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，是排名前十的疾病之一 儿科死亡原因。超过50%的移植器官在移植后10年内从 抗体介导的排斥反应，这是目前器官短缺的重要原因。的发展。 对移植器官产生抗体的原因多种多样，包括多次输血，在 服用抗排斥药物、既往移植或怀孕。这些抗体会破坏 器官移植导致同种异体移植失败，增加病人死亡率。要克服此限制，请使用 移植肾病学、生物医学工程、免疫学和 在血液学方面，我们开发了一种靶向抗体去除的创新方法。目前的治疗方法 抗体介导的排斥反应不是供者特有的，也不是为儿童量身定做的。分离，一种 抗体介导的排斥反应的标准疗法包括一台抗体去除机器，该机器已经被 是为成年人开发的。然而，在儿童中使用当前的设备与多种疾病有关 包括低血压和需要输血以维持血流动力学稳定，这反过来 刺激更多的抗体产生。此外，婴儿由于体型较小，常常没有资格接受人工授精。 尺码。分离也受到非特异性抗体清除和显著抗体反弹的限制。缺乏一种 可伸缩的分离机不仅排除了对小血量儿童的治疗，而且还限制了 开发合适的临床前模型以测试安全性和治疗效果。在之前的研究中，我们表明 声流分离器能够利用声波有效地将抗体从 其他细胞成分，如小体积的红细胞、白细胞和血小板(&lt；20 毫升)全血和致敏啮齿动物模型。我们已经成功地开发出抗原特异性珠子来 捕获啮齿动物体内的供体抗体。我们的中心假设是诱捕技术的创新性增加 将导致更有效的治疗抗体介导的排斥反应比目前的方法，通过去除供体- 更有效地产生特异性抗体，保持内源性免疫，减少抗体反弹。要实现 为此，我们将开发一种利用仔猪血液样本在声流控装置中捕获抗体的方法 抗体水平很高。同时，我们将检查体内的仔猪致敏模型，其中抗体 对供体抗原的水平极高。我们的总体目标是开发一种声流分离设备 这去除了针对移植器官的有害抗体，留下了有益的抗体。 它能抵抗感染。有效治疗抗体介导的排斥反应的能力将降低儿童死亡率， 延长移植器官的寿命，有助于缓解器官短缺。这部小说的应用 设备将是范式转换的，可以直接翻译给进行实体器官移植的儿童，以及 自身免疫性疾病，从而挽救了无数儿童的生命。