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Nanoimmunotherapy for chronic immune-mediated diseases

纳米免疫疗法治疗慢性免疫介导疾病

基本信息

批准号：
10483819
负责人：
DAVID A HORWITZ
金额：
$ 30万
依托单位：
GENERAL NANOTHERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-14 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10483819
关键词：
Address Alpha Interleukin 2 Receptor American Animal Model Anti-Inflammatory Agents Antibodies Antigen-Presenting Cells Antigens Artificial nanoparticles Attention Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Assay CD3 Antigens CD8B1 gene Cells Chimeric Proteins Chronic Clinical Clinical Trials Disease Disease Outcome Disease Progression Disease remission Drug usage Encapsulated Engineering Environment Experimental Autoimmune Encephalomyelitis FOXP3 gene Flow Cytometry Formulation Generations Goals Grant Homeostasis Host Defense Human Hyperactivity Immune Immune Tolerance Immune response Immune system Immunosuppressive Agents Impairment In Vitro Individual Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Interleukin-2 Learning Lupus Lymphocyte Lymphocyte Function Mediating Methodology Multiple Sclerosis Mus Nanoimmunotherapy Natural Killer Cells Pathogenicity Peptides Peripheral Blood Mononuclear Cell Pharmacologic Substance Phase Phenotype Play Population Prevalence Process Production Property Public Health Publishing Recombinants Regulatory T-Lymphocyte Role Safety Suppressor-Effector T-Lymphocytes Systemic Lupus Erythematosus T-Lymphocyte Therapeutic Therapeutic Agents Time Tissues Toxic effect Transforming Growth Factor beta United States National Institutes of Health Work autoreactive T cell comparative efficacy cost cost effective cytokine design disability effector T cell experimental study graft vs host disease human model humanized mouse immunoregulation improved in vitro activity in vivo lupus-like mortality nanoparticle novel novel strategies phase 1 study prevent response scale up side effect virtual

项目摘要

ABSTRACT Current pharmaceutical agents that are used for the treatment of immune-mediated inflammatory conditions including autoimmune diseases generally do not lead to remission and frequently carry toxic side effects. Here we propose a strategy that can harness the capacity of the immune system to induce immunoregulatory response that can suppress immune hyperactivity and chronic inflammation in vivo. The product that we propose consists of nanoparticles (NPs) targeted to immunoregulatory cells for their expansion and functional activity in vitro and in vivo. Our approach to generate and expand functional immunoregulatory cells that become impaired in autoimmune diseases should contribute to restoring immune homeostasis and improve disease outcomes. This approach is especially designed to treat systemic lupus erythematosus. The proof-of-concept for this Phase 1 studies will be to show that our cell-targeted NPs can markedly expand ex vivo both CD4+ and CD8+ Tregs, and TGF-ß producing NK regulatory cells that we recently described. Complementary experiments in humanized mice will address the in vivo functional efficacy of those NP-induced immunoregulatory cells in suppressing effector immune responses in vivo, including in an animal model of human lupus. By demonstrating that NP-expanded human immunoregulatory cells are functional in vivo in humanized mice, we propose a new nanoimmunotherapeutic approach to restore immune regulation and induce remission in autoimmune disease. Importantly, this in vivo cell-targeted strategy has the potential to overcome the undesired side effects of the broadly non-specific, anti-inflammatory and immunosuppressive drugs presently used to treat autoimmune diseases.

摘要目前用于治疗免疫介导的炎性疾病的药剂包括自身免疫性疾病在内的病症通常不会导致缓解，副作用.在这里，我们提出了一种策略，可以利用免疫系统的能力，免疫调节反应，可以抑制体内免疫过度活跃和慢性炎症。我们提出的产品由靶向免疫调节细胞的纳米颗粒（NPs）组成，它们在体外和体内的扩增和功能活性。我们的方法来生成和扩展在自身免疫性疾病中受损的功能性免疫调节细胞应该有助于恢复免疫稳态并改善疾病结果。这种方法是特别设计的，治疗系统性红斑狼疮。本1期研究的概念验证将显示我们的细胞靶向纳米颗粒可以显着扩增离体的CD 4+和CD 8 + T细胞，和TGF-β 产生我们最近描述的NK调节细胞。人源化的补充实验小鼠将解决这些NP诱导的免疫调节细胞在体内的功能功效，抑制体内效应免疫应答，包括在人狼疮的动物模型中。通过这证明NP扩增的人免疫调节细胞在人源化免疫调节细胞中体内是有功能的。小鼠，我们提出了一种新的纳米免疫方法来恢复免疫调节，自身免疫性疾病的缓解。重要的是，这种体内细胞靶向策略有可能克服广泛非特异性、抗炎和抗病毒药物的不良副作用目前用于治疗自身免疫性疾病的免疫抑制药物。