SALLY ANN FLECKER
Frankly, a lot of people are going to give a damn about new findings by Fadi Lakkis and colleagues. It turns out that organ rejection in transplantation doesn’t happen for the reasons scientists had assumed.
Fadi Lakkis, an MD and scientific director of the Thomas E. Starzl Transplantation Institute, appreciates the elegance of simplicity. He has an affinity for the simpler question. He savors a good, clean, simple answer. One summer, before he started medical school at the American University of Beirut, he spent his time reading several books on immunology. One of the books was extremely well, and simply, written, he remembers. “That attracted my attention that someone can explain things in a very simple way,” he says. “It turned out to be quite exciting.”
As the young man progressed through his medical education, the intricacies of kidney disease also captured his imagination, again for the straight- forwardness of the physiology. “I found that in nephrology you can diagnose a problem just by understanding the science behind it,” he says. “Instead of having to memorize a set of symptoms and signs and then make a diagnosis, I thought, ‘Oh, if I understood how the kidney handles sodium, I [could] understand why this patient’s sodium is low and what to do to treat it.’ To me it was very appealing that you can start with a very simple thing and then make a very complex diagnosis.”
More recently, Lakkis (professor of surgery, immunology, and medicine, who holds the Frank and Athena Sarris Chair in Transplantation Biology at the University of Pittsburgh) asked a simple biological question about organ rejection in transplant patients. The answer surprised everyone, turned a long-held assumption on end—and just may pave the way for better, and much-hoped-for, antirejection therapies.
Finding a way to achieve tolerance is a lofty goal for many people. For transplant immunologists, it’s the quest of a lifetime. Many a transplant scientist has spent a career looking for a way for the human body to accept an organ without having to resort to immunosuppressive medication.
That’s not to say that contemporary immunosuppressive medication hasn’t been a godsend. It’s allowed for countless successful transplants, legions of lives saved. And over the years the regimen has been finessed, most notably by Pitt’s Thomas E. Starzl. Starzl developed a two-pronged immunosuppressive approach that reduces the amount of drugs a transplant patient takes. Even at the minimum effective dosage, though, the side effects can be unpleasant—and a suppressed immune system lacks the basic ammunition to fight off opportunistic infections and other attacks on the body, such as malignancies.
There are some reports of patients, a handful, becoming tolerant of grafted organs on their own. In other cases, bone marrow trans- plants have convinced the immune system to halt the attack on the organ. “It’s a little bit drastic,” Lakkis says of that approach. Patients have to undergo chemotherapy or radiation to eliminate their own bone marrow, which leaves them at great risk for infection until the donor bone marrow starts to kick in. “It’s a bit too much for someone coming in for a kidney transplant,” says Lakkis, especially knowing that the immunosuppressive medications are a feasible, if not perfect, course of action.
So the search for tolerance continues. A few years ago, Lakkis decided to go about it from a different angle. “When something has been resistant to good solutions for so many years,” he says, “you start worrying a bit that you’ve been missing something.” He decided to question the fundamental mechanisms of rejection—starting with a paradigm that has been accepted for the past 25 years.
“Organ rejection may seem quite complex,” he says. “In reality, it’s dependent on a single cell type—without that cell type, rejection will not happen. That cell is the T cell. If you take an animal or human that does not have T cells, they will not reject.” The T cell is a lymphocyte, a type of white blood cell originating in the thymus (hence the “T”). It has to get activated—prepared for duty—before it can go to the transplanted organ and initiate rejection. Some T cells are memory cells; they’re already primed by past infections or vaccinations to fight the foreign tissue. Other T cells are naïve and have to be turned into effector T cells before they’re ready to go up against what they perceive to be the enemy—the grafted tissue.
Lakkis was interested in taking another look at exactly how the activated T cells got to the graft. The paradigm involved chemokines—a flexible set of small proteins that can handily fold themselves up and pass through from one side of a membrane to the other. When tissue is inflamed, certain chemokines are present in droves. And a transplanted organ will inevitably result in lots of inflammation, particularly in the delicate endothelium lining of blood vessels.
The long-held assumption was that the crowd of chemokines signaled the T cells to get their attention. An inflamed endothelium is a sticky place. The T cells would slowly roll through the endothelium to the chemokines. Once they met up, receptors on the T cells would bind to the chemokines. With the T cell firmly adhered to the chemokine, the T cells slide smoothly through the barrier of the endothelium and into the grafted tissue where the T cells can initiate the rejection process. You can see how it would follow that if you blocked the chemokines from signaling, you would stop the rejection process. However, attempts to do that had been unsuccessful.
- See more at: http://pre.pittmed.health.pitt.edu/story/rejection-reconsidered#sthash.DfWoFnQ8.dpuf