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

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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.