Too often, it's only after a transplanted organ has sustained serious damage that a biopsy reveals the organ is in rejection. A new screening method using sensor particles and a urine test could catch rejection much earlier, more comprehensively, and without a biopsy needle.
When the body's immune system has just begun attacking cells of a transplanted organ, the new method's particles send a fluorescent signal into the urine. In a new study, researchers validated the method in a mouse model, and they have engineered the sensor with highly biocompatible components, which could make the path to potential future trials easier.
A patient may feel fine, and a biopsy may look deceptively clean when T cells have already begun attacking a transplanted organ. The sensor particle, a nanoparticle, detects a T cell weapon, an enzyme called granzyme B, that pushes a transplanted organ's cells into the self-destruction process called apoptosis.
"Before any organ damage can happen, T cells have to produce granzyme B, which is why this is an early detection method," said a co-principal investigator in the study.
"This is sensitive enough to possibly detect budding rejection before you see significant injury to the transplanted organ and that could help clinicians treat early to prevent damage," said another co-principal investigator. "Right now, most tests are aimed at organ dysfunction, and sometimes they don't signal there is a problem until organ function is below 50 percent."
The study's results published in the journal Nature Biomedical Engineering.
The nanoparticles are put together with iron oxide in the middle like a ball. It is double-coated with dextran, a sugar, and polyethylene glycol, a common ingredient in laxatives, to keep the body from disposing of it too quickly. Bristles made of amino acids stick out from the iron ball with fluorescent "reporter" molecules attached to their tips.
The particles are injected intravenously. They are too big to accumulate in native tissue or to pass through the kidneys and out of the body but small enough to accumulate in the tissue of struggling transplanted organs, where they keep a lookout for rejection.
Once T cells start secreting granzyme B, it severs amino acid strands in the transplanted organ's cells, triggering the cells to unravel and die.
"The nanoparticles' bristles mimic granzyme's amino acid targets in the cells, so the enzyme cuts the bristles on the nanoparticle at the same time," said the author. "That releases the reporter molecules, which are so small that they easily make it through the kidney's filtration and go into the urine."
In the experiment, the animals' urine glowed and could be seen in their bladders in near-infrared images.
The researchers plan to augment their new sensor to detect the other major cause of transplant rejection, attacks by antibodies, which are not living cells but proteins the body creates to neutralize foreign entities.
"Antibodies kill their target cells through similar types of enzymes. In the future, we envision a single sensor to detect both types of rejection," the author said. But there is even more potential.
"This method could be adapted to tease out multiple problems like rejection, infection or injury to the transplanted organ," the author said. "The treatments for all of those are different, so we could select the proper treatment or combination of treatments and also use the test to measure how effective treatment is."
That could also allow clinicians to carefully dose powerful immunosuppressant medications that the vast majority of transplant patients receive.
"Adjusting the dose is very difficult but very important because heavy immunosuppression increases occurrence of infections and patients who receive it also get cancer more often," the author said.
For this experiment, the researchers used small skin grafts on mice and got a very clear, timely signal from the nanoparticle sensor. Since organ transplants represent a lot more tissue, the researchers believe that any occurrence of organ rejection would trigger a much larger signal from the sensor.
Urine Test Detects Organ Transplant Rejection
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