Indiana University Research & Creative Activity

The Art and Science of Medicine

Volume XXVI Number 1
Fall 2003

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David Wilkes
David Wilkes
Photo 2003 Tyagan Miller

Saving Your Breath

by David Bricker

Patients who receive newly transplanted lungs have a fifty-fifty chance of being alive five years later.

"As things currently stand, lung transplants aren't a cure," says Indiana University School of Medicine immunologist David Wilkes, who has devoted the majority of his medical career to improving lung transplant survival rates. "In many instances, transplants just buy patients a little time."

An expert on sarcoidosis (a chronic inflammatory disease that affects lungs) and interstitial lung diseases, Wilkes is sought out by patients and colleagues nationally for his diagnostic specialties. He joined the School of Medicine faculty in 1992 to help expand the school's growing organ transplant program.

People whose lungs are sure to fail are said to have end-stage lung disease, a catchall name for a number of conditions, some genetic, some environmental, all painful. Common causes of end-stage lung disease are emphysema (usually the result of smoking tobacco), cystic fibrosis, pulmonary fibrosis, pulmonary hypertension, bronchiectasis, and congenital cardiopulmonary diseases. Provided the ailing patient qualifies as a lung candidate--and many do not if the likelihood of survival is deemed too low--there is a one-and-a-half year wait just to get lungs. Wilkes, who runs the Center for Sarcoidosis and Immunologic Lung Diseases at the IU Medical Center, says many qualified candidates on the lung list die waiting.

And those who are lucky enough to receive replacement lungs? Many get a scant few years of life in exchange for emotional, physical, and financial strain.

Survival rates for transplant patients who have end-stage liver, kidney, or heart disease are stunningly higher than those for lung transplant patients. In contrast with lung recipients' coin-toss odds of survival, seven out of 10 liver transplant patients will still be alive and producing bile in five years.

One of the problems, Wilkes explains, is that transplanted livers, kidneys, and hearts are embedded in the body, protected from the elements. Lungs, on the other hand, brave a constant barrage of potential intruders: airborne bacteria and viruses, fungal spores, and air pollution lead the assault.

"In addition to getting a patient's body to accept someone else's lungs as their own, the problem of infection is much greater for transplanted lungs than for other organs," Wilkes says. "Lungs are not exposed only to the bloodstream."

Therein lies a paradox that has frustrated immunologists, internal medicine physicians, and transplant surgeons for decades. Doctors must use immunosuppressive drugs to prevent the body from eating up donor organs, but suppressing the body's immune system also makes the patient more susceptible to infection.

The leading cause of death among lung recipients is an unrelenting, downward spiral known as bronchiolitis obliterans, or chronic lung rejection--it claims hundreds of lives in the United States every year. What causes chronic rejection is poorly understood, but it may be the consequence of too many temporary "acute" rejection episodes. A patient experiencing an acute episode usually goes to the hospital for treatment, is given new immunosuppressive drugs or kept on the same drug regimen, and is sent home.

Doctors are doing the best they can, Wilkes says. Advances in immunosuppressive drug technology have reduced the chances of organ rejection and modestly improved postoperative survival.

Advances in drug technology will only go so far, however, in correcting the underlying problem. Wilkes says low survival rates for lung transplant recipients mean something is broken in the lung transplantation medical protocols used around the world. And it just so happens Wilkes is pretty good at fixing things.

Wilkes's father, an electrical engineer, spent many weekend afternoons teaching his son how to get rusty, decrepit lawnmowers working again. So skilled was the young Wilkes in the intricacies of machines that his knowledge of automobiles helped pay his way through college and a portion of medical school. "People think I'm joking when I tell them I was an auto mechanic once," Wilkes says. "Fixing things has always been fun for me."

While he does not admit a direct connection between his mastery of machines both metallic and biological, Wilkes's workbench-like fiddling with physiological processes before, during, and after lung transplantation in rats turned up a serendipitous discovery.

Wilkes's find involved antibodies--small immune-system proteins that mob foreign matter for later removal. Once foreign matter is sufficiently blanketed, antibodies signal other cells to grab the whole mass and expunge it from the body. "We looked at how antibodies were behaving after donor lungs were put in place," Wilkes explains. "We found all of the important antibodies were in patients' own connective tissue, which surrounds structures within the donor lungs. We were shocked. This meant some of the immune response to donated lungs was autoimmune in nature."

Autoimmunity (auto- means "self") happens when the body doesn't recognize its own tissue and attacks it, causing damage. But in their efforts to compel the body not to destroy foreign tissue, lung transplant physicians have been far more focused on alloimmunity (allo- means "other").

Because Wilkes's discovery was so unexpected, many scientists and doctors in the field had a hard time accepting that the organ-rejection response was largely due to the body responding to something within itself.

"I actually got laughed at when I presented this information for the first time at an academic meeting years ago," Wilkes recalls. "What I was suggesting was considered almost heresy. So my collaborators and I sort of went underground with the research, because we were convinced what we'd found was real and important."

That conviction served Wilkes well. Since the lukewarm response to his autoimmunity discovery in 1995, a series of results confirming an autoimmune response to donated lungs has led to wide respect for Wilkes and his work in the larger lung transplant community. No longer derided or doubted, Wilkes now pursues lung rejection response research projects with the aid of three National Institutes of Health grants.

"David Wilkes is that rare kind of scientist who chooses a problem to study, and then follows his experiments wherever they take him, even if the problem is outside areas protected by current paradigms and peer appreciation," says Charles Orosz, director of transplant research at Ohio State University's College of Medicine. "This path can lead to problems with publication and funding, which deter less committed individuals. Perseverance has made David a pioneer in the interface between autoimmunity and alloimmunity."

When donor lungs are introduced, Wilkes and his coinvestigators learned that a protein called type-V collagen, or collagen V, is released from its normal place of residence inside connective tissue. Collagen, in its many incarnations, gives structure and strength to hair, organs, and other tissues throughout the body. In connective tissue, collagen V is a part of the molecular pillars that are believed to keep the tissue from collapsing on itself. The freed collagen V, sequestered in surrounding tissue before the transplant operation, comes from the transplant recipient's own body.

While the connective tissue does not seem to collapse as collagen V extricates itself from its hiding spots, the body's immune system reacts as though it has been called to a V-alarm fire.

The body is simply not accustomed to hoards of its own collagen V floating freely through connective tissue. The immune system begins producing antibodies to wrap up the collagen in the first phase of what is a catastrophic autoimmune response that may eventually lead to rejection.

From research done on other kinds of transplants, Wilkes knew it might be possible to suppress some of this collagen V autoimmune response by conditioning the body with small doses of collagen V before lung transplantation. This way, the body might be gently made accustomed to the collagen V instead of being thrown into a panicked immune response. Wilkes and colleagues from the IU School of Medicine and Chiba University School of Medicine in Japan decided to test this hypothesis.

A moment of truth had arrived--in rats, at least-- and it amazed the lung transplant world. Wilkes's team of scientists reported in the journal Transplantation (Vol. 73, No. 4) that rats who were fed a little collagen V prior to their lung transplant surgeries accepted their donor lungs better than rats that had been given no collagen V. But even more remarkable, Wilkes also learned the collagen V-fed rats would accept donor lungs even when they were not given immunosuppressive drugs.

"This was a very important finding," says University of Wisconsin Medical School transplant researcher William Burlingham. "It linked two areas of research people didn't think were related--autoimmunity and transplantation. In the field of autoimmunity, it has become quite common to use oral conditioning to inhibit the autoimmune response. But it had not been commonly thought that a similar approach might be used with transplantation. David's idea was really quite a radical departure from previous ideas about how transplant, immunity, and tolerance work."

The traditional human lung transplant patient receives a hefty regimen of immunosuppressive drugs, cyclosporine and tacrolimus among the most common. But such immunosuppressive drugs impair the ability of T-cells--the corporeal corporals that mediate many immune responses--to recognize invaders of real concern, like airborne viruses. As a result, Wilkes says doctors are presented with a difficult, perhaps impossible, situation. Drugs that get transplant patients through their first few years are responsible for much of the patients' health complications years later. "Drugs are definitely a part of the problem," Wilkes says. "They poison the very T-cells you need to protect you from an autoimmune response."

One of the next steps, he says, is to see whether the collagen V treatment achieves similar success in humans. Wilkes has a patent pending on the use of collagen V to prepare patients for new lungs and is currently waiting for approval to begin human clinical trials applying the technique. "Even if collagen V does not prove as successful in humans as it has in rats, we will have learned new things about autoimmunity problems in lung transplantation," he says.

Whatever the outcome of Wilkes's collagen V investigations, he remains committed to one goal: doing whatever must be done--unconventional research, if necessary--to increase the lifespan of lung recipients.

"My approach to science has always been, what are we not seeing? When you are able to see what is unseen," Wilkes says, "you can ask entirely new and different questions, the answers to which may make people's lives healthier and longer."

David Bricker works for the IU Office of Communications and Marketing and is a freelance science writer in Bloomington, Ind.

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