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：
10379320
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/10379320
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 rational design receptor regenerative response scaffold sheep model success translation to humans translational barrier 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：美国心脏协会估计美国瓣膜性心脏病的患病率为 2.5%，需要超过每年更换 100,000 个阀门。目前的置换心脏瓣膜远非理想，领先 NHLBI 心脏外科工作组建议增加对心脏瓣膜生物材料研究的支持。虽然戊二醛固定异种组织瓣膜（例如牛心包（BP））可提高短期存活率，慢性移植物特异性免疫反应持续存在，导致长期生物材料损伤、钙化和最终失败（~2-10岁，取决于植入时的年龄）。事实上，NHLBI 异种移植工作组指出生物材料的抗原性是扩大异种材料使用的主要转化障碍临床实践中的组织。消除人类相关抗原的未固定血压有可能作为用于心脏瓣膜生物假体的免疫学可接受的细胞外基质（ECM）支架。然而，识别人类相关的 BP 抗原并促进其从候选 ECM 支架中去除代表开发此类生物材料的关键转化障碍。我们假设消除人类相关抗原可以通过在 BP ECM 支架过程中采用靶向抗原溶解步骤来获得生产。该提案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（目标 1，阶段 1），量化去除（目标 1，阶段 2）并目标消除此类来自 BP ECM 支架的人类相关抗原（目标 1，第 3 阶段）。不固定的 ECM 支架可避免破坏性移植物特异性适应性免疫反应有可能调节受者的建设性促再生先天免疫反应。我们的小组之前已经证明，天然组织 ECM 生态位的保留 BP 支架对于促进体内受体反应的促再生至关重要。然而，在多大程度上暴露天然基质位点可以进一步增强促再生先天免疫极化完整的 BP ECM 支架仍然未知。我们假设 ECM 利基和基质信号暴露是调节人巨噬细胞极化和最终体内支架命运的关键因素。这个提议旨在确定不同的机制（即 ECM 生态位成分和巨噬细胞受体）基质信号暴露源调节人类巨噬细胞极化（目标 2，阶段 1）并结合每个矩阵暴露源的最佳水平，以最大化促再生极化（目标 2，第 2 阶段）。目标 1 和目标 2 因素被确定为具有积极调节人类体内支架命运的潜力将使用体内绵羊心脏瓣膜置换模型进行验证（目标 3）。该提案的完成将提供对负责启动移植物特异性免疫的人类相关抗原的机制见解对当前临床使用的异种生物材料的反应，定义了基质隐性的机制信号传导调节人类巨噬细胞极化，并利用这些发现来开发下一代生成免疫学上可接受的促再生未固定 BP ECM 支架，用于心脏瓣膜置换术。