Molecular assemblies as immunomodulators

描述（由申请人提供）：调节宿主免疫应答的生物分子组装体在免疫治疗和组织工程应用中具有广泛的潜力。例如，增强宿主免疫应答的自组装肽可以提供具有精确作用机制的化学上明确定义的疫苗佐剂。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可能性来提高组织工程治疗的功效。该项目的指导假设是，用外源蛋白修饰的自组装肽将引起强烈的免疫反应，而经工程改造以模拟抑制天然系统内免疫反应的机制的自组装肽将降低这些生物材料的免疫原性。该项目是基于对肽抗原修饰的自组装肽生物材料的明确的免疫应答，所述肽抗原修饰的自组装肽生物材料在不存在抗原的情况下是非免疫原性的。目的1设计具有免疫原性的自组装肽生物材料，提呈蛋白质抗原。模型蛋白抗原绿色荧光蛋白（GFP）将通过与GFP融合的酶和由材料呈递的配体之间形成共价键而固定在自组装肽生物材料上。然后将在小鼠模型中体内表征GFP修饰的自组装肽生物材料的免疫原性。这些研究旨在提供用蛋白抗原修饰的自组装肽生物材料引发稳健且长寿命的免疫应答的原理证明。这一目标的结果将为开发针对临床相关病原体（如耐甲氧西林金黄色葡萄球菌）的生物材料疫苗提供基础。目标2将设计自组装肽生物材料，通过模仿天然免疫豁免机制来减少抗材料免疫反应。为此，S.A.1中开发的GFP修饰的自组装肽生物材料将进一步用非共价结合蛋白质半乳糖凝集素-1的二糖修饰。选择半乳糖凝集素-1作为免疫应答的负调节剂是基于半乳糖凝集素在肿瘤免疫豁免和胎儿-母体耐受中的良好作用。然后将用GFP和半乳糖凝集素结合二糖修饰的自组装肽生物材料在存在或不存在可溶性半乳糖凝集素-1的情况下注射到小鼠中。将使用与S.A.1相同的模型和方法分析对这些材料的免疫反应。这些研究旨在提供原理性证据，证明经工程改造以模拟天然免疫豁免机制的生物材料可减少对材料的免疫反应。这一目标的结果将为开发生物材料提供基础，这些生物材料可减少宿主免疫反应，以限制组织工程和再生医学治疗的组织或植入物的排斥反应。 公共卫生相关性：增强免疫应答的生物分子组装体在免疫治疗应用中是有希望的，而减少免疫应答的生物分子组装体可以通过减轻植入物或组织排斥的可能性来提高组织工程治疗的功效。该项目提出，用外源蛋白修饰的组装体将引发强大的免疫应答;而模拟在自然系统中观察到的下调免疫应答的机制的组装体将降低这些材料的免疫原性。通过建立可以推广到各种不同生物材料的调节免疫反应的机制，本研究将为开发用于不同组织工程和免疫治疗应用的调节免疫反应的生物材料提供基本的设计规则。!

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. PUBLIC HEALTH RELEVANCE: Biomolecular assemblies that boost immune response are promising in immunotherapy applications, while biomolecular assemblies that diminish immune response can improve the efficacy of tissue engineering therapies by alleviating the potential for implant or tissue rejection. This project proposes that assemblies decorated with foreign proteins wil elicit robust immune responses; while assemblies that mimic mechanisms to down-regulate immune responses observed in natural systems will diminish the immunogenicity of these materials. By establishing mechanisms to modulate immune response that can be generalized to a variety of different biomaterials, this study will provide fundamental design rules to develop biomaterials that modulate immune responses for diverse tissue engineering and immune therapy applications. !