Dendritic cell phenotype upon contact with biomaterials

说明(申请人提供)：组合产品可以将生物材料与细胞、DNA或蛋白质结合；例如，组织工程构建物和疫苗的非病毒聚合载体。组合产品的生物成分可以通过设计(例如DNA疫苗)或通过选择(例如组织工程构建中的同种或异种细胞)具有免疫原性。由于生物材料在这种组合产品中用作载体，因此，由于生物材料的佐剂作用，阐明生物材料成分在增强对生物成分的免疫反应中的作用是很重要的。树突状细胞(DC)在先天免疫中发挥作用，识别外来病原体和启动适应性免疫反应的危险信号。本研究的目的是了解生物材料接触对DC表型的影响、生物材料化学的作用及其机制。该项目的长期目标是在分子水平上设计生物材料来控制DC表型，并通过这种方式控制免疫反应。具体地说，生物材料将被设计为不支持免疫反应不受欢迎的DC成熟，如组织工程设备，而设计为支持免疫反应所需的DC成熟，如疫苗的非病毒递送载体。该研究计划包括以下具体目标：(1)证明生物材料接触足以使DC成熟为有效的抗原提呈细胞(APC)和T细胞刺激器，并且成熟受到不同类型和形式的生物材料的不同调控。(2)阐明生物材料诱导DC成熟的机制，特别是涉及先天免疫系统Toll样受体(TLRs)的受体。(3)生物材料化学通过吸附蛋白质层影响DC成熟过程。(4)评估DC在生物材料存在下的成熟程度，使其在调节对设备相关抗原的适应性免疫反应中扮演专业APC的角色。

DESCRIPTION (provided by applicant): Combination products can combine biomaterials with cells, DNA or proteins; e.g. tissue engineered constructs and non-viral polymeric carriers for vaccines. The biological component of combination products can be immunogenic either by design (e.g., DNA vaccine) or by selection (e.g., allogeneic or xenogeneic cells in a tissue engineered construct). Since biomaterials are used as vehicles in such combination products it is important to clarify the role of the biomaterial component in potentiating the immune responses towards the biological component due to the adjuvant effect of the biomaterial. Dendritic cells (DCs) function in innate immunity to recognize foreign pathogens and 'danger signals' to initiate an adaptive immune response. The goal of this research is to understand the effect of biomaterial contact on DC phenotype, the role of biomaterial chemistry and the mechanism involved. The long-term goal of this project is to design biomaterials on a molecular level to control DC phenotype and in this way control immune responses. Specifically, biomaterials will be designed to not support DC maturation where immune responses are undesirable, as for tissue engineered devices, while designed to support DC maturation where immune responses are desired, as for non-viral delivery vehicles for vaccines. The research plan is comprised of the following specific aims: (1) Demonstrate that biomaterial contact is sufficient for DC maturation into efficient antigen presenting cells (APCs) and T cell stimulators, and that maturation is differentially regulated depending on the type and form of the biomaterial. (2) Elucidate the mechanism of DC maturation by biomaterials, particularly the receptors involved focusing on Toll-like receptors (TLRs) of the innate immune system. (3) Show that biomaterial chemistry influences the process of DC maturation through an adsorbed protein layer. (4) Evaluate the extent of DCs maturation in the presence of biomaterials such that they act as professional APCs in mediating an adaptive immune response to device-associated antigens.