Organ transplants are a lifesaving procedure for thousands of people each year. But transplant recipients have to take medications the rest of their lives to suppress their immune system enough so that it doesn’t attack the organ. This is similar to the way the body fights off infection, by attacking the viruses and bacteria it sees as foreign invaders.
Immunosuppressive drugs prevent the body from rejecting a transplanted organ, but they also limit its ability to fight off infection. The trick is finding out how to selectively inhibit the immune system’s reaction to the organ, or alloreactive response, while leaving the normal immune response to pathogens intact. To help find the right balance, two researchers at the University of Chicago Medicine are studying the complex relationship between the two.
Anita Chong, PhD, professor of surgery and immunology, said she first started thinking about this relationship when she was studying why certain organ transplants are more successful than others. Kidney, liver and heart transplants typically have better outcomes than lungs, skin and small bowels. The difference, Chong thought, may be that the latter group is exposed to the environment and the bacteria that come with it. Our bodies are colonized by a unique mix of bacteria, but what’s normal and tolerated by one person may activate an immune response in someone else.
“I had one of these moments where I thought, ‘Aha!’ The skin is an exposed organ and there are commensal bacteria with it,” she said. “Maybe it’s these bacteria that are shaping the immune response to the skin, and they’re not there in the liver or kidney.”
She talked about this idea with Maria-Luisa Alegre, PhD, professor of medicine, who was studying how to induce permanent tolerance of a transplanted organ so patients would no longer need to take immunosuppressive medications. “We were investigating approaches to retrain the immune system in order to achieve permanent acceptance of transplanted organs,” she said.
The two are working together on mouse models that simulate different scenarios for organ acceptance and rejection. For instance, Alegre has observed that mice that are genetically modified to inhibit a particular protein in immune cells can accept a heart transplant without immunosuppresion, but still reject a skin transplant. Other mice that are genetically modified so that their immune system doesn’t respond to bacteria can permanently accept a skin transplant, however.
Understanding what elicits these different responses could lead to better ways of preventing rejection without putting a patient at risk for infection. “What can we do to intervene so that we stop stimulating the immune responses that cause rejection, but still leave enough protective immunity so that patients don’t die from an infection while we try and save the organ?” said Chong. “We’ve been working on how to define the specific cues that are involved in this cross-talk between immune responses that are elicited in response to the bacteria, and how they inadvertently turn on the alloreactive immune response.”
Both Chong and Alegre are looking forward to working in the new germ-free facility at the University of Chicago. In this special lab, mice are born and raised in an environment completely free of any outside pathogens. This controlled environment will allow them to perform a skin transplant from one germ-free mouse to another, knowing that the tissue is free of commensal bacteria, and study the immune response to the transplanted tissue. Then they can selectively introduce different types of bacteria to study their effects as well.
It’s a process of elimination in a way. “We’re starting to understand that different types of viruses, bacteria and fungi elicit different immune responses, and different organs elicit slightly different shades of immune responses too,” Chong said. “How much of the immune response is actually driven by the tissue itself, and how much of it is due to the combination of the microbiota and the tissue is not really well-known. That’s why we’re very excited to be moving forward to these experiments in the germ-free facility.”
To learn more about the impact of infection in organ transplantation, read Dr. Chong’s and Dr. Alegre’s review paper in Nature Reviews Immunology.