Polymeric nanoassemblies for precise tuning of immune responses (Supplement for Equipment Purchase)

用于精确调节免疫反应的聚合物纳米组件（设备购买补充）

• 批准号: 10797874
• 负责人: Ryan Matthew Pearson
• 金额: $ 15.16万
• 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/10797874
• 关键词: Address; Affect; Agonist; Allergic; Antigen-Presenting Cells; Antigens; Area; Autoimmune; Autoimmunity; Biological; CD27 Antigens; Celiac Disease; Cells; Clinical Treatment; Clinical Trials; Custom; Development; Disease; Disease Progression; Encapsulated; 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; Maintenance; Outcome; Outcome Study; Peptides; Phase; Polymers; Property; Proteins; Research; Sepsis; Therapeutic; Therapeutic Agents; Tissues; Toll-like receptors; antigen-specific T cells; chemical property; clinical implementation; clinical translation; clinically relevant; design; equipment acquisition; human disease; immune activation; immunoengineering; immunoregulation; improved; in vivo Model; microbial; mouse model; nanoassembly; nanoparticle; nanopolymer; novel; 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.

项目摘要/摘要 炎症是一种强大的多因素宿主防御机制，旨在保护人体免受微生物的侵害 侮辱和组织损害。因此，炎症不仅对维持体内平衡至关重要，而且是 当监管机制出现问题时，它自己有害。异常免疫激活在 人类疾病，可能有助于炎症（例如败血症），自身免疫性和 可用的治疗选择有限的过敏性疾病可以解决潜在的免疫 功能障碍。我的研究计划的总体目标是阐明基本和功能 在炎症的背景下，纳米颗粒设计与生物反应之间的关系 状况。实际上，纳米颗粒可以具有固有的免疫调节特性设计，可以限制 通过非特异性或抗原特异性机制的炎症反应程度。我们的小组有 在这两个领域都取得了长足的进步，我们表明我们的定制设计的纳米颗粒 可以在多种受过toll样受体激动剂引起的非特异性促炎反应中钝化 缺乏其他治疗剂。进一步证明了这些无货物的纳米颗粒 在LPS诱导的内毒素血症的致命小鼠模型中提高了生存率，达到70％。肽的封装或 蛋白质抗原进入耐纳米颗粒（TNP）允许抗原特定递送给先天性 免疫细胞。通过操纵先天免疫细胞抗原向T细胞的抗原，激活 抗原特异性T细胞和疾病进展停止。最近在I期和II期评估了TNP 成功治疗乳糜泻的临床试验。纳米颗粒的快速发展 朝着临床实施强调了迫切需要机械研究以阐明 控制基于纳米颗粒的免疫调节的基本原理。我们旨在满足这一需求 通过利用我们在包括聚合物在内的纳米颗粒设计和免疫工程方面的专业知识 合成，纳米颗粒制剂和免疫学。在接下来的五年中，我们将特别关注 纳米颗粒的物理和化学特性如何影响与 使用临床上与脓毒症，自身免疫性和体内模型相关的炎症反应 过敏。这些研究的结果将使我们能够建立一组管理规则 纳米颗粒和免疫系统的免疫调节活性和相互作用，以指导发展 以及新型纳米颗粒的临床翻译，用于炎症和抗原特异性疾病干预。 通过成功实现我们的计划，我们不仅会为我们的理解做出贡献 纳米颗粒与免疫细胞相互作用并内化的属性是必需的属性 制定一套设计规则，该规则管理基于纳米颗粒的免疫调节，该规则将立即具有 治疗价值适合将来的翻译应用。

项目成果

Modified Suberoylanilide Hydroxamic Acid Reduced Drug-Associated Immune Cell Death and Organ Damage under Lipopolysaccharide Inflammatory Challenge.

修饰的辛二酰苯胺异羟肟酸可减少脂多糖炎症挑战下药物相关的免疫细胞死亡和器官损伤。

• DOI: 10.1021/acsptsci.2c00119
• 发表时间: 2022
• 期刊: ACS pharmacology & translational science
• 作者: Truong,Nhu;Goodis,ChristopherC;Cottingham,AndreaL;Shaw,JacobR;Fletcher,Steven;Pearson,RyanM
• 通讯作者: Pearson,RyanM

Microfluidic-Generated Immunomodulatory Nanoparticles and Formulation-Dependent Effects on Lipopolysaccharide-Induced Macrophage Inflammation.

• DOI: 10.1208/s12248-021-00645-2
• 发表时间: 2021-12-02
• 期刊: The AAPS journal
• 作者: Truong N;Black SK;Shaw J;Scotland BL;Pearson RM
• 通讯作者: Pearson RM