Giving transplant patients an easier recovery
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For transplant patients, taking toxic immunosuppressant drugs to prevent graft rejection often feels like the lesser of two evils because of the drugs' severe side effects.
Patients must take the drugs, but they also suffer serious side effects. Now a new combination of drugs could open the door to treatments that are less toxic.
A popular class of immunosuppressive drugs known as calcineurin inhibitors (examples are cyclosporine and tacrolimus) can damage patients' kidneys and lead to high blood pressure, among other problems. A combination of treatments can effectively replace calcineurin inhibitors in preventing graft rejection when kidney transplants are performed on monkeys, scientists at the Emory Transplant Center have shown.
The finding opens the door to a less-toxic post-transplant treatment that could be administered once a week rather than the current dizzying mound of pills that must be taken every day, says Allan Kirk (surgery), a Georgia Research Alliance Eminent Scholar.
One key ingredient in the combination is an experimental therapy called a costimulation blocker, designed to interfere with the T cells that cause graft rejection without affecting other organs. Costimulation refers to one of two signals T cells need from other cells to become fully activated.
The other key ingredient, a protein called alefacept, subdues memory
T cells, which allow the immune system to respond faster and stronger to an infectious agent or vaccine upon second exposure.
Costimulation blockers are sufficient for allowing mice to tolerate a transplanted kidney, but not monkeys or people, Kirk says. Memory cells appear to prevent costimulation blockers from working as well in monkeys as they do in mice.
"One of the big differences we've found between mice and both monkeys and people is that we primates have more exposure to infections that require us to develop immunologic memory," he says. "Memory cells are quicker to become activated and don't need costimulation as much, so blocking costimulation doesn't slow them down."
By themselves, neither costimulation blockers (in this case, a molecule called CTLA4-Ig) nor alefacept could prevent rejection in monkeys after the eight-week treatment period, Kirk and his colleagues found. They had more success by combining costimulation blockers, alefacept, and the transplant drug sirolimus. Under this regimen, monkeys could last for months after treatment ended without developing rejection or self-reactive antibodies.
Both CTLA4-Ig and alefacept are proteins and must be administered intravenously or possibly subcutaneously. However, their stability means they don't need to be taken every day—once a week is enough, Kirk says.
