Gene pattern may identify kidney transplant recipients who don't need lifelong anti-rejection drugs

May 24, 2010

To prevent rejection of their new kidneys, kidney transplant recipients need to take immunosuppressive drugs for the rest of their lives. A handful of people, out of the thousands who have undergone transplantation, have been able to stop taking these drugs without losing their kidneys.

Researchers studying these rare individuals have identified a pattern of genes turned on in their white blood cells, which may one day be used to help identify other transplant recipients who could reduce or completely taper their immunosuppressive therapy without ill effect.

The study, whose results were reported this week in the Journal of Clinical Investigation, was performed by the Immune Tolerance Network (ITN), an international research consortium with headquarters at University of California, San Francisco.

The paper's lead author is Kenneth Newell, MD, PhD, director of the Living Donor Kidney Program at Emory Transplant Center and professor of surgery at Emory University School of Medicine. Senior authors are Laurence Turka, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center, and Vicki Seyfert-Margolis, PhD, former chief scientific officer at the ITN, now an advisor in the Food and Drug Administration Office of the Chief Scientist.

The authors emphasize that their study looked at "tolerant" patients. These are patients who had stopped taking their prescribed immunosuppressive medications for at least a year, yet did not reject their kidneys. They are not encouraging others to follow the same course of action.

"The signature that we discovered in these individuals may be useful for identifying kidney transplant recipients who are already tolerant. Whether or not this same signature will identify those kidney transplant recipients still taking immunosuppressive medications who are predisposed to developing tolerance in the future remains unknown," Newell says. "Carefully supervised studies will be necessary to answer this question as well as to determine whether attempting to completely withdraw all immunosuppressive drugs will prove advantageous in the long term."

A representative of "tolerant" transplant recipients is Lisa Robinson, who owns her own real estate company in Colorado Springs. She received a kidney from her sister at age 30 in 1996. Robinson needed the kidney transplant because of Wegener's granulomatosis, a condition in which her immune system was attacking her own blood vessels, causing kidney and lung damage.

Three years after her kidney transplant, she found it hard to tolerate the side effects of the immunosuppressive drugs, which included swelling, weight gain and depression. On top of that, her creatinine levels were rising, indicating that her donated kidney was losing function. Without explicit approval from her doctor, she decided to taper off her drugs, first cyclosporine and then steroids.

"This turned out to be the right choice for me, but I'm not suggesting that others do what I did," she says. "Everyone has to figure out what works for them. My main motivation was that I didn't want to go through another kidney transplant."

The drugs taken by transplant recipients can reduce an individual's ability to fight infections, lead to high blood pressure and high blood sugar and, ironically, tend to damage the kidney over time. In rare cases, a physician may stop a transplant recipient's immunosuppressive drugs because of a serious medical problem such as cancer or life-threatening infection; in other cases, transplant recipients decide to reduce or stop their immunosuppression therapy against their physicians' advice, even though by doing so, they risk losing their transplanted organ. Only in a very small percentage of such cases, rejection does not occur after the drugs are stopped.

"In the vast majority of patients, stopping or reducing immunosuppression medications without doctor supervision will have serious health consequences, including loss of the transplanted kidney," cautions Newell. "We certainly don't encourage anyone to try this on their own."

The ITN study examined 25 kidney transplant recipients who had ceased taking their immunosuppressive drugs and yet had retained normal kidney function for more than one year. The researchers compared this group with two other groups: recipients who were still taking their medication and had healthy kidneys, as well as healthy, non-transplanted controls.

The ITN team analyzed the genes turned on in samples of blood cells from each of the three groups and observed that the transplant recipients who were not taking medication had a distinct pattern of genes turned on in B cells, a type of white blood cell. Further study showed that zeroing in on three B cell genes could distinguish patients who had stopped taking their medications yet maintained good graft function.

White blood cells include both T and B cells. Most studies of immune tolerance have focused on the role of a subset of T cells, called regulatory T cells (Tregs). More recent work in animal models, however, indicates that some kinds of B cells may also help regulate the immune system and promote tolerance of a transplanted organ.

"We expected to find a difference between the tolerant and immunosuppression groups in the genes associated with Tregs," Newell says. "However, we were surprised that our data showed that B cell genes may play an important role in maintaining and possibly inducing tolerance to transplanted organs."

A European group that conducted a similar study in kidney transplant patients found corroborating results, which appear in the same issue of the Journal of Clinical Investigation.

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More information: View this article at: www.jci.org/articles/view/39922?key=49040753bf93809451f5

Provided by Journal of Clinical Investigation

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