Diagnostics & Imaging Week

Carnegie Mellon University (Pittsburgh) researchers, led by Chien Ho, PhD, have developed what they call a "promising tool" that uses MRI to track immune cells as they infiltrate a transplanted heart in the early stages of organ rejection.

The preclinical advance, published online in the Proceedings of the National Academy of Sciences (PNAS) on Jan. 23, could provide a non-invasive way to detect transplant rejection by tracking macrophages as they gather inside a transplanted heart, the university said.

Ultimately, the procedure, which allows scientists to view individual macrophage cells – or those cells that typically ingest foreign materials inside the body, such as bacteria – could potentially be used to track stem cells within the body after they have been injected and as they make their way to repair an injured organ, Ho told Diagnostics & Imaging Week.

"We report for the first time the ability to monitor single immune cells in a live animal using MRI," Ho, a biological sciences professor at the university, said in a statement. "This could revolutionize the management of transplant patients."

Ho, who directs the Pittsburgh NMR Center for Bio-medical Research, said "Successful translation of this work to the clinic ultimately will reduce the number of biopsy procedures and should greatly improve the quality of life for cardiac transplant patients, especially children."

Perhaps more importantly, the university said, the research could be used to enable physicians to provide "highly personalized care" in order to prevent transplant rejection.

While organ transplantation is the current "gold standard" for addressing end-stage organ failure, transplant patients always risk losing the new organ due to rejection, the university said.

Frequent biopsies are required for the first year after transplant, and it is a highly invasive procedure. The university said that such biopsies "involve threading a catheter through the jugular vein to the heart's right ventricle and snipping out several fragments of tissue." That tissue then has to be evaluated by a pathologist to identify immune cells, such as macrophages, and any other pathological changes in the new heart that might indicate it is being rejected by the body.

In explaining how the researchers decided to take this approach, Ho said he and his colleagues have been interested in tracking cell migration for "over 10 years."

He said: "We were able to do that by tracking a particular type of cell. So, once we have been able to do a thing, we like to do something interesting and important, because immune cells [macrophages] are involved in all kinds of biological activity and diseases."

There are two ways to label a cell, Ho said. One way is to isolate it from the body, culture it and then you can see the specific type of cell you want to label, or highlight for study. That is done by adding a contrast agent to the culture, which is taken up by the cell in question.

"Then you return them to the animal, and hopefully in the future to humans, you can use MRI to follow where they go," he said.

Another way to label a cell – and the method used in Ho's group of scientists – was to inject the contrast agent into a rat. Contrast agents can be taken up by "all kinds" of cells, he said.

"We used MRI to visualize individual macrophages," he said. "By tracking single cells, we also were able to observe, for the first time, that rejection progresses from the outside of the heart to the inside," Ho said. "Up to now, this phenomenon hasn't been observed in preclinical or clinical research because biopsy samples are very limited in location and size."

For the research reported in PNAS, Yijen Wu, research biologist at the Pittsburgh NMR Center, tagged macrophages with nanometer (USPIO) or micrometer (MPIO)-sized paramagnetic iron oxide particles, which are very sensitive to magnetic fields used during MRI.

Wu injected MPIO or USPIO particles into rats that had received heart transplants three days earlier. Macrophages incorporated the particles, and by using MRI, the researchers then track-tagged macrophages that infiltrate transplanted hearts. Ho described these new proposed contrast agents as "very, very sensitive."

Feridex I.V., a contrast agent produced by Advanced Magnetics (Cambridge, Massachusetts) that is also a superparamagnetic iron oxide particle, already is approved by the FDA to use with MRI. That product is a particle size between the nanometer and micrometer, Ho said. He is hoping that one day his group's paramagnetic iron oxide particles, MPIO or USPIO, will be approved by the agency.

"This finding indicates that the new, real-time tracking method is very good at pinpointing exactly when and where rejection is occurring," the university said.

The next step in Ho's studies will be to use the procedure in larger animals, he said. Specifically, the University of Pittsburgh Medical Center has a pig model for heart transplantation that his group expects to employ.

"Once those results look very good, then we can think about applying them to humans," he said.

XDx (South San Francisco, California) in April of last year launched a blood test for the management of heart transplant patients in the hope that it would eliminate the need for biopsies. The test was launched at the International Society for Heart and Lung Transplantation's (Addison, Texas) annual meeting in Philadelphia (Diagnostics & Imaging Week, April 28, 2005).

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