Genes Identify Renal Graft Tolerant Patients

NANTES, France, Aug. 21 -- Geneticists are on the trail of a way to determine which kidney transplant recipients can be taken off immunosuppressants safely.

Groups here and at Stanford have found that recipients with a particular set of 33 genes appear to be able to tolerate new organs with little or no long-term immunosuppression, they reported online in the Proceedings of the National Academy of Sciences.

Comparing gene expression profiles from a variety of renal transplant recipients and healthy volunteers, the investigators found that more than 90% of patients who had developed tolerance to their grafts carried the genes, according to Jean-Paul Soulillou, M.D., Ph.D., of the French National Institute of Health and Medical Research, and Minnie Sarwal, M.D., Ph.D., of Stanford.

They also found similar gene expression patterns in one of 12 patients with stable graft function on a triple immunosuppressant regimen, and five of 10 patients who were stable on modified low-dose steroid therapy.

The gene-expression profile may be present in about half of all patients, and if validated in further studies, it could help physicians titrate immunosuppressive therapy to the needs of individual patients, and perhaps allow some patients to be taken off immunosuppressants entirely, the authors wrote.

"For the first time, we now have evidence that will help us say to the five out of 10 patients without this expression pattern, 'Please, please don't think about changing your medications'," said Dr. Sarwal. "At the same time, we may be able to say a different patient, 'We'd like to try to cut back your drugs'."

Spontaneous, long-term allograft tolerance has been documented in a small number of patients who received renal allografts, a phenomenon known as "operational tolerance."

In an attempt to discover the frequency of this immune adaptation and identify potential biomarkers for it, the authors examined blood gene expression profiles from 75 adult renal-transplant patients and from 16 healthy volunteers.

The transplant recipients included 22 patients with stable graft function, 36 who had acute /or chronic graft rejection, or both, and 17 with operational tolerance.

Using microarray analysis, they compared a subset of samples from patients in each of the three renal graft groups, and came up with a "tolerant footprint" consisting of 49 genes.

They then tested the genes with microarray and real-time polymerase chain reaction in samples from the other patients to determine whether they could accurately predict immune response and the need for immunosuppression.

They found that 33 of the 49 genes correctly segregated tolerance phenotypes with 99% specificity, and chronic rejections phenotypes with 86% specificity.

They found the tolerance signature in one of 12 patients who were stable on triple immunosuppressant therapy, and in five of 10 who were stable on low-dose steroid monotherapy.

The tolerance conferred upon allograft recipients who possessed the expression profiles appears to be related to a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T-cell responses, the authors wrote.

"With the exception of a modest number of genes showing age-associated variation in expression, no association with other potential confounding factors such as immunosuppressive drugs, gender, serum creatinine, and cytomegalovirus or cancer history was observed," they wrote. "This finding lends credence to the fact that the identified gene signature is directly related to the state of tolerance."

The tolerance profile might be mediated through the action of transforming growth factor-b, which may regulate specific phenotypes of peripheral regulatory T cells, or alter the threshold of T-cell activation, the authors speculated.