Emory transplant researchers have identified a control mechanism the immune system uses to tamp down chronic inflammation. The findings provide insight into how some people were able to stop taking immunosuppressive drugs after kidney transplant.
In addition, they may be important for a full understanding of how many drugs for cancer and autoimmune disorders (therapeutic antibodies) work. The results were published on January 14 in Immunity.
In a twist, scientists have known about the molecules involved for a long time. They’re Fc receptors. Usually, we can think of them acting like oven mitts that immune cells use to grab onto antibodies. Fc receptors bind the constant (unvarying) portions of antibodies, which are the same no matter what they’re directed against.
Mandy Ford, PhD and graduate student Anna Morris
The news here is that an inhibitory variety of Fc receptor – FcγRIIB — is found on CD8+ T cells, and is a way of squeezing off T cell activity. Dogma over the past few decades held that T cells do not express Fc receptors, although evidence for them doing so went back to the 1970s.
“Our data suggest that the physiologic relevance of this pathway is to allow for control of active, highly differentiated effector T cells in the setting of chronic inflammation in order to limit immune pathology,” says senior author Mandy Ford, PhD, scientific director of Emory Transplant Center.
Emory scientists have identified a way to stop troublemaker cells that are linked to immune rejection after kidney transplant. The finding could eventually allow transplant patients to keep their new kidneys for as long as possible, without the side effects that come from some current options for controlling immune rejection.
The standard drugs used for many years, calcineurin inhibitors, show side effects on cardiovascular health and can even damage the kidneys over time. A newer FDA-approved medication called belatacept, developed in part at Emory, avoids these harmful effects but is less effective at stopping acute rejection immediately after the transplant. Belatacept is a “costimulation blocker” – it interferes with a signal some immune cells (T cells) need to proliferate and become activated.
Researchers led by Emory transplant surgeon Andrew Adams, MD, PhD suspected that long-lasting memory CD8+ T cells were resistant to belatacept’s effects.
“Our previous work identified that memory CD8+ T cells may be elevated in animals and human patients who go on to reject their transplanted organs while taking belatacept,” says Dave Mathews, an MD/PhD student who worked with Adams and is the first author of the paper.
The researchers identified a certain marker, CD122, which was present on memory CD8+ T cells and important for their activity. On T cells, CD122 acts as a receiving dish for two other secreted molecules, IL-2 and IL-15, generally thought of as inflammatory cytokines, or protein messengers that can encourage graft rejection. Read more
Emory scientists have identified troublemaker cells—present in some patients before kidney transplantation—that are linked to immune rejection after transplant. Their results could guide transplant specialists in the future by helping to determine which drug regimens would be best for different groups of patients. Eventually, the findings could lead to new treatments that improve short- and long-term outcomes.
Transplant patients used to have no choice but to take non-specific drugs to prevent immune rejection of their new kidneys. While these drugs, called calcineurin inhibitors, are effective at preventing early rejection, they lack specificity for the immune system and ironically can damage the very kidneys they are intended to protect. In addition, their side effects lead to higher rates of high blood pressure, diabetes, and cardiovascular disease, ultimately shortening the life of the transplant recipient. This changed with the advent of costimulation blockers, which avoid these harmful side effects. Emory transplant surgeons Chris Larsen and Tom Pearson, together with Bristol-Myers Squibb, helped develop one of these new drugs called belatacept, which blocks signals through the costimulatory receptor CD28.
In a long-term clinical study of belatacept, kidney transplant patients tended to live longer with better transplant function when taking belatacept compared with calcineurin inhibitors. Despite these desirable outcomes, acute rejection rates were higher in patients treated with belatacept.
Andrew Adams, an Emory transplant surgeon who focuses on costimulation blockade research, notes: “While the acute rejection seen with belatacept is treatable with stronger immunosuppression, there may be long-term effects that linger and impair late outcomes.”
Most transplant centers have not yet adopted this new therapy as their standard of care because of the higher rejection rate as well as other logistical concerns, thus limiting patients’ access to potential health benefits afforded with belatacept treatment.
Adams and colleague Mandy Ford have identified certain types of memory T cells, which typically provide long-lasting immunity to infection, as potential mischief-makers in the setting of organ transplants treated with belatacept. Evidence is accumulating that the presence of certain memory T cells can predict the likelihood of “belatacept-resistant” rejection. Two recent papers in American Journal of Transplantation by Ford and Adams support this idea. Read more
When facing a life-threatening infection, the “yuck factor” is a minor concern. Fecal microbiota transplant (FMT for short) has become an accepted treatment for recurrent Clostridium difficile infection, which can cause severe diarrhea and intestinal inflammation.
In a new video, Emory physicians Colleen Kraft and Tanvi Dhere explain how FMT restores microbial balance when someone’s internal garden has been disrupted.
C. difficile or “C diff” is a hardy bacterium that can barge into the intestines after another infection has been treated with antibiotics, when competition for real estate is low. In the last few years, doctors around the world have shown that FMT can resolve recurrent C diff infection better than antibiotics alone.
At Emory, Kraft and Dhere have performed almost 300 FMTs and report a 95 percent success rate when treating recurrent C diff. They have established a standard slate of stool donors, whose health is carefully screened.
Building on their experience with the procedure, Kraft and Dhere are studying whether FMT can head off other antibiotic-resistant infections besides C diff in kidney transplant patients. They have teamed up with infectious disease specialists Aneesh Mehta and Rachel Friedman-Moraco to conduct this study. Read more
Twenty years of research and you start toÂ improve outcomesÂ for transplant patients.
TheÂ Nature paperÂ from Chris Larsen and Tom PearsonÂ on “costimulation blockers” and their ability to head off graft rejection in rodentsÂ first appeared in 1996.
Almost 20 years later, a seven-year study of kidney transplant recipients has shown that the drug belatacept, a costimulation blocker based on Larsen and Pearson’s research, has a better record of patient and organ survival than a calcineurin inhibitor, previously the standard of care.
Kidney transplant recipients need to take drugs to prevent their immune systems from rejecting their new organs, but the drugs themselves can cause problems. Long-term use of calcineurin inhibitors, such as tacrolimus, can damage the transplanted kidneys and lead to cardiovascular disease and diabetes.
In the accompanying video, Larsen -Â now dean of Emory University School of Medicine – and Pearson -Â executive director of Emory Transplant Center – explain.
To go with the paper, NEJM has an editorial with some revealing statistics (more than 14,000 of the 101,000 patients listed for kidney transplantation are waiting for a repeatÂ transplant) and a explanatory video.Â MedPage Today has an interview with Larsen, and HealthDay has a nice discussion of the issues surrounding post-transplant drugs. Read more
While preparing to discuss Ebola virology with Emory infectious disease specialist Aneesh Mehta next week, we noticed two recent research papers on which he is a co-author. Both have to do with organ transplantation, since Mehta isÂ Assistant Director of Transplant Infectious Diseases.
Fecal transplant is gaining ground as a remedy for C. difficile-driven diarrheal infections, which can appear in patients whose normal intestinal bacteria are wiped out by antibiotics. Fecal transplant has not been widely studied in organ transplant recipients, who must take drugs to keep their immune systems from rejecting the transplanted organ, because of concerns about infectious disease complications. This paper describes two patients, one a lung transplant recipient and one a kidney transplant recipient, who received fecal transplants to resolve their C. difficile diarrhea without complications. The lead authors are infectious disease specialists Rachel Friedman-Moraco and Colleen Kraft. Kraft has beenÂ a pioneer in this area of research.
Medical school dean Chris Larsen and Emory Transplant Center executive director Tom Pearson (both co-authors) were key members on the team that developedÂ belatacept, a FDA-approved drug since 2011. Belatacept was designed to get away fromÂ the cruel paradox where a kidney recipient, to prevent transplant rejection, has to take calcineurin inhibitor drugs that slowly poison the kidney and cardiovascular health. Belatacept inhibits the immune response by a different mechanism. Yet transplant specialists have generally been cautious in moving toward a regimen that relies on it.
As reportedÂ in this paper, Emory transplant doctors tookÂ off the training wheels, aimingÂ to get to the point where kidney transplant recipients are takingÂ a once-a-month infusion of belatacept only. With some patients, it was possible to reach that goal, but not all. In fact, as the authors describe, some patients chose not to try to wean themselves off the other drugs, and doctors advised against the attempt for a handful. This clinical trial was also notable because some transplant recipients received immune-educational cells from their organ donors in the form of bone marrow.
When Jon Pomenville of Anderson, SC, decided to donate a kidney altruistically to someone â€“ anyonein need, anywhere in the country â€“ little did he know his selfless sacrifice would in turn change the lives of not one, but numerous individuals and their families, including one little boy from Atlanta.
And little did he know that the selfless, anonymous act would quickly become not so anonymous. During a recent post-surgical clinic visit to Emory University Hospital, Pomenville met by accident â€“ right in the transplant clinic waiting room â€“ many of the individuals whose lives were changed. Soon the patients â€“ recipients and donors â€“ two father and son combinations and Pomenville, the man who would give to anyone â€“ were hugging, shaking hands, and recounting their backgrounds and experiences.
Pomenville and the others, who were all part of what is called a paired kidney exchange, were unwittingly scheduled for appointments within a short period of one another. As one person began recounting the experience, eyes and ears began to focus on the tale being told from across a crowded room.
A chance meeting in a doctors’ waiting room led to a meeting between most of the people involved in the paired kidney exchange.
The Emory Transplant Center created and opened its innovative Paired Donor Kidney Exchange Program in 2009, providing greater hope for patients in need of kidney transplants. According to Kenneth Newell, MD, director of Emory’s living donor program, a paired exchange donation allows healthy individuals to donate a kidney to either a friend, loved one, or even altruistically to a stranger, despite incompatible blood matches. In paired donation, a donor and recipient are matched with another incompatible donor and recipient and the kidneys are exchanged between the pairs.
The procedure is another form of living donor transplantation. Donated kidneys also come from recently deceased donors. While most kidneys from deceased donors function well, studies have shown that a kidney from a living donor, either a blood relative or an unrelated person, provides the greatest chance for long-term success.
“Paired donor exchanges allow us to cast a much wider net to find compatible donors and recipients,” says Newell. “With a paired kidney transplant, one incompatible donor-pair is able to give a healthy kidney to a compatible recipient. In exchange, the second donor-recipient pair will give a compatible kidney to the first donor-recipient pair, making two compatible living donor transplants possible and increasing the potential number of available donor kidneys. This option can help those patients waiting for kidney transplants who have family members or friends willing to be donors and who are medically suitable, but who have an ABO blood type that is incompatible with the recipient’s blood type.”
Because of Pomenvilleâ€™s donation, a 7-year-old boy named Zion was able to receive a lifesaving kidney from an unrelated donor because his dad, Mike, was able to donate. His surgery took place at Children’s Healthcare of Atlanta at Egleston.
And Gerald Smith of Five Points, Ala., would receive his life-saving kidney because his son, Matt, a recent University of Alabama graduate, would donate his to Zion. And finally, 20 year-old Edward Hill of Macon, a young man with a history of health challenges, would also receive his transplant at Childrenâ€™s Healthcare of Atlanta â€“ completing the six-person cycle, although the donor of Edwardâ€™s kidney is still unknown.
And Zion and Matt Smith will not only share a common bond and connection throughout life in the form of a kidney, but something even sweeter that that â€¦ blue Powerade.
â€œIâ€™ve always really enjoyed drinking Powerade, particularly the blue flavor,â€ says Smith. Shortly after Zion awoke from his surgery, he inexplicably began requesting the blue-tinted soft drink too.
Other powerful kidney transplant stories out of Emory:
Nearly 45 years after she cared for Georgia’s first organ transplant recipient, Millie Elliott, 84, visited the Emory Transplant Center outpatient transplant clinic to see how things have changed since her time at Emory. Elliott, who was Millie Burns at the time, worked at Emory University Hospital first as an obstetrics nurse, then as head nurse of an NIH-sponsored clinical research unit at Emory from 1961 to 1967. She served as a dialysis nurse on that unit and may have been the Southeast’s first renal transplant coordinator.
During her recent visit to Emory, this former Cadet Nurse Corps nurse and World War II veteran regaled the transplant center staff and kidney transplant program director Thomas Pearson, MD, PhD, with her stories about the first transplant at Emory. Elliott recalled spending a lot of time researching medical sources to prepare herself and her nurses for that remarkable day. The first transplant patient was a 16-year -old boy with renal failure who received a donor kidney from his father.
B cells are workhorses of the immune system. Their main function is to produce antibodies against bacteria or viruses when they encounter something that they recognize.Â But recently researchers have been getting hints that certain kinds of B cells can also have a calming effect on the immune system. This property could come in handy with hard-to-treat conditions such as graft-vs-host disease, multiple sclerosis, or Crohn’s disease.
Hematologist Jacques Galipeau has found that B cells treated with an artificial hybrid molecule called GIFT15 turn into “peacemakers”. These specially treated B cells can tamp down the immune system in an experimental animal model of multiple sclerosis, suggesting that they could accomplish a similar task with the human disease.
Galipeau’s paper inÂ Nature Medicine from August 2009 says succinctly: “We propose that autologous GIFT15 B regulatory cells may serve as a new treatment for autoimmune ailments.”Â Galipeau, a recent arrival to Emory from McGill University in Montreal, explains this tactic and other aspects of personalized cell therapy in the video above. Read more
A multi-patient organ swap, known as a paired donor exchange, can now save the lives of numerous people while matching each patient with the very best kidney for his or her blood profile.
Nearly 85,000 Americans are on a waiting list for a donated kidney â€“ nearly 3,000 in Georgia alone. The opportunity to quickly identify and match more organ donors and recipients is critical to saving more lives.
This month, Emoryâ€™s transplant team performed this type of exchange involving a total of six patients â€“ three donors and three recipients – from Texas, Colorado and Georgia.
In April, Howard Irving Scott, III, received a new kidney at Emory University Hospital. The kidney came to him as part of a six-person paired kidney transplant “chain,” in which three recipients and three donors were cross-matched. One of the participants was a friend of his, Casey Campbell. Although Scott did not receive Campbell’s kidney, her participation in the program made the “chain” transplant possible, saving Scott the possibility of waiting five years on a kidney.