A breakthrough discovery at the Medical College of Georgia in how a developing fetus is protected from the mother's immune system is now at the brink of being tested as a way to help prolong organ transplants.
And a Georgia foundation is helping the researchers get there.
Officials from the Carlos and Marguerite Mason Trust visited MCG on Tuesday after giving the MCG team a three-year, $1 million grant to further their work.
"A key point about this award is that we are going to translate what we know into the clinic," said principal investigator Andrew Mellor. "That is setting the goalpost quite high because there are quite a lot of hurdles yet to be surmounted."
The MCG team and its collaborators are looking at manipulating a molecule known as indoleamine 2,3 dioxygenase -- IDO for short. The molecule appears to deactivate the response of killer T cells in the immune system and also promotes regulatory or suppressive T cells that tamp down an immune response. That kind of natural system is found in the lungs, for example, to keep the body from overreacting to things it inhales, co-investigator David Munn said.
Unfortunately, it is also believed to be one way cancerous tumors avoid detection by the immune system, he said. Dr. Munn helped start early stage clinical trials in cancer patients this year on a drug that inhibits IDO in hopes of boosting an immune response to the cancer.
In transplants, the researchers are looking for the opposite effect. One way is to use drugs to induce IDO in the recipient. One drug they plan to work on, Abatacept, is already approved for autoimmune diseases that make the body's immune system mistakenly attack its own tissues.
Though inducing IDO is not listed as one of its mechanisms of action, Drs. Mellor and Munn believe that is how it works and hope to work on similar formulations to help boost that effect.
The question is, "Can we make it into a better molecule?" Dr. Mellor said.
Another key approach will be working with a deactivated virus to deliver an IDO-expressing gene into the organ itself to create a long-lasting immune suppression around it without affecting the rest of the body.
Another approach could be using IDO to manipulate the donor's white blood cells, for example, then introduce them to the recipient before transplant to create a tolerance for the organ.
"There is a long-standing, intriguing, but poorly understood phenomenon in which some transplant recipients who received a transfusion from their respective donor have less rejection and a better acceptance rate," Dr. Munn said.
The hope is in the third year of the grant to have begun testing in nonhuman primates in collaboration with Dr. Allan Kirk of Emory Transplant Center.
"The direction is key," Dr. Mellor said. "It is not to continue basic studies in mice, it's to get toward the clinic. And nonhuman primates are absolutely essential to get to the clinic."
The MCG team received about $3 million from the Mason Trust to help fund much of the early research into basic questions about how IDO worked and its relationship to cancer and immune system tolerance.
Now it is exciting to see where it is going, said George W.P. Atkins Jr., the chairman of the trust's distribution committee.
"That was fascinating to me," he said. "To take pregnancy and to relate it to transplants just blew my mind."
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THE MASON TRUST
The Carlos and Marguerite Mason Trust, based in Atlanta, was created to fund research into organ transplantation and to help Georgians who need a transplant but can't afford it.
Mr. Mason was a merchant who bought local stocks, including Coca-Cola, during the Depression and built up quite a portfolio. The couple was very frugal and never owned a home or even a car -- Mrs. Mason got around by bus. But by the time she died in 1991, the estate was worth about $25 million, and Wachovia Trust built it up to about $70 million by the time the trust was begun, said George W. P. Atkins Jr., the chairman of the trust's distribution committee.
It has been as high as $110 million to $115 million and is still performing well, he said.
In the 15 years the trust has been making grants, it has distributed close to $70 million, said Alice J. Sheets, the trust's relationship manager.
"All in the state of Georgia," she said, which is one of the conditions placed on the money. About $10 million has gone to the Medical College of Georgia.
When the trust began, there was little research being done in Georgia on organ transplants, but that has certainly changed, Mr. Atkins said.
"Now, Georgia is leading the nation," he said. "That is all because of Mr. and Mrs. Mason."