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

基本信息

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
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/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

项目摘要

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.

抽象的抗体介导的疾病，包括与实体器官移植相关的疾病，是十大疾病之一儿童死亡的原因。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，这在很大程度上导致了当前的器官短缺。的发展移植器官产生抗体的原因有多种，包括多次输血、抗排斥药物的剂量、先前的移植或怀孕。这些抗体会破坏移植器官导致同种异体移植失败并增加患者死亡率。为了克服这个限制，使用移植肾病学、生物医学工程、免疫学和在血液学方面，我们开发了一种用于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体特异性的，也不是针对儿童的。血浆分离术，其中之一抗体介导的排斥反应的标准疗法涉及一台用于去除抗体的机器，该机器已被专为成人开发。然而，儿童使用现有设备会导致多种疾病包括低血压和需要输血以维持血流动力学稳定，这反过来又刺激更多抗体产生。此外，婴儿由于体型较小，通常不适合进行血浆分离术。尺寸。单采术还受到非特异性抗体去除和显着抗体反弹的限制。缺乏一个可扩展的单采机不仅妨碍了对血量较少的儿童的治疗，而且限制了开发合适的临床前模型来测试安全性和治疗效果。在之前的研究中，我们表明声流控单采装置能够利用声波有效地将抗体与其他细胞成分，例如小体外体积中的红细胞、白细胞和血小板（<20 mL）全血和致敏啮齿动物模型。我们已成功开发出抗原特异性珠子捕获啮齿动物中的供体抗体。我们的中心假设是捕获技术的创新添加通过去除供体，将比目前的方法更有效地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，减少抗体反弹。达到为此，我们将使用仔猪血液样本在声流控装置内开发一种抗体捕获方法具有高水平的抗体。与此同时，我们将检查体内仔猪致敏模型，其中抗体供体抗原的水平极高。我们的总体目标是开发声流控单采装置去除移植器官特有的有害抗体并留下有益抗体对抗感染。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，有助于缓解器官短缺。这部小说的应用该设备将实现范式转变，并可直接应用于接受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。