Taming transplantation
Transplanted organs and cells are often rejected by the body's own immune system. Dr. Ron Gill is looking for ways to "teach" the body to accept them.
Story by Laura Ly/Illustration by Hugo Dubon
As part of the body's innate immune system, natural killer (NK) cells are one of our first lines of defense against foreign pathogens such as bacteria and viruses. However, NK cells can also launch an attack against transplanted tissues and cells, which causes transplant rejection. Recent research shows that a certain set of chemical responses in NK cells can also encourage transplant tolerance. How can NK cells be responsible for both transplant rejection and tolerance? This is what AHFMR Scientist Dr. Ron Gill aims to find out.
Transplant patients must take immunosuppressive drugs for the rest of their lives to prevent the body from rejecting the transplanted organ or tissue. "Unfortunately, when the immune system encounters a transplant, it doesn't realize the transplant is supposed to be there. All it sees is something that isn't 'self', and initiates a normal immune response against it," explains Dr. Gill. Immunosuppressive drug treatment stops the immune system from responding to the foreign cells—which includes blocking NK cell activity, in order to allow the body to accept the transplant.
However, researchers made the surprising discovery that inhibiting all NK cell activity also leads to decreased transplant tolerance. "What we didn't know is that the same immune pathways that can kill the transplant are also used in some cases to regulate and inhibit the immune response itself. And that can be essential to promoting tolerance. In fact, in some settings, if you didn't have functioning NK cells, you couldn't promote tolerance at all," notes Dr. Gill.
"Immunosuppressant drugs prevent rejection, but they probably also prevent tolerance as well. If the same cell is used to both injure the transplant and regulate the immune system, if you just generically block the whole pathway, you leave yourself in a state of limbo. That may be why transplants usually deteriorate over time," he adds.
Dr. Gill studies the "split personality" of NK cells to figure out which functions in the cell promote transplant tolerance, and which cause transplant rejection. "There are two issues: what kind of cellular immune response actually damages the transplant, and what are the biological mechanisms that can keep that from happening. We want to identify which immune pathways to block and which ones to preserve."
By identifying the chemical responses that NK cells use to promote tolerance, scientists can develop more effective immunosuppressant drugs—drugs that only block the pathways that cause transplant rejection. Ultimately, Dr. Gill hopes to "teach" the immune system to accept the transplant—a process known as immunological tolerance. Immunological tolerance would permit long-term transplant survival and eliminate the need for immunosuppressant drugs. Dr. Gill explains, "We're trying to train the immune system to see the transplant as another form of self, and not something that is foreign."
Dr. Gill's NK cell research deals with all types of transplants, including those of cells and tissue, solid organs, and bone marrow, but his primary interest is in diabetes research. He was recruited from the University of Colorado to be the scientific director of the Alberta Diabetes Institute at the University of Alberta. He was chiefly attracted by the Institute's approach to diabetes research, which investigates both type 1 and type 2 diabetes together.
As Dr. Gill explains, "Type 1 and type 2 diabetes have traditionally been segregated and studied as different diseases. Researchers considered type 1 diabetes an autoimmune response that kills the insulin-producing cells, and type 2 diabetes as insulin resistance and the inability to use the insulin you make." However, recent research suggests there are, in fact, more similarities between the two diseases than diabetes researchers thought. For example, patients with type 1 diabetes have damaged insulin-producing islet cells, but researchers have found damaged islet cells in patients with type 2 diabetes as well.
"The whole view of diabetes research has been changing, and to have diabetes researchers—both clinical and basic—look at both diseases is very important and a real plus. When you put that together, the Alberta Diabetes Institute has promise to be a great diabetes centre."