Researchers have identified a distinct pattern of gene expression in the largest reported group of kidney transplant recipients who have not rejected the transplant kidneys even though they stopped taking anti-rejection drugs. This finding may help identify other transplant recipients who could safely reduce or end use of immunosuppressive therapy. In 2008, more than 80,000 people in the United States were living with a kidney transplant.
The findings come from the Immune Tolerance Network (ITN), an international research consortium supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases, of the National Institutes of Health, and the Juvenile Diabetes Research Foundation International. The research team included three lead investigators, Kenneth Newell, M.D., Ph.D., of Emory University in Atlanta; Laurence Turka, M.D., of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston; and Vicki Seyfert-Margolis, Ph.D., the former Chief Scientific Officer of ITN and currently at the Food and Drug Administration. Their report appears online in the Journal of Clinical Investigation.
"The immunosuppressive therapy regimens that organ transplant recipients must endure have toxic side effects and increase the recipients' vulnerability to infections and cancer," says NIAID Director Anthony S. Fauci, M.D. "This study holds promise for identifying kidney transplant recipients who might be able to minimize or withdraw from their use of anti-rejection drugs. However, large, prospective studies will be necessary to determine if the same biomarkers identified in the current study are reliable predictors of immune tolerance."
Following a kidney transplant, recipients must be placed on immunosuppressive therapy or their immune systems will reject the transplanted organ. However, these drugs suppress the entire immune system, reducing an individual's ability to fight infections, and sometimes leading to diseases related to a weakened immune system, such as cancer. The drugs also have other severe side effects such as diabetes, hypertension and heart disease, as well as swelling, weight gain, and excessive hair growth and acne that many people find intolerable.
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 immunosuppressive therapy against their physicians' advice, even though by doing so, they risk losing their transplanted organ. However, in a very small percentage of such cases, rejection does not occur after the drugs are stopped.
This study included 25 kidney transplant recipients who had ceased taking their immunosuppressive drugs of their own accord 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 immunosuppressive medication and had healthy kidneys, and healthy, non-transplant controls.
The team examined blood samples taken from participants in each of the three groups. They analyzed the gene expression of the cells in whole blood and observed that the transplant recipients who were not taking medication had a distinct pattern of genes expressed by B cells, a type of white blood cell. This pattern differed from those seen in participants who were still on immunosuppressive therapy and in non-transplant healthy control subjects. Further study identified a pattern of expression of three B cell genes that was far more common in patients who had stopped taking their medications yet maintained good graft function.
White blood cells include T and B cells. Recent studies of immune tolerance have focused on the role of a subset of T cells, called regulatory T cells (Tregs). Work in animal models indicates that B cells also may help promote immune tolerance.
"We expected to find a difference between the tolerant and immunosuppression groups in the genes associated with Tregs," says Dr. Newell. "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."
According to Dr. Turka, identifying potential biomarkers of immune tolerance is the first step in identifying transplant recipients whose immunosuppression therapy could be reduced. "If we could develop a reliable tolerance signature-a pattern of gene expression that indicates that someone will not reject a transplant-then we could find patients who would make good candidates for supervised drug withdrawal," he said.
The study team stresses that transplant patients should never consider reducing or changing their medication regimen unless under the direct supervision of their physician. According to Drs. Newell and Turka, doing so would "almost certainly result in the rejection of the kidney, leaving the patient in need of another transplant."
Follow-up studies of this gene pattern are being planned. Similar findings already have been provided by a European group, led by King's College in London, that conducted a comparable study in kidney transplant patients. Their results appear in the same issue of the Journal of Clinical Investigation.
"The goal of ITN is to understand how immune tolerance can be induced or achieved in a variety of settings, including allergy, autoimmune disease and transplantation," says Daniel Rotrosen, M.D., director of the Division of Allergy, Immunology and Transplantation at NIAID. "Potentially, a biomarker for tolerance in kidney transplant recipients may predict tolerance in individuals following transplantation of other organs or with other immune-mediated diseases. Having a cooperative program like ITN allows investigators to explore this possibility and apply the findings of one study across different fields of clinical research."
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