Inviting healthy intruders to stay

Stem-cell transplant specialist V.K. Gadi is on a mission to find easier, reliable, more affordable ways for physicians to diagnose and prevent cell rejection
Nick Boespflug (seated) and Dr. V.K. Gadi
Research technician Nick Boespflug (seated) works with the guidance of Dr. V.K. Gadi in the Nelson Lab. Photo by Stephanie Cartier

You're probably not aware of it, but you are under attack. Every minute of every day, a variety of threats confront your body. Fortunately, a number of defense mechanisms stand at the ready, willing to take on intruders, which can be anything from bacteria to a splinter in your finger. The immune system is a crucial component of the body. Without it, your daily attackers would win.

This tendency to battle foreign objects, while lifesaving in most cases, is non-discriminatory. Anything labeled as an intruder is subject to attack. That can be problematic if the intruder happens to be something as crucial as a donated organ.

Dr. V.K. Gadi, of Dr. Lee Nelson's Clinical Research Division lab, is on a mission to help the body distinguish between good and bad intruders and help the new organ avoid friendly fire.

Gadi is a stem-cell transplantation specialist and medical oncologist with a special interest in immunology for both cancerous and non-cancerous conditions. Understanding how the body deals with foreign objects is tricky.

"Right now, the way we tell if a transplanted organ is not working or being attacked by the immune system is by sticking a needle in it and looking at the sample under the microscope. In certain organs, those surveillance biopsies are very difficult to do," Gadi said. Surveillance biopsies are not popular with physicians or patients, because the samples must be drawn routinely, he said. "Obviously, that's not pleasant or practical, and it's very expensive."

That method isn't always accurate either. Some organs can lose almost 90 percent of the graft before there are clinical signals that anything is wrong. "And by then, the cat is out of the bag," Gadi said.

So Gadi has made it his mission to find an easier, more reliable and affordable way for physicians to catch problems early.

A potential answer came up during conversations in the hallways of the Thomas Building. Dr. Chris Kuhr, a former Center researcher, and Gadi played with the idea of using a new test being developed in the Nelson Lab to look for rejection. His question: "Since these cells are dying and releasing the contents of their cells into the bloodstream, is there anything in the bloodstream that we can see, using these modern techniques, that might be indicative of how much rejection is going on?"

They started their quest with the blueprint of life: DNA. Around the time that Gadi began working in the lab, Nelson was developing a test to recognize foreign DNA in the bloodstream. Seeing foreign DNA against a background of the host DNA could provide researchers a clearer picture of the scale of rejection. "Because it's quantitative, we can actually say how many copies there are of it," Gadi said. "We can do the math to say on this day, at this time point, in this amount of serum, this is how many copies of this DNA are there, which can be extrapolated to say how many cells have been damaged. We initially looked to see if higher levels correlated with more damage in the organ and if lower levels correlated with a healthy organ."

Pancreatic islet-cell transplants

In fact, there was a correlation. The first study, which looked at banked serum specimens and compared the DNA levels with biopsy results from patients who had received combined kidney-pancreas transplants, was published in 2006 in the journal Clinical Chemistry. Higher levels correlated with more damage in the pancreas and lower levels with less. "It was a very rough estimate, but it looked really promising as something we should further pursue," Gadi said.

Now, Gadi is looking ahead to prove the test by tracking events before they happen. While the original study looked at the kidney-pancreas model, Gadi wanted to use something that would affect more people, so he chose to look at two other types of transplants. One, pancreatic islet-cell transplants, holds promise for people with type 1 diabetes. In collaboration with Dr. James Shapiro and Colin Anderson at the University of Alberta in Edmonton, Gadi and colleagues have generated quite a bit of information from serum samples obtained from recipients of islet-cell transplants, although the final analysis has not been completed. Gadi recently received a grant from the Juvenile Diabetes Foundation for this work.

The other test involves kidney transplants, which are common procedures in the Seattle area. The kidney has some reasonably good markers of function, but there are a lot of things physicians don't know without a biopsy.

"This is a situation where it would be good to have a simple test to get a sense of whether or not an allograft, or transplanted tissue, is healthy or sick, and if it is sick, then we could do a biopsy," Gadi said. "The benefit of looking at kidneys is that instead of doing a blood draw, urine can be analyzed for donor DNA. There have been only about 10 tests so far, but results look promising. We're easily detecting the donor sequences, and we can identify them distinctly from host sequences, and it looks like initially more damage correlates again with more DNA and less damage with less DNA, although it is still too early to say anything concrete," Gadi said.

Another arm of Gadi's research questions whether T-regulatory cells, the cells that suppress the body's initial reaction to an invader and maintain balance, could inhibit graft-vs.-host disease in an animal model. The work is being done in collaboration with Kuhr and the Seattle Cancer Care Alliance's Dr. George Georges. The researchers are trying to reproduce large quantities of T-regulatory cells outside of the body with the hope that by infusing more T-regulatory cells could prevent or treat graft-vs.-host disease. The same techniques could be used to treat organ-graft rejection.

It could be years before the diagnostic tests are helpful to a patient, and even more time before T-regulatory cells could be considered for use to fight GVHD, but Gadi said he plans to keep looking for better tests to make sure the body is inviting the right intruders to stay and kicking the wrong ones out.

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