Getting streetwise immune system cells to ignore a transplanted heart or kidney is Dr. Adam W. Bingaman’s idea of tolerance.
“Your body was designed to recognize everything that is not you. That includes bacteria, viruses, funguses and transplanted organs, unfortunately,” says the transplant surgeon and immunologist at the Medical College of Georgia.
There’s a bitter irony in the fact that even though the body needs and the patient wants the new organ, the immune system rapidly targets the foreign object for elimination.
“The beauty of transplant surgery is it’s a surgery patients really want, wait for and need. There are more than 60,000 people on the kidney transplant waiting list alone and the average wait time nationally is over three years,” says Dr. Bingaman, who came to MCG last summer from the University of Maryland.
“It’s been shown that kidney transplants can significantly prolong your life compared to kidney dialysis. Never mind your quality of life.” But patients then must take broad-action immunosuppressive medicines that increase their risk for infections and even cancer, plus there’s the ongoing cost of the drugs, he says. “Ideally what you would like to be able to do is treat patients just around the time of the transplant, have them accept the organs as their own, then allow them to stop the medicines forever.”
Within the confines of research laboratories in animal models with pristine immune systems, some selective, short-term approaches to manipulating immunity have worked like a charm. But the findings typically don’t hold up in more humanlike primates. One theory is that primates – and humans as well – have more savvy immune systems that are harder to trick.
T-cells, orchestrators of the immune response, are born naïve, without programmed targets. “You start out 100 percent naïve,” Dr. Bingaman says of T-cells produced by the thymus. “Your memory pool increases as you age, so by the time you are an adult, you have many memory cells. They are experienced. If you get re-infected, your body will say, ‘I have seen this before’ and attack more quickly and aggressively.” The cells even travel in different circles, with naïve cells staying within the lymph nodes and spleen while memory cells travel throughout the body.
Dr. Bingaman wants to know exactly how these traveling memory cells avoid suppression and exactly what it takes to activate them.
“We have given mice memory,” he says of transgenic mice with skin grafts that are enabling him to map that process. The mice have naïve and memory versions of either CD4 or CD8 T cells, known to recognize and respond to the skin grafts. “We are manipulating their immune system so we can track naïve and memory cells and look in the draining lymph nodes or in the spleen of a mouse that got a transplant and ask, ‘How can we try to turn some of these cells off?’” Dr. Bingaman says.
Some antibodies, already in human trials, can inhibit naïve CD4 responses but can’t suppress memory CD4 responses, he said.
A huge amount remains unknown about the immune response and how it can best be locally manipulated to save a transplanted organ without putting its recipient at risk for other disease. “What we are trying to achieve, tolerance induction, should be applicable to all transplants,” says Dr. Bingaman.
Having that goal in common with other researchers, such as Drs. Andrew Mellor and David Munn, is one reason Dr. Bingaman, who recently completed an immunology research fellowship and a renal and pancreas transplant fellowship in Maryland, decided to come to MCG.
Drs. Mellor and Munn reported in Science in 1998 that the fetus uses the enzyme, IDO -- indoleamine 2,3-dioxygenase -- to locally disable the mother’s immune system and avoid rejection. They have since explored the potential of using the IDO mechanism to manipulate immune response in areas such as fighting tumors and HIV infection as well as transplanted organ rejection.
Dr. Mellor, Georgia Research Alliance Eminent Scholar in Immunogenetics, now directs the MCG Immunotherapy Center where researchers are exploring many different ways of manipulating the body’s natural defense mechanisms to better fight disease. Dr. Bingaman has a faculty appointment in the Immunotherapy Center as well as the Department of Surgery.
“The immunology community here I would classify as really outstanding,” he says. “In surgery, like in science, you are only as good as the people around you.” He particularly relished the chance to work with good people on both sides of the street – the team transplanting kidneys and pancreases and research colleagues seeking better ways to help patients keep those organs.
“I would only want to do both,” says Dr. Bingaman. “Surgery keeps you close to the patient. In surgery they can call me now and we can do a transplant in a couple of hours and the patient does well and there is some immediate gratification. Science is a bit of a dream deferred. But it’s also the opportunity to come up with things that nobody has come up with before, novel approaches. I can think of something today and do it tomorrow. You would never want to do that in surgery. I think the two fields go together beautifully.”
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