by Elise Wachspress
Imagine you need a new heart to survive.
First, there is the drama of waiting for a donor heart that is a good match—knowing that your chance at life depends on someone else losing theirs.
Then, there is the actual surgery—having your chest opened and an entire team implanting this new organ, followed by both the euphoria of success—one year survival rates are now over 85 percent—and the realization that rehabilitation will require strength of body, mind, and will.
Next comes an intense drug regimen to protect your new heart from being rejected by your body’s immune system. The early danger is that your body’s specialized T-cells will attack the new heart itself. Over the past few decades, transplant specialists have developed a number of strategies to tamp down these cellular incursions, balanced with vigorous antibiotic management to address opportunistic infections. So your chances of thriving through this early stage are strong.
Yet even with a carefully calibrated drug regimen, a significant number of patients still fall prey to serious problems later, especially later during the first five years after surgery. Most common is a condition known as cardiac allograft vasculopathy (CAV). In CAV—known as the Achilles heel of heart transplantation—fibers grow down the inside of the cardiac artery wall, thickening the vessels, not dissimilar to how old galvanized pipes in a home’s plumbing eventually corrode and slow the flow of water to a trickle. Though this kind of thickening can happen in other types of cardiac disease, it progresses much more quickly in patients with heart transplants and often leads to failure of the graft.
Transplant specialists like Ann Nguyen, MD, have suspected for a while that CAV results from an attack not by the body’s immune cells, but by immune proteins—antibodies—circulating in the blood. Growing evidence suggests that certain sensitizing events, like a blood transfusion or pregnancy, can cause the body to create new donor-specific antibodies. Fewer than 10% or so of patients have these antibodies before transplant, but up to three times that many develop these antibodies afterward, and their presence can increase the odds of a failed heart graft fivefold.
Nguyen and her fellow, Mark Dela Cruz, MD, have been following the work of Duchossois Family Institute Director Eric Pamer, MD. His research has shown that certain gut microbes can protect against infections in patients receiving a bone marrow transplant and that bacterial diversity in the gut decreases mortality after the transplant. Nguyen and Dela Cruz are interested in understanding how a patient’s individual microbiome might affect the production of donor-specific antibodies and the outcomes patients experience after heart transplants.
To do so, they have designed an observational clinical study, with one fairly simple change in each patient’s regimen: the addition of one more type of sample—stool—to the blood and urine samples normally collected to monitor patients before and for months after heart transplant. The stool samples will allow Pamer and the DFI team to assess the patient’s microbiome before surgery and track any changes after transplant. They will then correlate what they learn about each patient’s microbiome with the progress of their cardiac transplant for at least the first two years after each patient’s transplant.
UChicago is extremely well-positioned to conduct this study. Not only does the University of Chicago Medicine perform 40 heart transplants per year—with the best survival rates in the state—but the DFI provides facilities for microbial characterization and study matched by few other research centers. Nguyen and Dela Cruz aim to enroll as many patients as possible within one year.
With what they learn about the microbiome’s effects on long-term success after cardiac transplant, they hope they can keep transplanted hearts beating healthily for many more years.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
by Peter Wang
When I started college at UChicago, I thought “This is going to be the best four years of my life! Don’t waste any of it!” I would try out for water polo, make lifelong friends, and jump into research. I wanted to become a doctor in the future and was eager to get my hands dirty.
The spring of my first year, I joined the lab of Maria-Luisa Alegre, MD, PhD. Her lab studies the responses of T-cells, the guardians of the body against foreign invaders, in solid organ transplantation: T-cell tolerance to donor grafts, the impact of infection and inflammation on anti-graft immunity, and interactions between the host immune system against the transplant and microbiota at different body sites.
Roughly 40,000 transplants were performed last year, and over 100,000 people are still on the national transplant waiting list. What the Alegre lab uncovers about the immune mechanisms involved in transplant rejection and tolerance has important implications for the health of these transplant recipients.
My first year as a scientist went by quickly, like when you’re driving somewhere and you lose your sense of time. I found my own groove, balancing chemistry classes in the morning with mouse experiments in the afternoon, not to mention lots and lots of pipetting. I felt I was doing something important, and life couldn’t be better.
Then my life—everybody’s lives—hit a massive speed bump. In March 2020, we were faced with the looming COVID-19 pandemic. My daily routine quickly shifted to life under lockdown: online classes, no labs, stress and anxiety and facing the anti-climactic reality that all I could do to help was to stay indoors. I had so much to look forward to that month; not only exciting experiments, but also a water polo tournament in Des Moines—vanished.
This pandemic has undoubtedly affected the lives of millions of students, small business owners, and brave healthcare workers on the front lines. But I get to give you my perspective, that of the cohort I am joining—scientists—the people best positioned to get us out of this mess.
Scientists in immunology are all motivated by the desire to understand health and disease and improve human health. The more we know about the immune system, the better outcomes we can provide for patients experiencing cancer, organ failure, infection, and allergy.
To advance knowledge, many immunologists utilize unique mouse models. In studying transplantation, Dr. Alegre suggests that “mice are relatively easy to alter genetically, offering the smallest animal model in which it is still possible to transplant an organ (if you are a skilled microsurgeon) and which allows mechanistic investigations into how a given immune gene can lead to graft rejection or graft tolerance. These genes can then become therapeutic targets and improve patient outcomes.”
In the Alegre lab, we use mouse models to study T-cell responses following skin and heart transplantation. Many of our mice are transgenic; like genetically altered fruits or vegetables, our mice have T-cells or tissues engineered to express or lack certain genes and proteins. We use these as donors or recipients of transplanted organs or as sources of transplant-reactive T cells to understand the immune response to the graft.
Because of the limitations in the number of complex surgeries that can be performed in a day, we often plan and perform multiple mouse experiments simultaneously. In her lab, Alegre says that “many of our experiments look at the maintenance phase of transplantation tolerance, 30-60 days after transplantation. Our microsurgeon usually generates a continuous stream of transplanted mice of the various gene backgrounds to have a lineup of experimental mice that have already reached the desired time point.”
Confronted with the necessity to evacuate the lab, we knew there would be few, if any, people left to care for the mice. Soon, universities and labs across the world would ask researchers to wrap up all ongoing experiments and think long and hard about the mice they needed, freeze the embryos of rare and special strains, prioritize the young pups of unique strains, and in many cases, cull the rest.
“The week in which we had to shut down the lab and dramatically reduce our mouse colony was distressing,” Alegre said. “In the span of a week, we erased years of work, prioritized irreplaceable strains and sacrificed all non-essential animals. Mentoring experimental design, methods and data interpretation is obviously much less effective when bench experiments cannot be performed, impacting undergraduate and graduate education.”
Our final in-person lab meeting was heartbreaking. We prioritized our mice: the young and pregnant were spared, with the hopes of ramping up breeding once the lab shutdown is over. Alegre estimates that this crisis has caused a “setback of about a year to be where we were before the lab shutdown. Publication of our findings will be delayed until we can ramp up transplantation and get to the point where we can repeat experiments and generate new data.”
As we adjust to this newfound reality, many at UChicago and the Duchossois Family Institute are confident that our life-saving work will continue, but at a different time and pace. When asked about the future, Alegre expressed that “we scientists are resilient by nature, however we’ll miss the thrill of new discovery and the quiet satisfaction of doing something useful that advances scientific knowledge.” We’ve shifted to lab meetings and journal clubs via Zoom, and I am writing about our work now in a different way—for the public rather than in scientific journals for other researchers. But the sacrifice and isolation in the age of social distancing is one of our important duties as citizens, and saving lives is what I value most.
Peter Wang is a second-year undergraduate student in The College.
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.
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.