MicroRNAs provide telltale signature of organ rejection

Nobody likes rejection. For most people it means emotional distress, but for people with organ transplants, rejection could mean organ loss or even the loss of life.

Now scientists have found a signature of organ rejection that could help detect the disorder and treat it before transplanted organs sustain damage, the team reports online March 16 in the Proceedings of the National Academy of Sciences.

Researchers led by Manikkam Suthanthiran, a transplant physician at NewYork-Presbyterian Hospital and Weill Cornell Medical College in New York City, uncovered a pattern of microRNA levels that distinguishes healthy transplanted tissue from tissue undergoing acute rejection.

MicroRNAs are very short pieces of RNA about 20 units long. The molecules are small but mighty, regulating hundreds to thousands of genes by attaching to the messenger RNAs, or mRNAs, made by those genes. Some mRNAs are stabilized by their micro-partners to prevent breakdown. Others are slated for destruction. MicroRNAs may also prevent protein-building machinery from using the mRNA as a template until certain conditions are met.

Suthanthiran and his colleagues had previously identified two mRNAs in urine that reveal when a kidney is being rejected. But the method predicts rejection with only about 85 percent accuracy, Suthanthiran says. And mRNAs are notoriously fragile, breaking down easily. MicroRNAs, on the other hand, are far more stable and easy to work with, and their vast regulatory reach made them ideal candidates for markers of rejection.

In the new study, the researchers took blood from and biopsied patients with transplanted kidneys, both patients with healthy transplanted kidneys and patients whose transplanted kidneys were beginning to fail. The team found increased levels of three microRNAs — miR-142-5p, miR-155 and miR-223 — in purified white blood cells in people whose kidneys were being rejected. Biopsies showed that levels of three other microRNAs — miR-10b, miR-30a-3p and let-7c — decrease in kidney tissues during rejections.

Elevated levels of miR-142-5p, miR-155 and miR-223 probably indicate that immune cells are infiltrating the kidney and setting off inflammation and damage. Decreased levels of the other three microRNAs could indicate damage to the kidney cells, Suthanthiran says. The researchers hope in the future to detect the signature before organ damage occurs. They don’t yet know what the first step in the rejection process is — whether the kidney sends out a signal that invites immune cells in, or immune cells invade the kidney and sound an alarm when they recognize foreign tissue, he says.

Techniques such as the microRNA test in blood, and possibly in urine, may eventually help doctors detect rejection without the need for biopsies, says David Sachs, director of the Transplantation Biology Research Center at Massachusetts General Hospital in Boston. Researchers are also working on ways to help transplant patients’ bodies learn to tolerate new organs without the use of immune suppressing drugs, he says. MicroRNA profiles might help doctors track who is tolerating an organ well and who needs immune suppressors.