cardiac; Cardiac Myosins; Cations; Cells; Clinical; Dendritic Cells; Development; Dexamethasone; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Engineering; Epithelial; Experimental Models; Fibrosis; Flow Cytometry; Formulation; Goals; Graft Rejection; Histology; Hypersensitivity; IL2RA gene; Image Cytometry; Immune; Immune response; Immune system; Immunize; Immunosuppression; Immunotherapy; Infiltration; Inflammatory; Infusion procedures; Injections; Intranasal Administration; Label; Liver; Lymphoid Tissue; Malignant Neoplasms; Measures; Mediating; Minocycline; Mucous body substance; Multiple Sclerosis; Mus; Myocarditis; Nasal Epithelium; Nose; Opportunistic Infections; Ovalbumin; Pain; Pathogenicity; Pathology; Patients; Peptides; Phagocytes; Phenotype; Phosphatidylserines; Play; Polymers; Pre-Clinical Model; Regulatory T-Lymphocyte; Risk; Severities; Signal Transduction; Sulfhydryl Compounds; Symptoms; T-Lymphocyte; Technology; Therapeutic; Tight Junctions; Water; Work; base; clinical translation; design; di-block copolymer; efficacy validation; heart function; immunoregulation; infection risk; monomer; mouse model; nonhuman primate; novel; pre-clinical; prevent; programs; receptor; response; small molecule; whole animal imaging

1. Abstract: The number of patients with autoimmunity and other antigen-specific immunoregulatory disorders is increasing worldwide at a rate of 4 to 8% per annum. Current therapies for autoimmunity only treat disease symptoms and are systemically immunosuppressive, resulting in an increased risk of infection and malignancy. The Holy Grail of autoimmune therapies would specifically abrogate pathogenic autoantigen-specific immune response. To this end, we propose the development of a novel biomaterial- based intranasal antigen-specific immunotherapy engineered to elicit auto-antigen specific regulatory T cells that control autoimmunity. Our in intranasal AIST is composed of autoantigens conjugated to a water- soluble polymer that binds to nasal mucus, facilitates paracellular transport across the nasal epithelium, and targets autoantigens and tolerance-programming small molecules (i.e., minocycline and dexamethasone) to underlying nasal DCs, resulting in the induction of autoantigen-specific regulatory T cells that suppress autoimmune responses. In this application, we propose: (1) the synthesis of our novel intranasal ASIT, (2) the demonstration of the ability of our platform to suppress antigen-specific immune responses, and (3) the use of our platform to treat and prevent experimental autoimmune myocarditis. Completion of this project will deliver a clinically viable treatment for autoimmune myocarditis and a therapeutic platform that can be easily tailored to treat other diseases driven by antigen-specific immune dysregulation, including diabetes, multiple sclerosis, transplant rejection, and numerous allergies.

1. 摘要：自身免疫及其他抗原特异性免疫调节患者的数量 全球范围内疾病以每年 4% 至 8% 的速度增加。目前的疗法仅针对自身免疫 治疗疾病症状并具有系统性免疫抑制作用，导致感染风险增加 和恶性肿瘤。自身免疫疗法的圣杯将专门消除致病性 自身抗原特异性免疫反应。为此，我们建议开发一种新型生物材料—— 基于鼻内抗原特异性免疫疗法，旨在引发自身抗原特异性调节 T 控制自身免疫的细胞。我们的鼻内 AIST 由与水结合的自身抗原组成 可溶性聚合物与鼻粘液结合，促进跨鼻上皮的细胞旁运输，以及 靶向自身抗原和耐受程序小分子（即米诺环素和地塞米松） 潜在的鼻 DC，导致诱导自身抗原特异性调节 T 细胞，从而抑制 自身免疫反应。在此应用中，我们建议：(1) 合成我们的新型鼻内 ASIT，(2) 证明我们的平台抑制抗原特异性免疫反应的能力，以及（3） 使用我们的平台治疗和预防实验性自身免疫性心肌炎。本项目完成情况 将为自身免疫性心肌炎提供临床上可行的治疗方法和可用于治疗的治疗平台 易于定制以治疗由抗原特异性免疫失调引起的其他疾病，包括糖尿病， 多发性硬化症、移植排斥和多种过敏症。