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From Medical Oddity to Clinical Hope

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No physician likes to hear that a patient went rogue and stopped taking critical medication. But doctors of organ transplant patients usually don’t have to worry about that — most recipients of an organ take their anti-rejection meds like they’ve found religion.

So you can imagine the surprise of a very small number of doctors who have discovered that their transplant patients have not only stopped taking their anti-rejection drugs but, against all odds, they’re also perfectly healthy.

That’s where Minnie Sarwal comes in. A transplant nephrologist and immunologist at Stanford University, Sarwal regularly faces the conundrum of all organ transplant patients: while immunosuppressant drugs lower rejection rates, they leave patients open to a host of serious infections and other medical problems. “There’s an increasing percentage of patients who are getting into trouble because of too much drugs,” Sarwal says.

So she and her team turned to the rare patients who somehow avoid rejection without drugs to see if biology could provide clues for better treating all transplant patients. Their initial study looked at five patients who had been off their meds for at least five years but hadn’t suffered any ill effects. The team screened patient versus control blood samples on cDNA microarrays and turned up 49 genes that appeared to correlate to these people’s ability to tolerate their transplanted organs as if they were native. Then Sarwal used that panel of genes in a blind study on other groups of patients and narrowed the list down to an expression signature of 33 genes that so far appears to be 100 percent predictive of whether a patient will need anti-rejection therapeutics. Results from the early phase of the project were published this summer in PNAS.

The initial groups of patients under study have been smaller than statisticians would like, but Sarwal says finding people who have not only stopped taking their medications but also not suffered any consequences is a tremendous limitation. She has applied to NIH for funding for clinical trials to help expand the numbers of patients involved in testing the gene expression signature.

What Sarwal finds most promising about this work is not the possibility of finding the rare patients who will not need immunosuppressant drugs after a transplant, but rather the potential for lowering the amount of drugs that most people have to take. The average transplant patient is on a three-drug cocktail so powerful that it eventually causes a number of problems in the rest of the body and kills off the transplanted organ. (Sarwal notes that while rejection rates have plummeted thanks to new drugs on the market, the life of the average kidney transplant has remained steady at about eight to 10 years.)

Doctors have been able to wean some patients off two of the three drugs, and Sarwal says that having patients on a single anti-rejection therapeutic is a vast improvement for health outcomes. By looking at the gene expression signature in regular patients, her findings show that of patients taking all three drugs, one in 12 has a good shot at being able to tolerate the transplant with just one drug. She hopes that eventually physicians will be able to perform “a simple blood test and tell if somebody is approaching this pattern of genes. That could be used to titrate somebody’s drugs,” she says.

Despite Sarwal’s advances, the mystery remains as to how certain people simply don’t need immunosuppressant drugs when most people would immediately reject their organs without them. Sarwal says there’s no clue yet as to whether the gene expression panel represents a stable state — that is, these people could be identified at any time in life as not needing meds — or it’s a follow-on to the transplant, and perhaps represents immune systems that are able to adapt to the new organ.

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