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：自身免疫和其他抗原特异性免疫调节剂的患者数量 疾病在世界范围内以每年4%至8%的速度增加。目前仅针对自身免疫的治疗 治疗疾病症状，并具有全身免疫抑制作用，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的工程化以引发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内AIST是由自身抗原结合到一个水- 可溶性聚合物，其与鼻粘液结合，促进跨鼻上皮的细胞旁转运，和 靶向自身抗原和耐受性编程小分子（即，二甲胺四环素和地塞米松）， 潜在的鼻DC，导致诱导自身抗原特异性调节性T细胞，其抑制 自身免疫反应在这项应用中，我们提出：（1）我们的新的鼻内ASIT的合成，（2） 证明我们的平台能够抑制抗原特异性免疫应答，以及（3） 使用我们的平台来治疗和预防实验性自身免疫性心肌炎。完成本项目 将为自身免疫性心肌炎提供一种临床可行的治疗方法， 易于定制以治疗由抗原特异性免疫失调驱动的其他疾病，包括糖尿病， 多发性硬化症，移植排斥反应，还有很多过敏症