Molecular assemblies as immunomodulators

作为免疫调节剂的分子组装体

基本信息

批准号：
8309672
负责人：
Gregory Hudalla
金额：
$ 5.22万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309672
关键词：
Address Adjuvant Antibodies Antibody Formation Antigens B-Lymphocyte Epitopes Binding Biocompatible Materials Chemicals Chimeric Proteins Development Disaccharides Engineering Enzymes Epitopes Future Galactose Binding Lectin Galectin 1 Green Fluorescent Proteins Haplotypes Immobilization Immune Immune response Immunomodulators Immunotherapy Implant Life Ligands Maternal-Fetal Exchange Mediating Modeling Mus N-acetyllactosamine Outcome Peptides Polymers Process Proteins Reaction Regenerative Medicine Research Research Design Role Solvents Sulfhydryl Compounds System T-Lymphocyte Testing Tissue Engineering Tissues Vaccine Adjuvant Vaccine Antigen Vaccines Work base biomaterial development clinical application clinically relevant covalent bond cutinase design fetal immunogenic immunogenicity implantation improved in vivo methicillin resistant Staphylococcus aureus molecular assembly/self assembly mouse model pathogen patient population phosphonate polyclonal antibody polysaccharide peptide response tissue regeneration tumor

项目摘要

DESCRIPTION (provided by applicant): Biomolecular assemblies that modulate host immune responses have widespread potential in immunotherapy and tissue engineering applications. For example, self-assembled peptides that boost host immune responses may provide chemically well-defined vaccine adjuvants with precise mechanisms of action. On the other hand, self-assembled peptides that diminish host immune responses may improve the efficacy of tissue engineering therapies by alleviating the potential for tissue or implant rejection. This project is guided by the hypothesis that self-assembled peptides decorated with foreign proteins will elicit robust immune responses, while self-assembled peptides engineered to mimic mechanisms that inhibit immune responses within natural systems will diminish the immunogenicity of these biomaterials. This project is based on the well-defined immune response to peptide antigen- decorated self-assembled peptide biomaterials, which are non-immunogenic in the absence of antigen. Aim 1 will engineer immunogenic self-assembled peptide biomaterials presenting protein antigens. The model protein antigen green fluorescent protein (GFP) will be immobilized on a self-assembled peptide biomaterial through formation of a covalent bond between an enzyme fused to GFP and a ligand presented by the material. The immunogenicity of GFP-modified self-assembled peptide biomaterials will then be characterized in vivo in a mouse model. These studies are designed to provide proof-of-principle that self- assembled peptide biomaterials decorated with a protein antigen elicit robust and long-lived immune responses. The outcomes of this aim will provide the basis for developing biomaterial-based vaccines against clinically-relevant pathogens, such as methicillin-resistant staphylococcus aureus. Aim 2 will engineer self-assembled peptide biomaterials that diminish anti-material immune responses by mimicking native immune privilege mechanisms. In this aim, the GFP-modified self- assembled peptide biomaterials developed in S.A.1 will be further modified with a disaccharide that non- covalently binds to the protein galectin-1. The choice of galectin-1 as a negative modulator of immune response is based on the wel-established role of galectins in tumor immune privilege and fetal-maternal tolerance. Self-assembled peptide biomaterials decorated with GFP and a galectin-binding disaccharide will then be injected into mice in the presence or absence of soluble galectin-1. The immune response to these materials will be analyzed using the same models and approaches as in S.A.1. These studies are designed to provide proof-of-principle that biomaterials engineered to mimic native mechanisms of immune privilege diminish the immune response to the material. The outcomes of this aim will provide the basis for developing biomaterials that diminish host immune responses to limit rejection of tissues or implants for tissue engineering and regenerative medicine therapies.

描述（由申请人提供）：调节宿主免疫反应的生物分子组件在免疫疗法和组织工程应用中具有广泛的潜力。例如，增强宿主免疫反应的自组装肽可以提供精确的作用机理的化学定义疫苗佐剂。另一方面，减少宿主免疫反应的自组装肽可以通过减轻组织或植入物排斥的潜力来提高组织工程疗法的功效。该项目的指导下是通过假设，即用异物蛋白质装饰的自组装肽将引起强大的免疫反应，而自然组合的肽则设计为模拟自然系统中抑制免疫反应的机制，将减少这些生物材料的免疫原性。该项目基于对肽抗原装饰的自组装肽生物材料的明确定义的免疫反应，在没有抗原的情况下，该反应是非免疫原性的。 AIM 1将设计呈现蛋白质抗原的免疫原性自组装肽生物材料。模型蛋白抗原绿色荧光蛋白（GFP）将通过形成与GFP融合的酶与材料提出的配体之间形成共价键，将自组装的肽生物材料固定在自组装的肽生物材料上。 GFP修饰的自组装肽生物材料的免疫原性将在小鼠模型中在体内表征。这些研究旨在提供原则上的证明，表明用蛋白质抗原装饰的自组装肽生物材料会引起鲁棒和长寿命的免疫反应。该目标的结果将为针对临床上与临床相关的病原体（例如耐甲氧西林的金黄色葡萄球菌）开发基于生物材料的疫苗提供基础。 AIM 2将通过模仿天然免疫特权机制来设计自组装的肽生物材料，从而减少抗材料免疫反应。在此目的中，S.A.1中开发的GFP修饰的自组装肽生物材料将通过二糖进一步修饰，该二糖非共价结合与蛋白质galectin-1。 lectectin-1作为免疫反应的负调节剂的选择是基于半乳糖素在肿瘤免疫特权和胎儿妇女耐受性中的欢迎作用。在存在或不存在可溶性半乳糖素-1的情况下，将用GFP和半乳糖素结合二糖装饰的自组装肽生物材料将被注入小鼠。对这些材料的免疫反应将使用与S.A.1相同的模型和方法进行分析。这些研究旨在提供原则上的证明，即生物材料设计为模仿免疫特权的天然机制，从而减少了对材料的免疫反应。此目标的结果将为开发生物材料的基础，以减少宿主免疫反应，以限制组织工程和再生医学疗法的组织或植入物的排斥。