Xenotransplantation: Rounding a Very Long Corner

Photo above: Dr. Stuart Knechtle (left), joins transplant surgeons Drs. Ralph Bollinger (center) and Allan D. Kirk (right) at the unveiling of the Duke Transplant photo exhibit in January 2020. The display celebrates several patients who received care at the Duke Transplant Center. | Photo credit: Duke Surgery

Xenotransplantation refers to transplantation across the species, which comes with formidable immunological barriers and complex ethical considerations. There is a common quip that ‘xenotransplantation is right around the corner… it’s just a very long corner.’ The first heart xenotransplant was performed by Dr. James Hardy in 1964 with a chimpanzee heart, and most early attempts at xenotransplantation focused on nonhuman primates as the donors.

Stuart Knechtle, MD, is a Professor of Surgery and the Executive Director of the Duke Transplant Center; he was recruited to Duke in 2015 by Chair of the Department of Surgery Allan D. Kirk, MD, PhD. They have been collaborating for over thirty years, first meeting here at Duke when Dr. Knechtle was a surgery resident and Dr. Kirk was a medical student, both mentored by Ralph Randal Bollinger, MD.

“My interest in xenotransplantation actually began in Dr. Bollinger’s lab when I began doing hamster-to-rat heart transplants using total lymphoid irradiation to prevent rejection,” says Dr. Knechtle. 

There has been a renewed interest in the scientific community in the context of using pigs as donors, but the evergreen concerns and controversies that have surrounded the field include xenozoonosis, the risk of introducing a virus or infection from another species into humans.

While pig heart valves have been used for decades to replace human heart valves, they are not vascularized and are not subject to immunologic rejection. Duke has been partnering with eGenesis, a biotechnology company, that is sponsoring research in both islet and kidney transplantation from pigs to nonhuman primates.

“We have very strong immunology expertise at Duke, and we're particularly interested in complement and costimulation blockade and their impact on transplant rejection versus tolerance,” says Dr. Knechtle. “Drugs that block these pathways are very likely to be part of the immunosuppressive regimen for xenotransplantation, and we're developing an understanding of how to apply these drugs with the help of genetically modified organs from eGenesis, which are in themselves a huge engineering undertaking.”

"Everybody can contribute something different, and while some people want to be the very first to do something and thus attract a lot of attention, what Duke can contribute is a better understanding of the science behind xenotransplants, providing a better rationale for directing how we take next steps and increase the likelihood of their success.”

— Dr. Stuart Knechtle, Professor of Surgery, Division of Abdominal Transplant Surgery

Duke has focused its research on the pragmatic applications of xenotransplantation. With the use of pig islet cells, introducing and guaranteeing the survival of functional islets in a human could cure diabetes.

Dr. Kirk's work is directing transplanted pig islets and developing immunosuppressive strategies that allow for long term survival. Dr. Knechtle and Jean Kwun, PhD, Assistant Professor in Surgery, Division of Abdominal Transplant, also focus on immunosuppressive strategies, but with pig kidneys into nonhuman primates.

“One question we’re addressing is: if you were to put a pig kidney into a human, do you immunize them to a possible future human kidney transplant? In other words, are we going to disadvantage them in some immunologic way?" says Dr. Kwun. "The second question we're trying to address is whether a highly allosensitized human (immunized to other humans) is a suitable candidate for a pig kidney.”

Through previous transplants, blood transfusions, or pregnancy, some humans become sensitized to major histocompatibility complex antigens—or, immunized to other human beings.

“If you take a highly allosensitized primate [who is] immunized with skin grafts from other primates, how do they fare with a pig kidney xenograft compared to a non-sensitized recipient?” asks Dr. Knechtle. "The answer we get should help guide the patient selection criteria for allocating pig kidney transplants.”

The research that the Duke Transplant Center performs will help form the building blocks of future xenotransplantation. Dr. Knechtle states, “Everybody can contribute something different, and while some people want to be the very first to do something and thus attract a lot of attention, what Duke can contribute is a better understanding of the science behind xenotransplants, providing a better rationale for directing how we take next steps and increase the likelihood of their success.”

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