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Surprise players in life after transplant: Diet, exercise, and microbes

Surprise players in life after transplant: Diet, exercise, and microbes

by Stephanie Folk

Organ transplants can offer patients with debilitating and deadly diseases a chance at a longer life and improved health.

But the new organs come with strings attached. Patients take on a life-long regimen of antirejection drugs, some with serious side effects, as we pointed out in a recent post.

Maria-Luisa Alegre, MD, PhD, is working to help transplant patients stay healthier longer, with fewer drugs. She is uncovering some surprising ways that diet, exercise, and microbes influence the immune system’s response to a transplant.

The immune system often attacks a new organ in much the same way it would defend against a viral or bacterial infection—a recipe for organ failure. To prevent transplant rejection, patients must take drugs to suppress the immune system, but there are consequences.

“People become more susceptible to infections and cancers when the whole immune system is suppressed,” says Alegre.

Scientists are exploring multiple strategies to improve outcomes. Alegre’s colleague Anita Chong is developing treatments designed to target only mechanisms of the immune system that react to the transplant, while maintaining its ability to fight disease. Other researchers are working to bolster tolerance, essentially retraining the immune system to treat the new organ as harmless.

Alegre and her team are approaching the challenge from yet another angle.

“In recent years my lab has become interested in the environmental factors that may influence immune response against the graft. What about dietary interventions? Things like exercise? More recently, we’ve been wondering about the microbiota.”

These are the army of microbes that colonize the body. While we often think of microbes as contributors to disease, most are actually important to health, aiding in the digestion, producing nutrients, tuning the immune system, and possibly even boosting the body’s ability to fight cancer. Alegre is using germ-free mice to test the impact of different types of microbes on transplant rejection.

“From this work we know, indeed, the microbiota influences rejection, and we have found some microbial communities that augment the immune response against a graft. But we have also found some microbial communities that can suppress the immune response.”

Alegre and colleagues are cultivating the bacteria that appear to slow down rejection to see whether they might work as a sort of probiotic therapy. They are also investigating the microbes that increase the speed of rejection in order to determine whether selectively eliminating these bugs could reverse the process.

Alegre notes that microbial influences could also help to explain why organs like lungs and intestines, which are exposed to the outside world and colonized by microbes, are typically rejected faster than organs like kidneys, which are sterile. She is exploring whether changing the microbes in a donated colonized organ like a lung could make it more like a kidney, a sterile organ, in terms of transplant tolerance.

Alegre’s studies in mice have shown that a high fat diet can also accelerate rejection of a graft, while exercise seems to slow rejection. Though the mechanism is not yet clear, the results suggest that a shot at a longer functioning transplant may be one more of the many benefits that come from staying active and eating a healthy diet.

While transplant success is a multivariable equation, Alegre’s work points out factors to improve the organ’s chances. Medical discovery takes not just a village but a giant community. By pooling their knowledge—sometimes over decades—scientists are creating a clearer picture of the complex workings of the immune system and how it responds to transplants. Their research could lead to better antirejection therapies that help patients live better, with fewer drugs.

No strings attached.

Stephanie Folk is a senior assistant director of development communications for the University of Chicago Medicine & Biological Sciences Development office.

 

The somewhat secret life of transplanted organs

The somewhat secret life of transplanted organs

by Stephanie Folk

In December 2018, doctors at UChicago Medicine set a new record. Over the course of two-and-half days, they completed not one, but two triple-organ transplants, replacing the failing hearts, livers, and kidneys of two 29-year old patients. It was the first time any US hospital had ever performed more than one of these incredibly complex surgeries within a single year—let alone within two-and-half days.

These remarkable, back-to-back surgeries made national news, and the donated organs will give the recipients new leases on life. But the story doesn’t end there. What happens after the surgery rarely makes the news—but it’s critical to the well-being of the patients. The next challenge is to keep the transplanted organs alive and functioning in their new and immunologically hostile environment. It’s a delicate balancing act that requires keeping peace between the donated organs and the recipient’s immune system. This is where scientists like Anita Chong, PhD, come in.

Chong is working to improve transplant success by creating better, more targeted therapies that keep the body from rejecting and eventually destroying the new organs.

The immune system sees new organs as intruders and unleashes an army of immune cells and an arsenal of secreted antibodies trying to kill the “invaders.” Transplant specialists try to reduce the intensity of the assault by matching organ donors with recipients who are as genetically similar as possible. A better match means fewer differences to trigger the body’s defenses.

“But unless you get organs from your identical twin, your immune system will recognize that this organ is something that is ‘non-self,'” Dr. Chong said.

This means that nearly all transplant patients need to take drugs to suppress the immune system, medications which are costly and can cause serious side effects.

“So the problem is maintaining a good quality of life as well as maintaining the graft,” Dr. Chong said. “If you take a lot of drugs, your body will not reject the graft. Ultimately, if you eliminate your immune system completely, you will never reject your graft. But that’s not compatible with normal living. And the higher your dose, the more side effects you will have with the drugs,” she said.

Researchers like Chong are working on ways to prevent rejection with fewer drugs. She and her colleagues are focused on an approach to essentially “turn off” only the parts of the immune system specific to the transplant reaction while maintaining the immune system’s ability to fight disease.

Creating this type of targeted treatment requires the ability to diagnose which of the many mechanisms of the immune system are attacking the transplant and then developing therapies that stop this process.

One of Chong’s projects focuses on preventing rejection driven by antibodies. These Y-shaped proteins circulate in the blood plasma and other bodily fluids to neutralize targets such as bacteria, and viruses. But antibodies can also attack transplanted tissue. In mouse models, Chong and colleagues identified a drug combination that can prevent antibody production and treat rejection.

Chong and colleagues also conducted a pilot study that involved using drugs that target antibody-producing white blood cells to treat six patients who were rejecting transplants. The drugs reduced the production of the antibodies damaging the graft. The transplanted organs were saved, and the health of the patients improved. Chong is now working with colleagues at the University of Chicago to conduct pilot studies to treat patients who have antibodies that prevent them from receiving organ transplants. If successful, this work will allow patients who have been waiting for many years to successfully receive organ transplants.

These and other research projects led by Chong and others at UChicago could lead to groundbreaking treatments that would help transplant patients live longer, healthier lives. In a future post, we will look at the work of Chong’s colleague, Maria-Luisa Algere, MD, PhD, who is investigating some surprising connections between transplant success and diet, exercise, and the microbiome.

Photo caption: Triple-organ transplant recipients, Sarah McPharlin and Daru Smith. Ben Bitton/UChicago Medicine.

Stephanie Folk is a senior assistant director of development communications for the University of Chicago Medicine & Biological Sciences Development office.