April 19, 2016

Long-lived pig-to-primate heart transplants

At a Glance

  • Researchers developed an immune-suppressing drug regimen that helped a heart transplant from a pig last in a primate for more than 2 years.
  • The accomplishment is an important step toward a strategy that could help relieve the severe organ shortage among people awaiting transplantation.
Stylized image of a heart. About 3,000 people in the United States are on the waiting list for a heart transplant on any given day. But only about 2,000 donor hearts become available each year. Wait times vary from days to several months.Dirk Püschel/Hemera/Thinkstock

Heart transplants are a life-saving measure for end-stage heart failure. Patients must turn to this option after all other treatments have failed, and the heart has become so damaged or weakened that it can’t pump enough blood to meet the body’s needs.

Unfortunately, donor hearts are in short supply. One possible solution for this and other organ shortages is xenotransplantation—organ transplantation between different species. But this approach faces many obstacles. The most challenging is the immune response of the organ recipient, which can lead to organ rejection and failure.

Researchers have been exploring strategies to minimize organ rejection, including modifying the organ donor’s genes and developing immune-suppressing drugs for recipients. Researchers from NIH’s National Heart, Lung, and Blood Institute (NHLBI) have been working for years to develop procedures for transplanting hearts from pigs to primates. Pigs share characteristics with humans that make them a promising species for xenotransplantation. The team’s latest study, led by Dr. Muhammad M. Mohiuddin, was published on April 5, 2016, in Nature Communications.

The scientists obtained a group of pigs that were genetically modified in several ways. First, they lacked a key molecule known to provoke organ rejection. The pigs were also engineered to produce human proteins that suppress blood clotting and activation of the immune response known as the complement cascade—common causes of xenograft failure.

The researchers transplanted hearts from these pigs into a total of 5 baboons. Since the team wanted to focus on the mechanism of organ rejection, they didn’t replace the baboon hearts. Rather, they implanted the pig hearts in the baboon’s abdomens so that the baboon’s own hearts continued to pump blood.

The scientists developed an immune-suppressing regimen using an immunomodulatory drug (mycophenolate mofetil) and antibodies against key immune system components (CD40 and CD20). With this regimen, the pig hearts survived in the baboons for a mean of 433 days. The longest lasted for 945 days (over 2 and a half years). This milestone shattered previous records of pig-to-primate heart transplant, also achieved by this group of researchers.

“We’ve done these experiments in the abdomen primarily to understand the mechanism of organ rejection and to test strategies to extend cardiac xenograft survival,” Mohiuddin explains. “Now we’re planning to transplant these genetically modified hearts to replace baboons’ hearts and see if these hearts sustain the life of baboons for a long period of time.”

While this approach is still years away from the clinic, Mohiuddin notes that most of the compounds in the immunosuppressive regimen are already being used in humans, with one exception that's now being prepared for human use.

—by Harrison Wein, Ph.D.

Related Links

Reference: Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Mohiuddin MM, Singh AK, Corcoran PC, Thomas Iii ML, Clark T, Lewis BG, Hoyt RF, Eckhaus M, Pierson Iii RN, Belli AJ, Wolf E, Klymiuk N, Phelps C, Reimann KA, Ayares D, Horvath KA. Nat Commun. 2016 Apr 5;7:11138. doi: 10.1038/ncomms11138. PMID: 27045379

Funding: NIH’s National Heart, Lung, and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases (NIAID), and Office of the Director (OD); and German Research Council.