Molecular assemblies as immunomodulators

描述(申请人提供)：调节宿主免疫反应的生物分子组件在免疫治疗和组织工程应用中具有广泛的潜力。例如，增强宿主免疫反应的自组装肽可能会为化学上定义明确的疫苗佐剂提供精确的作用机制。另一方面，减少宿主免疫反应的自组装肽可能通过减轻组织或植入物排斥反应的可能性来提高组织工程疗法的疗效。该项目的指导假设是，用外源蛋白质修饰的自组装肽将引发强大的免疫反应，而模仿自然系统内抑制免疫反应的机制而设计的自组装肽将降低这些生物材料的免疫原性。这个项目是基于对多肽抗原修饰的自组装多肽生物材料的明确免疫应答，这些生物材料在没有抗原的情况下是非免疫原性的。目标1将设计呈现蛋白质抗原的免疫原性自组装多肽生物材料。模型蛋白抗原绿色荧光蛋白(GFP)将通过融合到GFP的酶与该材料呈现的配体之间形成共价键，固定在自组装的多肽生物材料上。GFP修饰的自组装肽生物材料的免疫原性随后将在小鼠模型中进行体内表征。这些研究的目的是提供原理证明，用蛋白质抗原装饰的自组装多肽生物材料可以诱导强大而持久的免疫反应。这一目标的结果将为开发基于生物材料的疫苗以对抗临床相关病原体，如耐甲氧西林金黄色葡萄球菌提供基础。AIM 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物质免疫反应。为此，S.A.1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到蛋白Galectin-1上的双糖进行修饰。选择Galectin-1作为免疫反应的负性调节剂是基于Galectins在肿瘤免疫豁免和母胎耐受中的公认作用。然后，在存在或不存在可溶性Galectin-1的情况下，用GFP和Galectin结合的二糖修饰的自组装多肽生物材料将被注射到小鼠体内。对这些材料的免疫反应将使用与S.A.1中相同的模型和方法进行分析。这些研究旨在提供原理证据，即模仿免疫豁免天然机制的生物材料会减弱对该材料的免疫反应。这一目标的成果将为开发减少宿主免疫反应的生物材料提供基础，以限制组织工程和再生医学治疗中组织或植入物的排斥反应。 公共卫生相关性：增强免疫反应的生物分子组件在免疫治疗应用中很有希望，而降低免疫反应的生物分子组件可以通过减轻植入或组织排斥的可能性来提高组织工程疗法的疗效。该项目提出，用外来蛋白质装饰的组件将引起强大的免疫反应；而模仿在自然系统中观察到的下调免疫反应的机制的组件将降低这些材料的免疫原性。通过建立可推广到各种不同生物材料的免疫反应调节机制，本研究将为开发用于各种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设计规则。好了！

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. !