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：自身免疫和其他抗原特异性免疫调节的患者数量 疾病正以每年4%至8%的速度在全球范围内增加。目前仅针对自身免疫的治疗方法 治疗疾病症状，全身免疫抑制，导致感染风险增加 和恶毒。自身免疫疗法的圣杯将特别地消除致病 自身抗原特异性免疫反应。为此，我们建议开发一种新型的生物材料-- 基于鼻腔抗原特异性免疫疗法诱导自身抗原特异性调节性T细胞 控制自身免疫的细胞。我们的鼻腔AIST是由自身抗原与水结合而成的- 与鼻粘液结合的可溶性聚合物，促进鼻腔上皮的细胞旁运输，以及 靶向自身抗原和耐受编程小分子(即米诺环素和地塞米松)以 潜在的鼻树突状细胞，导致诱导自身抗原特异性调节性T细胞抑制 自身免疫反应。在这一应用中，我们建议：(1)合成我们的新型鼻腔内氨基转移酶，(2) 展示了我们的平台抑制抗原特异性免疫反应的能力，以及(3) 利用我们的平台治疗和预防实验性自身免疫性心肌炎。本项目竣工 将为自身免疫性心肌炎提供临床上可行的治疗方法，并提供一个治疗平台，可以 很容易定制来治疗其他由抗原特异性免疫失调引起的疾病，包括糖尿病， 多发性硬化症，移植排斥反应，以及大量过敏。