The Immune System: From Organ Rejection to Global Health

BY KRISTA CONGER

WINTER 2003 - The immune system does an admirable job of fighting off harmful bacteria and viruses. However, it also orchestrates the rejection of transplanted organs and the development of autoimmune diseases. Interfering with some of the key players of the immune system might help young transplant patients more readily accept their new organs, or dampen inappropriate attacks on the body's own cells. Several years ago, Alan Krensky, M.D., chief of the division of immunology and transplantation biology and the Shelagh Galligan Professor of Pediatrics, set out to identify proteins that might make good therapeutic targets.

Riley Maxwell was born with polycystic kidney disease and needed a kidney transplant by age 1. Today, Riley is a happy and healthy first-grader after successfully coping with an array of immunosuppression medications that kept his body from rejecting his new kidney. Research investigating the role of certain proteins in the immune system, led by immunologist Alan Krensky, M.D., holds hope for eliminating the necessity of anti-rejection drug therapy for transplant patients.

An important component of the immune system is a type of white blood cell known as T cells, which bind to specific antigens to elicit an immune response in the body. Because T cells toggle on and off like light switches, Krensky confined his search to proteins that are expressed in T cells only several days after activation, when the cells are primed for battle. He homed in on two in particular: granulysin and RANTES. Both influence how the body responds to a wide-ranging set of conditions.

"It turns out that both of these molecules, because of how the T cells work, are important in many diseases," says Krensky. "We started out looking at autoimmunity and transplantation, and the molecules we found turned out to be even more important in the major diseases of humanity: tuberculosis, HIV, and malaria."

Granulysin attacks foreign or tumor cells like a torpedo, burrowing into the cell membrane and releasing its contents. It can kill the bacterium that causes tuberculosis -- one of the world's biggest health threats -- as well as the organisms causing leprosy and malaria. It also destroys the fungus that is the major lethal complication of the immunosuppression faced by transplant or cancer patients. However, its good-guy reputation is tarnished by the fact that it may contribute to the rejection of transplanted organs, possibly by attacking the unfamiliar cells.

Like granulysin, RANTES, too, is a double-edged sword. In addition to T cells, it can be made by damaged tissue, where it sits on the surface of the cells like a red flag. Immune cells that flock to the site to protect the area from infection also occasionally cause inappropriate inflammation and tissue damage, which can lead to diseases like atherosclerosis and diabetes. Inflammation also can interfere with the acceptance of transplanted organs. Finally, the protein on the surface of the T cells that recognizes RANTES is also one of several used by the human immunodeficiency virus to latch on to and invade T cells.

Krensky and his colleagues are currently working on ways to understand how and why granulysin and RANTES are expressed. Coupled with additional research into another technique -- utilizing small bits of laboratory- synthesized proteins to affect how a T cell responds to an immune challenge -- their efforts may one day lead to therapies that decrease the likelihood of organ rejection, help a child vanquish tuberculosis, or reduce the rates of HIV infection.

"Studying these basic molecules of the immune response means that our findings may be widely applicable to many different conditions," says Krensky. "The implications of this type of research are huge."