Organ transplantation significantly improves patient survival and quality of life. However, majority of patients suffer from complications associated with the transplanted organ, such as acute and chronic rejection, over- immunosuppression, and infection. Currently, there is a critical need for simple, time-sensitive, reliable, and non-invasive methods to monitor transplant patients for donor organ rejection/ injury. Such a biomarker assay would enable early intervention, immunosuppression titration, and thus improve patient morbidity and mortality. This problem is especially relevant to the fields of heart and lung transplantation, where to this date there is no serum biomarker assay to monitor the status of the transplanted heart or lung. Exosomes are extracellular microvesicles released by many tissues into bodily fluids, including blood and urine. They represent stable and tissue-specific proteomic and RNA signature profiles that reflect the conditional state of their tissue of origin. Our group has shown that tissue specific exosome profiles and their RNA signatures are distinct in conditions of health versus injury/ pathology. Therefore, understanding tissue specific exosome profiles from bodily fluids has promise to serve as a "liquid biopsy" of the status of their tissue of origin. No study, to date, has assessed the exosome platform in the context of monitoring transplant organ status, or has shown whether transplant organ releases donor tissue-specific exosomes into the recipient blood/ bodily fluids. To our knowledge, we are the first to report that transplanted organ tissue releases a stable and detectable pool of donor-specific exosomes into the recipient blood/ bodily fluids. Given this proof of novel concept, we hypothesize that donor organ exosome platforms are distinct based on the conditional state of the transplanted organ - maintenance versus rejection/ injury. Therefore, isolation and characterization of transplant organ-specific exosomes and their associated RNA cargo, along with correlation of their differential expression with clinicopathologic data would lay the groundwork for development of a novel, time-sensitive, accurate, and non- invasive biomarker assay to monitor for transplant organ rejection/ injury. Since no study to date has characterized transplant organ specific exosome pools, we propose to investigate this novel concept in two in vivo transplant models: (1) established mouse model of heterotopic heart transplantation under controlled settings of tolerance versus rejection, and;(2) human living donor renal transplantation in the clinical setting. In both settings we will characterize transplant organ specific exosome pools and their RNA signatures in conditions of health versus rejection/ injury to discover distinct profiles associated with organ injury that would serve as the platform for the development of novel biomarker assay to monitor transplant rejection/ injury.

Public Health Relevance

In the field of organ transplantation, there is a critical need for the development of reliable and time-sensitive serum biomarkers to monitor for organ rejection/ injury, which remains a major cause of morbidity and mortality in transplant patients. To our knowledge, we are the first group to report that transplanted organs release donor tissue-specific microvesicles called exosomes into the recipient blood stream and other bodily fluids. We propose that the study of these donor organ-specific exosome profiles from transplant recipient patients'blood/ bodily fluids can serve as a novel, non-invasive, accurate, and time-sensitive biomarker assay to monitor transplant organ rejection/injury.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Rice, Jeffrey S
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University of Pennsylvania
Schools of Medicine
United States
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