Posted by Ellen on May 23, 2002 at 19:45:34:
Research Profile
Keeping Transplanted Islets Safe
Mark J. Holterman, MD, PhD
Occupation
Assistant Professor, University of Illinois at Chicago
Professional Focus
Immunology, pediatric surgery
Outside Interests
Ice-skating, travel, and rooting for his children's baseball and basketball teams
Funding
Innovation Award
There's much ado about islet cell transplants in the world of diabetes research. Teams of scientists around the world are working diligently to find ways of transplanting the insulin-producing cells into people with diabetes in order to cure the disease.
But there are hurdles to clear, and one of the biggest is transplant rejection. When cells are transplanted, the infection-fighting T cells of the recipient's body see them as "foreign" and attack them. As it stands now, recipients of all kinds of transplants must take powerful and expensive drugs that suppress their immune systems to prevent this from happening, and they must take those drugs for the rest of their lives.
Unfortunately, current drugs that suppress the immune response suppress the entire immune system, not just the T cells that are attacking the transplant. This can leave transplant recipients vulnerable to infections that they normally would not be vulnerable to, as well as to tumors. Recipients of islet cell transplants would face the same challenges as other transplant recipients.
That doesn't sit well with Mark Holterman, MD, PhD, assistant professor of pediatric surgery at the University of Illinois at Chicago and recipient of an American Diabetes Association Innovation Award.
"The side effects of immunosuppression are tough," he says. "If you don't get the dosage just right, you could overdo it and make recipients susceptible to the same kinds of things people with AIDS get, things that would never cause problems otherwise, from fungal infections to certain kinds of tumors.
"Then there is toxicity to the kidneys, the expense of a lifelong commitment to the drugs, and the challenge of complying with taking the drugs every day, especially for kids. These things bother me," he says. "I thought that there must be a better way of doing this."
Holterman believes the key is to get specific. "We want to turn off the immune system attack on what we want to protect: the islet cells," he says. Together with his research assistant, Chentha Vasu, PhD, Holterman is trying to devise a way of telling the T cells that attack transplanted islets-and only those particular T cells-to back off.
Cease And Desist
Scientists often use "reagents" (pronounced "ree-AY-jents") in their research. These are substances chosen and used for their chemical or biological activity.
Holterman has developed a reagent, which he mixes in a test tube with islet cells from mice. This substance binds, or attaches to, the outside of the islet cells to be transplanted. The coated islet cells are then transplanted into diabetic mice. The mice's T cells approach the islets with the intent to kill, but the reagent sends a signal to the T cells not to attack.
"Basically, the T cells are still going around, but the reagent is saying, 'Don't attack here, because if you do, we're going to bump you off,'" says Holterman. The reagent carries out its threat as well, and T cells that do attack the islets are destroyed. "We want those cells out of there," he says.
T cells that don't attack the transplanted islet cells go their own way, free to fight the real threats, like harmful bacteria and fungi.
But wait, there's more, says Holterman. Such a reagent might also be used to prevent Type 1 diabetes. Type 1 is rooted in a faulty immune response: T cells see the person's own islet cells as foreign and destroy them. Islet cells do not reproduce, and once they are destroyed, the body cannot replace them. Eventually, the pancreas makes virtually no insulin and the person must take insulin to survive.
"If you have a child or adult developing Type 1, and you introduce this reagent to their islets, maybe you can set up a way to prevent the attacks from happening and halt the progression of the disease," says Holterman.
Scientific Innovation
Holterman would eventually like to work with human cells. But his work is new to the field of immunology-"hence the Innovation Award," he says-and with an idea that fresh, you have to start small: with mice.
"Part of the problem is that we don't have a good hand on what makes it all tick," Holterman says. For instance, certain substances will induce certain behavior in cells, but exactly how they do so is a mystery. "We put them in, come back later, and see how they work," he says.
But sometimes, science requires a leap of faith to progress. Holterman's PhD is in cellular immunology. He has a thriving practice in pediatric surgery (the MD part of his credentials), but he returned to research in immunology after he saw how he might apply what he learned while pursuing his PhD to his current work as a pediatric surgeon. Holterman is collaborating with Cristiana Rastellini, MD, who is the director of islet cell transplantation at the University of Illinois at Chicago Hospital. Together they hope to develop the mouse reagents to the point where someday they can protect human islet cell transplants and lessen the danger of immunosuppressive drugs.
"When I came back to research, there were lots of new developments in the field regarding T cells. I thought some of it might work in transplantation. I thought, 'Let's try to do some experiments with islet cell transplant protection.'"
"It's a little bit outside of the immunology box," he adds. "But we're really excited about it. In fact, the person who reviewed my grant application told me, 'This is so novel it just might work.'"
By Terri Kordella.