Immunology of xenogeneic extracellular matrix scaffolds for heart valve tissue engineering

心脏瓣膜组织工程异种细胞外基质支架的免疫学

基本信息

批准号：
10199250
负责人：
Leigh Gareth Griffiths
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10199250
关键词：
Address Age American Heart Association Animal Model Antigen Targeting Antigens Biocompatible Materials Biological Biomaterials Research Bioprosthesis device Cardiac Surgery procedures Cattle Child Chronic Clinical Development Disease Ensure Excision Experimental Designs Extracellular Matrix Extracellular Matrix Proteins Failure Fibrosis Generations Glutaral Goals Heart Valve Diseases Heart Valve Prosthesis Heart Valves Heterophile Antigens Human Immune Immune Tolerance Immune mediated destruction Immune response Immunologics Immunology In Vitro Individual Inflammatory Innate Immune Response Knowledge Life Mediating Modeling Molecular Structure National Heart, Lung, and Blood Institute Outcome Patients Phase Play Population Prevalence Procedures Production Property Protein Chemistry Proteomics Protocols documentation Recommendation Regenerative response Reporting Residual state Role Safety Sheep Signal Transduction Site Source Tissue Engineering Tissues Translations United States Xenograft procedure adaptive immune response base calcification cardiac tissue engineering clinical practice clinical translation design experimental study heart valve replacement immunogenic immunogenicity implantation improved in vivo innovation insight longitudinal design macrophage next generation oxidation pericardial sac phase 1 designs prevent receptor regenerative response scaffold sheep model success translation to humans valve replacement working group

项目摘要

ABSTRACT: American Heart Association estimates a 2.5% prevalence of valvular heart disease in the US, requiring over 100,000 valve replacements annually. Current replacement heart valves are far from ideal, leading the NHLBI cardiac surgery working group to recommend increased support for heart valve biomaterial research. Although glutaraldehyde fixed xenogeneic tissue valves (e.g., bovine pericardium (BP)) improve short-term survival, chronic graft-specific immune responses persist, resulting in long-term biomaterial damage, calcification and ultimately failure (~2-10 yr depending on age at implantation). Indeed, NHLBI xenotransplantation working group noted that biomaterial antigenicity represents the primary translational barrier to expanding the use of xenogeneic tissues in clinical practice. Unfixed BP in which human-relevant antigens are eliminated has potential to serve as an immunologically-acceptable extracellular matrix (ECM) scaffold for heart valve bioprostheses. However, identifying human-relevant BP antigens and facilitating their removal from candidate ECM scaffolds represent critical translational barriers for development of such biomaterials. We hypothesize that elimination of human- relevant antigens can be achieved by employing targeted antigen solubilization steps during BP ECM scaffold production. This proposal seeks to define primary BP antigens responsible for initiating graft-specific immune responses in human patients (Aim 1, Phase 1), quantify removal (Aim 1, Phase 2) and target elimination of such human-relevant antigens from BP ECM scaffolds (Aim 1, Phase 3). Unfixed ECM scaffolds that avoid destructive graft-specific adaptive immune responses have potential to modulate constructive pro-regenerative recipient innate immune responses. Our group has previously demonstrated that retention of native tissue ECM niche in BP scaffolds is critical to promoting pro-regenerative in vivo recipient responses. However, extent to which exposure of natural matricryptic sites can further enhance pro-regenerative innate immune polarization towards intact BP ECM scaffolds remains unknown. We hypothesize that ECM niche and matricryptic signal exposure are critical factors in modulating human macrophage polarization and ultimate in vivo scaffold fate. This proposal aims to determine mechanisms (i.e., ECM niche component and macrophage receptor) by which differing sources of matricryptic signal exposure modulate human macrophage polarization (Aim 2, Phase 1) and combine optimal levels of each matricryptic exposure source toward maximizing pro-regenerative polarization (Aim 2, Phase 2). Aim 1 and 2 factors identified as having potential to positively modulate in vivo scaffold fate in humans will be validated using an in vivo ovine heart valve replacement model (Aim 3). Completion of this proposal will provide mechanistic insights into human-relevant antigens responsible for initiating graft-specific immune response towards current clinically-utilized xenogeneic biomaterials, define mechanisms by which matricryptic signaling modulates human macrophage polarization and leverage these findings towards development of next generation immunologically-acceptable pro-regenerative unfixed BP ECM scaffolds for heart valve replacements.

抽象的：美国心脏协会估计在美国估计瓣膜心脏病的患病率为2.5％每年100,000个阀门更换。当前的替换心脏阀远非理想，领导NHLBI 心脏手术工作组建议增加对心脏瓣膜生物材料研究的支持。虽然戊二醛固定异构组织瓣膜（例如牛心包（BP））改善了短期存活，慢性移植特异性免疫反应持续存在，导致长期生物材料损害，钙化和最终失败（〜2-10岁，取决于植入时的年龄）。确实，NHLBI异种移植工作组指出生物材料抗原性代表扩大异构化使用的主要翻译障碍临床实践中的组织。消除与人相关的抗原的未结合的BP有潜力心脏瓣膜生物蛋白酶的免疫学上可接受的细胞外基质（ECM）支架。然而，识别与人与人相关的BP抗原并促进其从候选ECM脚手架中取出这种生物材料发展的关键翻译障碍。我们假设消除人类可以通过在BP ECM支架期间采用靶向抗原溶解步骤来实现相关的抗原生产。该建议旨在定义负责启动移植物特异性免疫的主要BP抗原人类患者的反应（AIM 1，阶段1），量化去除（AIM 1，阶段2）和目标消除此类目标来自BP ECM支架的与人相关的抗原（AIM 1，第3阶段）。取消避免破坏性的ECM脚手架移植物特异性的适应性免疫反应有可能调节建设性促增长受体先天免疫反应。我们的小组以前已经证明了天然组织ECM生态位的保留 BP脚手架对于促进体内受体反应的促进再生至关重要。但是，在多大程度上天然母晶部位的暴露可以进一步增强促增长的先天免疫极化完整的BP ECM支架仍然未知。我们假设ECM利基和母体信号暴露是调节人类巨噬细胞极化和最终体内支架命运的关键因素。这个建议旨在确定不同的机制（即ECM细分成分和巨噬细胞受体）母系信号暴露的来源调节人类巨噬细胞极化（AIM 2，阶段1），并结合每种母系暴露源的最佳水平，以最大化促启动性极化（AIM 2，第2阶段）。 AIM 1和2的因素被确定为有可能在人体中调节体内支架命运的潜力将使用体内卵子心脏阀替换模型进行验证（AIM 3）。该提议的完成将提供有关负责发起移植特异性免疫的与人相关的抗原的机械见解对当前临床利用的异构生物材料的反应，定义了基质的机制信号传导调节人类巨噬细胞极化，并利用这些发现来发展下一步可通过免疫学上的产生可接受的促增再生的未固定BP ECM支架，用于替代心脏瓣膜。