Polymeric nanoassemblies for precise tuning of immune responses

用于精确调节免疫反应的聚合物纳米组件

• 批准号: 10434144
• 负责人: Ryan Matthew Pearson
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434144
• 关键词: Address; Affect; Agonist; Allergic; Antigen Presentation; Antigens; Area; Autoimmune; Autoimmunity; Biochemical Pathway; Biological; CD27 Antigens; Celiac Disease; Cells; Clinical Treatment; Custom; Development; Disease; Disease Progression; Endotoxemia; Formulation; Future; Goals; Homeostasis; Host Defense Mechanism; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intervention; Link; Maintenance; Mediating; Molecular; Outcome; Outcome Study; Pathogenesis; Peptides; Phase I/II Clinical Trial; Polymers; Property; Proteins; Research; Sepsis; Therapeutic; Therapeutic Agents; Tissues; Toll-like receptors; Vision; antigen-specific T cells; base; chemical property; clinical implementation; clinical translation; clinically relevant; design; human disease; immune activation; immunoengineering; immunoregulation; improved; in vivo Model; microbial; mouse model; nanoassembly; nanoparticle; novel; novel strategies; novel therapeutics; physical property; programs; response; success; translational applications

PROJECT SUMMARY/ABSTRACT Inflammation is a powerful, multifactorial host defense mechanism intended to protect the body from microbial insult and tissue damage. As such, inflammation is not only essential to the maintenance of homeostasis but is on its own deleterious when regulatory mechanisms go awry. Aberrant immune activation is prominent in human diseases and can contribute to the development of inflammatory (e.g. sepsis), autoimmune, and allergic conditions for which there are limited therapeutic options available that address the underlying immune dysfunction. The overarching goal of my research program is to elucidate fundamental and functional relationships between nanoparticle designs and biological responses in the context of inflammatory conditions. Indeed, nanoparticles can be designed with inherent immunomodulatory properties that can limit the extent of the inflammatory response through non-specific or antigen-specific mechanisms. Our group has made significant strides in both of these areas where we have shown that our custom-designed nanoparticles could blunt non-specific proinflammatory responses induced by multiple Toll-like receptor agonists in the absence of additional therapeutic agents. It was further demonstrated that these cargo-less nanoparticles improved survival in lethal mouse models of LPS-induced endotoxemia to 70%. Encapsulation of peptide or protein antigens into tolerogenic nanoparticles (tNPs) allows for the specific delivery of antigens to innate immune cells. Through manipulation of innate immune cell antigen presentation to T cells, the activation of antigen-specific T cells and disease progression was halted. tNPs were recently evaluated in a Phase I and II clinical trial for the treatment of celiac disease with success. The rapid progression of nanoparticles towards clinical implementation highlights the urgent need for mechanistic studies to elucidate the underlying principles that govern nanoparticle-based immunomodulation. We aim to address this need by capitalizing on our expertise in nanoparticle design and immune engineering, which includes polymer synthesis, nanoparticle formulation, and immunology. Over the next five years, we will specifically focus on how the physical and chemical properties of nanoparticles affect multiple outcomes associated with inflammatory responses using clinically-relevant in vitro and in vivo models of sepsis, autoimmunity, and allergy. The outcomes of these studies will enable us to establish a set of design rules that govern the immunomodulatory activity and interactions of nanoparticles and the immune system to guide the development and clinical translation of novel nanoparticles for inflammation and antigen-specific disease intervention. Through successful realization of our program, we will not only contribute to our understanding of the properties that are necessary for nanoparticles to interact with and internalize into immune cells but also develop a set of design rules that govern nanoparticle-based immunomodulation, which will have immediate therapeutic value suitable for future translational applications.

项目概要/摘要 炎症是一种强大的、多因素的宿主防御机制，旨在保护身体免受微生物侵害 侮辱和组织损伤。因此，炎症不仅对于维持体内平衡至关重要，而且 当监管机制出现问题时，其本身就是有害的。异常的免疫激活在以下情况中很突出： 人类疾病，并可能导致炎症（例如脓毒症）、自身免疫性疾病和 过敏性疾病，可解决潜在免疫问题的治疗选择有限 功能障碍。我的研究计划的总体目标是阐明基本和功能 炎症背景下纳米颗粒设计与生物反应之间的关系 状况。事实上，纳米颗粒可以设计为具有固有的免疫调节特性，从而限制 通过非特异性或抗原特异性机制产生的炎症反应的程度。我们组有 在这两个领域都取得了重大进展，我们证明了我们定制设计的纳米颗粒 可以减弱多种 Toll 样受体激动剂诱导的非特异性促炎反应 不存在额外的治疗剂。进一步证明这些无货物纳米粒子 将 LPS 诱导的内毒素血症致死小鼠模型的存活率提高至 70%。肽或的封装 将蛋白质抗原转化为耐受性纳米颗粒 (tNP)，从而将抗原特异性递送至先天性 免疫细胞。通过操纵先天免疫细胞抗原呈递给 T 细胞， 抗原特异性 T 细胞和疾病进展被阻止。最近对 tNP 进行了 I 期和 II 期评估 治疗乳糜泻的临床试验取得成功。纳米粒子的快速进展 临床实施凸显了迫切需要进行机制研究来阐明 管理基于纳米颗粒的免疫调节的基本原则。我们的目标是解决这一需求 通过利用我们在纳米颗粒设计和免疫工程（包括聚合物）方面的专业知识 合成、纳米颗粒制剂和免疫学。未来五年，我们将重点关注 纳米颗粒的物理和化学特性如何影响与相关的多种结果 使用脓毒症、自身免疫和临床相关的体外和体内模型来研究炎症反应 过敏。这些研究的结果将使我们能够建立一套设计规则来管理 纳米粒子和免疫系统的免疫调节活性和相互作用，以指导发育 以及用于炎症和抗原特异性疾病干预的新型纳米颗粒的临床转化。 通过成功实现我们的计划，我们不仅将有助于我们对 纳米颗粒与免疫细胞相互作用并内化到免疫细胞中所必需的特性，而且 制定一套管理基于纳米颗粒的免疫调节的设计规则，这将立即产生影响 适合未来转化应用的治疗价值。