Development of a novel platform for the selective delivery of AhR agonists to DCs.

开发一个新的平台，用于选择性地将 AhR 激动剂递送至 DC。

• 批准号: 8872596
• 负责人: David M Shepherd
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-08 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8872596
• 关键词: Address; Adverse effects; Affinity; Agonist; Allergic Disease; Antibodies; Antigen-Presenting Cells; Antigens; Aryl Hydrocarbon Receptor; Autoimmunity; Biodistribution; Cancerous; Cell Nucleus; Cells; Chemicals; Chronic; Cytosol; Dendritic Cells; Development; Disease; Effector Cell; Engineering; Environmental Pollution; Gene Targeting; Generations; Genetic Transcription; Health; Health Care Costs; Homeostasis; Human; ITGAX gene; Immune; Immune response; Immunobiology; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Infection; Inflammatory; Intention; Knowledge; Label; Ligand Binding; Ligands; Liposomes; Mediating; Methods; Molecular Target; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nature; Organogenesis; Patient Care; Patients; Peptides; Play; Protocols documentation; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Role; Route; Safety; Signal Pathway; Specificity; Symptoms; System; Testing; Therapeutic; Tissues; Xenobiotic Metabolism; activating transcription factor; adaptive immunity; aryl hydrocarbon receptor ligand; base; immune activation; immunoregulation; in vivo; man; manufacturing scale-up; mortality; nanoparticle; new therapeutic target; novel; novel therapeutics; prophylactic; public health relevance; receptor binding; screening; targeted delivery

 DESCRIPTION (provided by applicant): Immune-mediated diseases such as autoimmunity, allergic diseases and chronic inflammatory diseases are increasing annually and are responsible for significant morbidity and mortality in people in the U.S. and throughout the world. Recently, the Aryl hydrocarbon Receptor (AhR) signaling pathway has been successfully utilized to treat immune-mediated diseases in mice. To this end, activation of the AhR using various novel and relatively non-toxic ligands (i.e. ITE, VAF347, etc.) have effectively been used in a prophylactic and therapeutic manner to treat immune-mediated diseases, primarily by generating immunoregulatory dendritic cells (DCs), regulatory T cells (Tregs), and immunomodulation. However, because of the immunosuppressive nature of AhR agonists, many adverse side effects are associated with systemic administration of these compounds. In contrast, novel technological approaches to selectively deliver high-affinity AhR ligands in a tissue- and/or cell- specific manner have the potential to generate localized and/or antigen-specific therapies to treat and even cure immune-mediated diseases--dramatically enhancing the level of care for patients suffering from these conditions. In this proposal, we will develop and validate a novel, non-toxic method to deliver select AhR ligands to murine DCs using PEGylated liposomal based nanoparticles (LNPs), with/without monoclonal antibodies (for targeting delivery to CD11c+ murine DCs) and peptide antigen (for antigen- and disease-related specificity). This approach will generate immunoregulatory DCs, antigen-specific Tregs, and highly selective immunosuppression, ultimately leading to a significant advancement in the treatment of immune-mediated diseases.

 描述（由申请人提供）：免疫介导的疾病如自身免疫、过敏性疾病和慢性炎性疾病每年都在增加，并且是美国和全世界人群中显著发病率和死亡率的原因。 最近，芳烃受体（AhR）信号通路已成功地用于治疗小鼠免疫介导的疾病。为此，使用各种新颖且相对无毒的配体（即ITE、VAF 347等）活化AhR是可行的。已经以预防和治疗的方式有效地用于治疗免疫介导的疾病，主要是通过产生免疫调节性树突细胞（DC）、调节性T细胞（T细胞）和免疫调节。然而，由于AhR激动剂的免疫抑制性质，许多不良副作用与这些化合物的全身给药有关。相比之下，以组织和/或细胞特异性方式选择性递送高亲和力AhR配体的新技术方法具有产生局部和/或抗原特异性疗法以治疗甚至治愈免疫介导的疾病的潜力-显著提高对患有这些病症的患者的护理水平。在这项提案中，我们将开发和验证一种新的，无毒的方法来提供选择AhR配体的小鼠DCs使用聚乙二醇化脂质体为基础的纳米粒子（LNP），有/没有单克隆抗体（靶向交付CD 11 c+小鼠DCs）和肽抗原（抗原和疾病相关的特异性）。这种方法将产生免疫调节性DC、抗原特异性T细胞和高选择性免疫抑制，最终导致免疫介导疾病治疗的重大进展。