Repurposing a transplant drug for bone growth

The transplant immunosuppressant drug FK506, also known as tacrolimus or Prograf, can stimulate bone formation in both cell culture and animal Read more

Beyond the amyloid hypothesis: proteins that indicate cognitive stability

If you’re wondering where Alzheimer’s research might be headed after the latest large-scale failure of a clinical trial based on the “amyloid hypothesis,” check this Read more

Mother's milk is OK, even for the in-between babies

“Stop feeding him milk right away – just to be safe” was not what a new mother wanted to hear. The call came several days after Tamara Caspary gave birth to fraternal twins, a boy and a girl. She and husband David Katz were in the period of wonder and panic, both recovering and figuring out how to care for them. “A nurse called to ask how my son was doing,” says Caspary, a developmental Read more

Andrew Adams

Sensitive to (transplant) rejection

An experimental screening method, developed by Emory and Georgia Tech scientists, aims to detect immune rejection of a transplanted organ earlier and without a biopsy needle.

The technology is based on nanoparticles that detect granzyme B enzymes produced by killer T cells. When the T cells are active, they slice up the nanoparticles, generating a fluorescent signal that is detectable in urine. The results from a mouse skin graft model were published in Nature Biomedical Engineering, from Gabe Kwong’s lab at GT and Andrew Adams’ at Emory. More extensive story here.

Co-first authors Quoc Mac and Dave Mathews

Adams is also developing technologies for imaging transplant rejection via immunoPET, with Georgia Tech’s Phil Santangelo.

 

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Mopping up immune troublemakers after transplant

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 results are published in Journal of Clinical Investigation.

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

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Troublemaker cells predict immune rejection after kidney transplant

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

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Improving long-term outcomes after kidney transplant

Twenty years of research and you start to improve outcomes for transplant patients.

The Nature paper from Chris Larsen and Tom Pearson on “costimulation blockers” and their ability to head off graft rejection in rodents 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 - now dean of Emory University School of Medicine – and Pearson - executive director of Emory Transplant Center – explain.

Belatacept was approved by the FDA in 2011 and is produced by Bristol Myers Squibb. Results from the BENEFIT study of belatacept, led by Larsen and UCSF transplant specialist Flavio Vincenti, were published in the Jan. 28 issue of the New England Journal of Medicine.

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 repeat transplant) and a explanatory video. MedPage Today has an interview with Larsen, and HealthDay has a nice discussion of the issues surrounding post-transplant drugs. Read more

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