The body’s great balancing act
Understanding how to modify and even predict immune responses in patients could revolutionize treatment and open the door for a new kind of personalized medicine.
By Laura Mize
Here’s a medical riddle: What’s something every person has that can protect the body or fight against it?
If you guessed the immune system, you’re right.
Our immune systems do more than just ward off germs that could make us sick. They also respond when we are injured by initiating inflammation to start the body’s healing process. But the system isn’t perfect. Some people’s immune systems don’t respond to injuries or germs quickly or strongly enough. Others immune systems react too intensely, causing immune system cells and biochemicals to choke off vital body functions, leading to severe illness or even death.
Aspects of immunology have intrigued scientists for millennia. Astute observers in ancient and medieval societies wrote that those who survived vicious plagues that killed most of their neighbors were not touched by the same disease again. Primitive “vaccinations” were used sporadically hundreds of years before British scientist Edward Jenner’s famous use of cowpox to create a working vaccine against smallpox.
Today, the study of immunology is increasingly complex, and UF researchers are playing vital roles in moving it forward.
Looking at the big picture
What if a blood test could predict within minutes which car crash victims were likely to suffer great complications during their recovery in a hospital? What if oncologists could know which cancer patients would be most susceptible to infection while undergoing treatment? What if an injection could boost immune system function in people with AIDS or other illnesses that compromise the immune system?
Lyle Moldawer, Ph.D., and his team of researchers in the UF College of Medicine department of surgery’s laboratory of inflammation biology and surgical science are working on projects that might make these ideas reality in the not-too-distant future.
Moldawer is a professor and vice chair of research in the department of surgery. He has been conducting biomedical research, most of it related to immunology and inflammation, for 30 years. For him, doing this work is a dream come true.
“Ever since I can remember, I’ve wanted to do medical research,” he says. “I grew up right next door to the National Institutes of Health in Bethesda, and all my neighbors’ parents worked at either the NIH or the Bethesda Naval Laboratories.”
His research career began when he went to Sweden to earn a Ph.D. in experimental medicine at the University of Gothenburg. There, Moldawer worked with a team investigating nutrition in cancer patients and the critically ill.
“We were studying why you couldn’t feed people who had cancer or were critically ill — why they kept losing weight, losing body protein — and then we stumbled on that the reason they were doing this was because they had inflammation,” Moldawer says. “Then the question became ‘What was driving the inflammation?’ We started studying cytokines.”
Moldawer’s collaborators uncovered two peptides — tumor necrosis factor and interleukin 1 — which the group suspected played a role. A series of big developments followed. Moldawer calls this work on cytokines, proteins that help regulate the immune system, the most influential research of his career.
“We developed the antibodies and the inhibitors that (are) now clinically used to treat rheumatoid arthritis, inflammatory bowel disease and psoriasis,” he says.
During this time Moldawer worked in the same laboratory with Bruce Beutler, M.D., one of three men to win the 2011 Nobel Prize in Physiology or Medicine. At the same time, another 2011 winner, the late Ralph Steinman, M.D., worked one floor above them. Beutler and another scientist, Anthony Cerami, Ph.D., discovered a protein Moldawer eventually linked to cachexia, a wasting syndrome, in cancer patients.
Beutler and the third winner, Jules Hoffman, Ph.D., shared the prize for their work studying the mechanisms that trigger the body’s innate immune response, the first line of defense against illness. Steinman won for discovering a cell type, the dendritic cell, and the role it plays in the body’s adaptive immunity, a more strategic response that occurs after innate immunity gets started.
After working at Cornell University and Rockefeller University, Moldawer came to UF in 1993. He has led the laboratory of inflammation biology and surgical science since then, training residents, fellows and postdocs in research techniques and helping faculty members with their projects.
Moldawer has led or participated in dozens of NIH-funded projects at UF, most linked to immunology. Today’s approach to immunology has evolved beyond the search for specific proteins that drive inflammation, he says.
“There’s so much redundancy and complexity in inflammation, that we’re now moving from a reductionist, individual protein approach to more of a systems-biology approach, looking at the different cell populations that contribute to the inflammatory response,” he says.
Ultimately, Moldawer says, the goal is to develop methods for regulating immune system function to prevent and treat underactive and overactive immune responses, including inflammation.
“How do you prevent the wasting of lean tissue and body protein in the critically ill and patients with cancer?” Moldawer asks. “How do you modulate inflammation to prevent this wasting? In immune-suppressed patients who don’t generate an appropriate inflammatory response, how do we take what we know about the system and stimulate a pro-inflammatory response?”
To find answers to these and other questions about inflammation, the National Institute of General Medical Sciences launched a project in 2001, pulling together dozens of researchers from across the country in search of a more comprehensive view of immunology. It was one of five research efforts funded through the National Institute of General Medical Sciences’ Glue Grants program. The program ended in 2010, but the inflammation team continues work with remaining funds. Moldawer says they are applying for more funding to keep the research going.
Treating the problems that overactive and underactive immune responses cause (wasting and infection, respectively) once they have taken hold in patients is often difficult to do. Moldawer and his fellow Glue Grant researchers imagine a better approach — one that allows providers to predict which patients are likely to suffer these problems and taking steps to prevent them.
Using Glue Grant funding, Harvard researchers developed a device that may make such predictions possible — and practical. Called a microfluidics cassette, the device can rapidly isolate genes and proteins from cells in a small sample of blood or other bodily fluids, so they can be analyzed. It’s a more efficient version of previous approaches, which required lots of time and expertise, as well as large samples, to get results.
“We’ve identified a set of genes that are expressed differently very early after trauma,” Moldawer explains. “Now we’re setting up a multicenter trial to determine whether we can, using that gene test based on these microfluidics, look at the result and say, ‘This patient is likely to have a bad outcome, and we need to watch the patient closely and intervene when necessary.’”
The cassettes also could be customized and used to analyze genes and proteins for other medical purposes.
The potential ability to predict immune system over- or under-reaction raises an obvious question: What would providers do with a patient whose genes showed one of these problems was likely? One answer is to try to balance the immune system to allow a more normal response.
The need to develop ways to do this is one reason scientists study the immune system. Last year, a team of researchers that included Moldawer and other UF investigators identified two key chemicals that initiate the body’s innate immune system. They also found that B cells, a type of blood cell once thought to participate only in adaptive immunity, do play a role in innate immunity. The Journal of Immunology and The Journal of Experimental Medicine published the findings, and Nature Reviews Immunology ran an editorial discussing the importance of the finding on B cells.
The findings may lead to new treatments — perhaps injections of the chemicals that kick-start innate immunity — for cancer and AIDS patients and others with suppressed immune systems, Moldawer says.
“What we’re trying to do is translate these basic findings that we have into addressing the clinical issues,” he says.
Answers in our guts
Meanwhile, Mansour Mohamadzadeh, Ph.D., and his collaborators are working on solutions to overactive inflammation and immune system responses in the human digestive system.
Chronic inflammation in the digestive system is a hallmark symptom of inflammatory bowel disease, a set of chronic illnesses that cause intense abdominal pain and, in some patients, inadequate nutrient absorption. This class of diseases is difficult to treat. Some patients repeatedly go into remission following treatment, only to suffer a relapse. Ultimately, many patients have a portion of their intestines removed to alleviate suffering.
Developing effective prevention methods or a cure for IBD would spare patients pain and save millions of health care dollars.
But science has yet to definitively pinpoint the cause of IBD. Mohamadzadeh, a professor of immunology in the College of Veterinary Medicine’s department of infectious diseases and pathology, thinks the community of microorganisms that live in the human digestive system may be part of the problem. He’s focused on Lactobacillus acidophilus, typically regarded as a safe bacterium that helps balance the digestive system and treat a host of health problems.
Mohamadzadeh and his collaborators, however, have found that a specific acid molecule attached to the outside of Lactobacillus acidophilus might be harming IBD patients, instead of helping them.
“We identified some molecules which are strongly involved in the induction of undesired inflammation,” says Mohamadzadeh, a member of the UF Shands Cancer Center and Emerging Pathogens Institute. “Therefore, we went ahead and disrupted the genes that are responsible for those molecules.”
When the researchers administered this modified version of Lactobacillus acidophilus to mice, they were less susceptible to developing colitis, one form of IBD. And mice already suffering from colitis showed milder symptoms after ingesting the modified bacteria.
Mohamadzadeh says these results show that the modified bacteria helped rebalance immune responses and exaggerated inflammation in the mice, instead of inciting inflammation like the original version did.
An article in the April 2011 issue of the Proceedings of the National Academy of Sciences described the findings, which Mohamadzadeh and his colleagues at Northwestern University and North Carolina State University reached before he transferred to UF late last year. Nature Gastroenterology and Science published editorials on this work.
Mohamadzadeh brought a bevy of UF researchers into the work. Together, the team has found the same method also may be effective for preventing or treating colon cancer. The investigators are looking at other ways to modify Lactobacillus acidophilus in hopes of preventing or treating Sjogren’s syndrome, an autoimmune disease.
Meanwhile, Kevin McHugh, Ph.D., studies osteoimmunology, a relatively new field focused on immune system function in bones. McHugh transferred from Harvard Medical School to UF last year and now serves as an associate professor of periodontics in the College of Dentistry.
The U.S. Department of Defense has funded his research on ways to treat ectopic bone formation, also known as heterotopic ossification, after amputation in veterans who have survived explosions. Heterotopic ossification occurs when muscle near an amputation site transforms into bone, causing pain, limited mobility and problems wearing prosthetics.
Only a small percentage of patients have this problem after routine surgeries, McHugh says, but two-thirds of veterans who undergo amputation after a blast experience it. There is no proven explanation for the different rates of occurrence, nor for heterotopic ossification in the first place.
“Nobody knows how it got there,” he says. “Nobody knows a good way to treat it.”
McHugh believes the solution lies with osteoclasts, immune system cells that normally resorb out-of-place bone. He wants to understand why they aren’t doing their job and how to get them back to work.
“Virtually everyone else is looking at formation,” he says, adding that osteoclasts often are viewed as villains. “Really nobody studies enhancing bone resorption, because it’s usually the bad guy. It’s the guy that causes osteoporosis. It causes joint destruction and rheumatoid arthritis. It causes tooth loss and periodontal disease, and so normally people are trying to study how to block osteoclasts. I’m looking at it from the other side.”
The future of immunology
UF researchers and scientists across the world are increasingly finding that many of modern medicine’s biggest questions come back to immunology — whether in our bones, our bowels or our blood cells. The research leaders of today are making great strides and paving the way for a new generation of investigators to take the reins.
Moldawer believes this is his greatest contribution.
“I always think that the legacy of your career is defined not as much by what you have discovered, but whom you have trained,” he says. “Really, my legacy is that for the past 25, 30 years I’ve trained a large number of surgeons to do research, and now many of them are independent investigators of their own.”