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

 描述(申请人提供)：免疫介导性疾病，如自身免疫性疾病、过敏性疾病和慢性炎症性疾病每年都在增加，并导致美国和世界各地人们的显著发病率和死亡率。 近年来，芳香烃受体(AhR)信号通路已被成功地用于治疗小鼠免疫介导性疾病。为此，使用各种新的和相对无毒的配体(如ITE、VAF347等)激活AhR。已被有效地用于预防和治疗免疫介导性疾病，主要是通过产生免疫调节性树突状细胞(DC)、调节性T细胞(Tregs)和免疫调节。然而，由于AhR激动剂的免疫抑制性质，许多不良副作用与全身给药这些化合物有关。相比之下，以组织和/或细胞特异性方式选择性输送高亲和力AhR配体的新技术方法有可能产生局部和/或抗原特异性疗法来治疗甚至治愈免疫介导性疾病--极大地提高了对患有这些疾病的患者的护理水平。在这项提议中，我们将开发和验证一种新的、无毒的方法，使用基于聚乙二醇脂质体的纳米粒(LNPs)将特定的AhR配体递送到小鼠DC，并带有/不带有单抗(用于靶向递送CD11c+小鼠DC)和多肽抗原(用于抗原和疾病相关的特异性)。这种方法将产生免疫调节性树突状细胞、抗原特异性树突状细胞和高度选择性的免疫抑制，最终导致免疫介导性疾病的治疗取得重大进展。

 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.