New approach for immune modulation against T1D

针对 T1D 免疫调节的新方法

• 批准号: 10699223
• 负责人: Weston Daniel
• 金额: $ 76.18万
• 依托单位: EVOQ THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699223
• 关键词: Acute; Address; Adjuvant; Affect; Age; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apolipoprotein A-I; Autoantigens; Autoimmune Diseases; Autoimmunity; Beta Cell; Biological Assay; Bystander Suppression; CD8-Positive T-Lymphocytes; Cell physiology; Clinical Chemistry; Clinical Protocols; Data; Dendritic Cells; Disease; Disease susceptibility; Dose; Drug Kinetics; Epitopes; Evaluation; Experimental Autoimmune Encephalomyelitis; Feedback; Formulation; Future; Goals; High Density Lipoproteins; Human; Hyperglycemia; IL17 gene; IgG autoantibodies; Immune Tolerance; Immune mediated destruction; Immune response; Immunity; Immunologics; Immunotherapy; Impairment; In Vitro; Inflammatory; Insulin; Insulin Infusion Systems; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Knowledge; Laboratories; Link; Lymph; Modeling; Mononuclear; Mus; Organ; Outcome; Pancreas; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Phagocytosis; Phase; Phospholipids; Process; Public Health; Rattus; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Safety; System; T cell response; T-Lymphocyte; Therapeutic; Toxicology; Treatment Efficacy; Vaccines; analytical method; autoreactive T cell; autoreactivity; cancer vaccination; clinical development; clinical translation; cytokine; drug development; effective therapy; good laboratory practice; immunological intervention; immunomodulatory strategy; immunoregulation; lead candidate; lymph nodes; manufacture; manufacturing process; meetings; mouse model; nanodisk; nanoparticle; novel strategies; peptidomimetics; pre-Investigational New Drug meeting; prevent; process optimization; programmed cell death ligand 1; restraint; standard of care; tumor; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is an autoimmune disease that affects 1 in 300 people by the age of 18 in the US. T1D is characterized by acute onset of hyperglycemia resulting from immune-mediated destruction of the insulin- producing β-cells in the pancreas. There is currently no cure for T1D and the disease requires constant management where the current standard of care/management is injected or pumped insulin. Thus, there is an urgent need for new and effective treatment options for T1D patients. While self-reactive CD4 and CD8 T cells are central pathogenic drivers, regulatory T cells (Tregs) have been shown to restrain autoimmunity and maintain immune tolerance through multiple mechanisms. In T1D patients, impaired Treg function have been shown to contribute to disease susceptibility. Thus, induction of Tregs holds great promise in correcting the aberrant autoreactive T cell activities and preventing the progression of T1D. However, it remains unknown how to induce Tregs in a safe and effective manner for the potential treatment of T1D. Here, we propose to develop a novel strategy for immunotherapy against T1D. Toward this goal, we have developed synthetic high-density lipoprotein NanoDiscs that are particularly well suited for lymph node targeting. Our preliminary data generated in a murine model of T1D and experimental autoimmune encephalomyelitis have shown that NanoDiscs carrying antigens only induce robust Treg response and achieve immune tolerance. Based on our compelling proof-of-concept data, we propose to develop NanoDiscs carrying antigens to promote antigen-specific immune tolerance against T1D. The proposed research will provide a new strategy for modulating immune microenvironment of pancreas and an avenue for immune tolerance against T1D.

项目总结/摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，在美国18岁时影响1/300的人。T1 D是 其特征在于由免疫介导的胰岛素破坏引起的高血糖症的急性发作， 在胰腺中产生β细胞。目前还没有治愈T1 D的方法，这种疾病需要持续的 目前的护理/管理标准是注射或泵送胰岛素。因此， T1 D患者迫切需要新的有效治疗选择。而自身反应性CD 4和CD 8 T细胞 作为中枢致病驱动因子，调节性T细胞（Tcells）已被证明可抑制自身免疫并维持免疫原性。 免疫耐受通过多种机制。在T1 D患者中，Treg功能受损已被证明是 有助于疾病易感性。因此，归纳的Tenda持有很大的希望，在纠正异常的 自身反应性T细胞活性和预防T1 D的进展。然而，如何诱导 以安全有效的方式治疗T1 D。在这里，我们建议开发一种新的 针对T1 D免疫治疗策略。为了实现这一目标，我们开发了合成高密度脂蛋白 特别适合淋巴结靶向的NanoDisc。我们的初步数据是在一只 T1 D和实验性自身免疫性脑脊髓炎的模型已经表明， 仅诱导强烈的Treg应答并实现免疫耐受。基于我们令人信服的概念验证 数据，我们建议开发携带抗原的纳米盘，以促进抗原特异性免疫耐受， T1D本研究为胰腺免疫微环境的调控提供了新的策略 和对T1 D免疫耐受的途径。