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Biomarkers for early organ transplant rejection

A mouse pancreatic islet near a blood vessel; insulin in red, nuclei in blue.Jakob Suckale, Solimena lab, Paul Langerhans Institute Dresden/CC BY-SA 3.0

Organ and tissue transplants can be lifesaving. But a patient’s immune system may attack the new organ, causing the transplant to fail. Doctors can monitor whether a patient’s body is rejecting the organ using different methods, depending on the organ.

In people with type 1 diabetes, clusters of cells in the pancreas called islets are destroyed. These cells control blood sugar (glucose) levels. Pancreatic islet transplantation is performed in certain patients whose blood glucose levels are especially difficult to control. Tracking the patient’s blood glucose level is the current standard for monitoring islet cell transplant rejection. However, high blood glucose levels are a sign of an advanced stage of rejection. The ability to detect tissue rejection earlier―when fewer cells have been injured―would allow doctors to adjust treatments and help reduce damage to transplanted islets.

Many tissues release tiny, fluid-filled sacs called exosomes into the blood and other bodily fluids. These sacs are filled with tissue-specific proteins and genetic material. To investigate whether exosomes can be used as biomarkers to predict earlier stages of rejection, a research team led by Drs. Prashanth Vallabhajosyula and Ali Naji at the University of Pennsylvania transplanted human islet cells into mice. The work was funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), and National Center for Advancing Translational Sciences (NCATS). Results appeared online on March 20, 2017, in the Journal of Clinical Investigation.

The researchers first confirmed that transplanted islets released exosomes into the animals’ bloodstreams. These exosomes had donor-specific markers on their surfaces that could be used for detection. They also contained genetic material and proteins specific to pancreatic islets. Levels of the donor cell-released exosomes dropped sharply in the bloodstream―and their contents changed―before glucose levels changed in response to tissue rejection.

The scientists next analyzed blood samples from 5 people with type 1 diabetes who were enrolled in an islet transplantation clinical trial sponsored by NIH. The team showed that donor islet cell-released exosomes could be reliably characterized throughout a 5-year follow-up period. One patient experienced rejection of the transplanted islets. Researchers detected a decrease in donor cell-exosomes in this patient 6 months prior to an increase in blood glucose. In the 4 patients who didn’t undergo rejection, no decrease in donor cell exosomes was observed. The team also demonstrated that exosomes could be isolated and characterized from urine by analyzing samples from 5 people receiving kidney transplants.

These findings suggest that exosomes might one day be used to detect transplant injury earlier than current techniques. “I believe that analyses of exosomes released by transplanted organs into the patients’ blood will ultimately provide a very powerful and unprecedented ability to understand the conditional state of the organ as a whole,” Naji says.

—Tianna Hicklin, Ph.D.