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: 10688041
• 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/10688041
• 关键词: Allergens; Allergic; Allergic Disease; American; Animal Model; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Binding; Biocompatible Materials; Cardiac; Cardiac Myosins; Clinical; Dendritic Cells; Development; Dexamethasone; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Engineering; Epithelium; Experimental Models; Fibrosis; Flow Cytometry; Formulation; Goals; Graft Rejection; Histology; Hypersensitivity; IL2RA gene; Image Cytometry; Immune; Immune response; Immune system; Immunize; Immunosuppression; Immunotherapy; Infection; 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 Induction; Sulfhydryl Compounds; Symptoms; T-Lymphocyte; Technology; Therapeutic; Tight Junctions; Water; Work; clinical translation; compliance behavior; design; di-block copolymer; efficacy validation; heart function; immune cell infiltrate; immunoregulation; infection risk; monomer; mouse model; nonhuman primate; novel; pre-clinical; prevent; programs; receptor; response; small molecule; technology platform; 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：患者数量多与自身免疫及其他抗原特异性免疫调节有关