You’re a heart transplant patient. You’ve been on the waiting list for months, maybe years. Now, you’re being wheeled out of the operating room, a donated heart beating in your chest.
You’ve finished one journey, but are only just starting on a new one: keeping your body from rejecting your new heart.
Luckily for you, new methods under development could help tell early on when chronic rejection problems—the kind that arise five or 10 years after your transplant—start to loom. And even better, scientists are homing in on a new way to prevent chronic (and maybe short-term) rejection from happening in the first place.
Biomarkers: “seeing” rejection from a molecular standpoint
“Chronic graft rejection is a slow, insidious process that takes years,” says David Briscoe, MD, director of Boston Children’s Transplant Research Program. “We’ve made good gains in combating short-term rejection, but we haven’t made much progress against long-term rejection in the last 15 or 20 years.”
Together with Kevin Daly, MD, a cardiologist in Boston Children’s Heart Center, and S. Ananth Karumachi, MD, from the Beth Israel Deaconess Medical Center, Briscoe has been searching for biomarkers that could help detect chronic heart graft rejection, characterized by a vascular disease called cardiac allograft vasculopathy (CAV).
“The current method for screening both children and adults for CAV is annual coronary angiography, which is somewhat invasive,” Daly explains. “We’d like to be able to screen patients more often and less invasively so that we can catch CAV and intervene earlier.”
Damage presents an opportunity
Even when patients take anti-rejection drugs, the blood vessels within a transplanted heart experience ongoing, low-level damage.
The cells lining the damaged vessels respond by releasing proteins that encourage vessel repair. In a recent paper in the Journal of Heart and Lung Transplantation, the team suggests that a rise in blood levels of those proteins could be a warning flare that CAV is on the horizon.
Starting with 33 heart transplant patients and 55 factors involved in blood vessel growth, or angiogenesis, the team found three possible biomarkers of CAV: two vascular endothelial growth factors (VEGFs), classic angiogenesis factors; and platelet factor 4 (PL4), which plays a role in wound repair.
If the findings are validated in more patients, rejection screening in heart transplant recipients could become much easier, giving doctors more time to manage chronic rejection.
Making rejection a moot point
But what if chronic rejection could be avoided altogether? That’s what Paolo Fiorina, MD, PhD, wants to know.
“To prevent rejection, we currently turn down the immune system’s T cell response by giving patients immunosuppressive drugs for the rest of their lives,” says Fiorina, another TRP researcher. “This helps save the graft, but in the long run has its own adverse effects, like kidney disease, diabetes and cancer. We need a new strategy for reducing the amount of immunosuppression we give patients and teaching the body to tolerate the graft.”
Fiorina also uses cellular damage as a starting point: The transplantation process damages many cells in a donor heart, and when they die, they unleash large amounts of ATP, a molecule that stores energy within the cell.
When T cells see all that ATP floating around, they assume there’s trouble brewing and act like a pathogenic attack is underway. “The body knows there’s damage, but doesn’t know why,” Fiorina explains.
Putting the blinders on
Fiorina’s approach, which he and his colleagues presented in the journal Circulation, involves “blinding” T cells to ATP by blocking the cells’ receptors with a similar molecule called oATP (which is very similar to ATP).
Using a mouse model of heart transplantation, Fiorina found that giving oATP along with rapamycin, an anti-rejection drug, for a couple of weeks right after transplant prevented both acute and chronic rejection. Completely. For the rest of the animals’ lives.
“The combination keeps the T cells from seeing the graft and the inflammation from the surgery long enough for that inflammation to die down,” Fiorina says. “When we stop the treatment, the T cells act as though the new heart has always been there.
“It’s the most powerful of the methods we’ve tried in mouse models to block rejection,” Fiorina continues. “And we know that the receptor is present on human T cells as well. Our plan for the next year is to do what we need to in order to move into clinical trials as quickly as we can.”
To learn more about David Briscoe’s biomarker work, take a look at Boston Children’s Technology and Innovation Development Office. And to learn more about the care we provide for children’s hearts, take a look at our Heart Center.