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Gene Pattern May Identify Kidney Transplant Recipients Who Don’t Need Lifelong Immunosuppression Drugs
Researchers have identified a distinct pattern of gene expression in a large group of kidney-transplant patients, a finding that might eventually help transplant recipients safely reduce or end use of immunosuppressive therapy.
Date: 5/24/2010
BIDMC Contact: Bonnie Prescott
Phone: 617-667-7306
Email: bprescot@bidmc.harvard.edu
Press release prepared by National Institute of Allergy and Infectious Diseases
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 report appears online in the Journal of Clinical Investigation.
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 Beth Israel Deaconess Medical Center (BIDMC) investigator Laurence Turka, MD, together with Kenneth Newell, MD, PhD, of Emory University in Atlanta; and Vicki Seyfert-Margolis, PhD, of the U.S. Food and Drug Administration (FDA).
According to Turka, who is also a Professor of Medicine at Harvard Medical School (HMS), 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.
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 2 (more) 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 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.”
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.”
