Development of a novel acoustofluidic device for targeted antibody removal in pediatric organ transplant rejection

开发一种新型声流控装置，用于去除儿科器官移植排斥反应中的靶向抗体

• 批准号: 10372229
• 负责人: Eileen Tsai Chambers
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10372229
• 关键词: Acoustics; Address; Adult; Allografting; Animals; Antibodies; Antibody Formation; Antibody Therapy; Antigens; Autoimmune Diseases; Biomedical Engineering; Blood; Blood Cells; Blood Circulation; Blood Coagulation Factor; Blood Component Removal; Blood Platelets; Blood Transfusion; Blood Volume; Blood specimen; Cell Separation; Cells; Cellular Structures; Cessation of life; Child; Childhood; Coupling; Development; Devices; Disease; Dose; Engineering; Erythrocytes; Excision; Failure; Family suidae; Future; Goals; Graft Rejection; HLA Antigens; Heart Transplantation; Hematology; Hemorrhage; Human; Hypersensitivity; Hypotension; Immunity; Immunology; In Vitro; Infant; Infection; Interdisciplinary Study; Isoantibodies; Leukocytes; Life; Liquid substance; Longevity; Mediating; Methods; Modeling; Morbidity - disease rate; Mus; Nephrology; Organ; Organ Transplantation; Organ failure; Patients; Pharmaceutical Preparations; Physiological; Polystyrenes; Positioning Attribute; Pre-Clinical Model; Pregnancy; Process; Production; Rattus; Rodent; Rodent Model; Safety; Savings; Solid; Specificity; System; Technology; Testing; Time; Transfusion; Translating; Transplant Recipients; Transplant-Related Disorder; Transplantation; Treatment Efficacy; United States; Whole Blood; antibody-mediated rejection; base; combat; design; donor-specific antibody; effective therapy; fighting; hemodynamics; high risk; in vivo; in vivo Model; innovation; instrument; mortality; novel; organ transplant rejection; porcine model; post-transplant; pre-clinical; preservation; prototype; safety testing; sound; transplant model

ABSTRACT Antibody-mediated diseases, including those associated with solid organ transplantation, are one of the top ten causes of pediatric death. Over 50% of transplanted organs are lost by 10 years post-transplantation from antibody-mediated rejection, which contributes significantly to the current organ shortage. The development of antibodies to the transplanted organ occurs for various reasons including multiple blood transfusions, under dosing of anti-rejection medications, previous transplants or pregnancy. These antibodies damage the transplanted organ resulting in allograft failure and increased patient mortality. To overcome this limitation, using a multi-disciplinary collaboration between transplant nephrology, biomedical engineering, immunology, and hematology, we have developed an innovative approach for targeted antibody removal. Current therapies for antibody-mediated rejection are not donor specific nor are they tailored toward children. Apheresis, one of the standard therapies for antibody-mediated rejection, involves a machine for antibody removal that has been developed for adults. The use of the current devices in children, however, is associated with multiple morbidities including hypotension and the need for blood transfusions to maintain hemodynamic stability, which in turn stimulates more antibody production. Additionally, infants are often ineligible for apheresis due to their small size. Apheresis is also limited by non-specific antibody removal and significant antibody rebound. Lack of a scalable apheresis machine precludes not only treatment of children with small blood volumes, but also limits development of suitable pre-clinical models for testing safety and therapeutic efficacy. In prior studies, we show that an acoustofluidic apheresis device is capable of using sound waves to efficiently separate antibody from other cellular components such as red blood cells, white cells and platelets in small extracorporeal volumes (<20 mL) of whole blood and in sensitized rodent models. We have successfully developed antigen-specific beads to capture donor antibodies in rodents. Our central hypothesis is that the innovative addition of trapping technology will lead to more effective treatment of antibody-mediated rejection than current approaches by removing donor- specific antibody more efficiently, preserving endogenous immunity and reducing antibody rebound. To achieve this end, we will develop an antibody trapping method within an acoustofluidic device using piglet blood samples with high levels of antibody. In parallel, we will examine an in vivo piglet sensitization model, where antibody levels to donor antigens are extremely elevated. Our overall goal is to develop an acoustofluidic apheresis device that removes the detrimental antibody specific to the transplanted organ and leaves behind beneficial antibodies that fight infection. The ability to effectively treat antibody-mediated rejection will decrease pediatric mortality, increase the life span of transplanted organs, and help alleviate organ shortages. The application of this novel device will be paradigm shifting and directly translatable to children with solid organ transplantation, as well as autoimmune disease, thus saving the lives of numerous children.

摘要 抗体介导的疾病，包括与实体器官移植相关的疾病，是十大疾病之一 儿科死亡的原因超过50%的移植器官在移植后10年内丢失， 抗体介导的排斥反应，这是导致目前器官短缺的重要原因。的发展 针对移植器官的抗体的产生有多种原因，包括多次输血， 抗排斥药物的剂量、既往移植或妊娠。这些抗体破坏了 移植器官导致同种异体移植失败和增加患者死亡率。为了克服这一限制，使用 移植肾脏学、生物医学工程、免疫学和 血液学，我们已经开发了一种创新的方法，有针对性的抗体去除。的现行疗法 抗体介导的排斥不是供体特异性的，也不是针对儿童的。单采术， 抗体介导的排斥反应的标准疗法，涉及一种用于去除抗体的机器， 为成人开发的。然而，在儿童中使用当前设备与多种发病率相关 包括低血压和需要输血以维持血流动力学稳定， 刺激更多的抗体产生。此外，由于婴儿的小， 尺寸单采还受到非特异性抗体去除和显著抗体反弹的限制。缺乏 可扩展的单采机不仅排除了对血容量小的儿童的治疗， 开发用于测试安全性和治疗功效的合适的临床前模型。在之前的研究中，我们发现 声流单采装置能够使用声波有效地将抗体从 其它细胞成分，如红细胞、白色细胞和血小板，在小的体外体积（<20 mL）的全血和致敏啮齿动物模型中。我们已经成功地开发了抗原特异性珠粒， 捕捉啮齿动物体内的供体抗体。我们的核心假设是，诱捕技术的创新性增加 将导致比目前的方法更有效的治疗抗体介导的排斥反应， 更有效地产生特异性抗体，保留内源性免疫力并减少抗体反弹。实现 为此，我们将开发一种使用仔猪血液样品的声流控装置内的抗体捕获方法 抗体水平很高同时，我们将研究体内仔猪致敏模型，其中抗体 供体抗原的水平非常高。我们的总体目标是开发一种声流分离装置 去除对移植器官有特异性的有害抗体，留下有益抗体 that fight战斗infection感染.有效治疗抗体介导的排斥反应的能力将降低儿科死亡率， 延长移植器官的寿命，帮助缓解器官短缺。这本小说的应用 该设备将是范式转移，并直接转移到儿童与实体器官移植，以及 自身免疫性疾病，从而挽救了许多儿童的生命。