Following up last week’s story on Metformin’s effect on memory cells, Rapamycin, also known as Sirolimus, has recently been shown to stimulate the formation of memory CD8 T cells. Rapamycin is an immunosuppressant drug used to prevent rejection in organ transplantation; particularly kidney transplants. The discovery by scientists at the Emory Vaccine Center is reported online ahead of print June 21 in Nature1.
In the experiments, conducted in both mice and monkeys, rapamycin was able to stimulate formation of memory CD8 T cells, which facilitate faster and stronger response in the immune system to an infectious agent upon second encounters with it. The implication, says lead author Koichi Araki, PhD, would be that doctors may be able to enhance the effectiveness of vaccines with drugs that act similarly to Sirolimus.
Whether the same mechanism exists in humans remains to be seen.
Vaccination hinges on memory T cells, which survive after the immune system produces a profusion of T cells to fight an infection or respond to a vaccine. Araki had been examining rapamycin’s effects in mice infected with lymphocytic choriomeningitis virus (LCMV). LMCV is a rodent-borne virus that causes aseptic meningitis, encephalitis or meningoencephalitis.2
“Usually during the response to this virus, 90 percent of the CD8 T cells produced to fight an infection die after a few weeks. The memory cells are generated from the 10 percent that survive,” explains Araki.
Although T cells come in both helper CD4 and killer CD8 forms, scientists have found that CD8 T cells are more important for fighting LCMV. If mice were treated using sirolimus, more of the CD8 T cells that fight LMCV survived, Araki found. The mice not only produced more memory T cells, but the cells also had a greater ability to proliferate and respond upon a second exposure to LCMV.
Araki says Rapamycin’s effects are “surprising and unexpected”. During short term viral infections, the immune response’s enemies ultimately go away; this situation is distinct from that of a transplant. That difference may have helped him recognize rapamycin’s effects, Araki says. Also, rapamycin’s effects are dose dependent, in that too high of a dose will actually inhibit all T cells without regard to what type they are, he says.
Araki than joined with Christian Larsen, MD, PhD, director of the Emory Transplant Center and chair of the Department of Surgery, to show that rapamycin had similar effects in rhesus macaques infected with vaccinia virus as in mice. That research was conducted at Emory’s Yerkes National Primate Research Center.
Rapamycin, approved by the FDA in 1999 for use after kidney transplants, was first discovered as a product of the bacterium Streptomyces hygroscopicus , found in a soil sample from Easter Island. The Polynesian name of Easter Island is Rapa Nui, hence the drug’s name.
T Cell Paradox
Because transplant patients are usually given rapamycin in conjunction with other drugs, it’s paradoxical effects may have been masked, says Larsen. Paradoxical because for transplant patients, memory T cells can both play a role in graft rejection, but also protect against infections.
“We are appreciating more and more that memory T cells respond differently to interventions than normal T cells and we have to pay close attention to the situation of the individual patient,” Larsen says.
Scientists at the Emory Vaccine Center are going on with studies on how T cells decide whether to become memory cells, because of their importance in maintaining the immune response against chronic infections such as HIV and hepatitis C.
The effects of rapamycin were seen even if rapamycin was administered only for a week after the infection began, signifying that the beginning of the infection was when T cells were deciding whether or not to become memory cells.
By using an inhibitory technique (RNA interference) on the genes known to be targeted by rapamycin, Araki was able to show that rapamycin is acting on the CD8 T cells and not on other cells with which they interact.
1. K. Araki, A.P. Turner, V.O. Shaffer, S. Gangappa, S. Keller, M.F. Bachmann, C.P. Larsen and R. Ahmed. mTOR regulates memory CD8 T cell differentiation. Nature advance online publication 21 June 2009 | doi:10.1038/nature08155
2. Centers for Disease Control and Prevention. Lymphocytic Choriomeningitis Fact Sheet
3. Viola A, Lanzavecchia A. T cell activation determined by T cell receptor number and tunable thresholds. Science. 1996;273:104–106.