According to the Centers for Disease Control and Prevention, more than 10 percent of the adult population in America – about 20 million people — suffers from chronic kidney disease. Among these individuals, 600,000 are on dialysis and 120,000 are on the waiting list for a kidney transplant, yet only 16,000 kidney transplants are conducted each year due to a shortage of available organs.
Compounding this stark reality is the very real possibility that a transplanted kidney will be rejected by the immune system of the patient receiving the organ. Mismatched organs, or organs that are not matched closely enough, can trigger a blood transfusion reaction or an outright transplant rejection.
Developing a more effective and accessible means of conducting organ transplantation -- even between species – is the research focus of A. Joseph Tector, MD, PhD, FACS, a professor of surgery and director of the Xenotransplant Program at the University of Alabama at Birmingham. Dr. Tector delivered the UC San Diego School of Medicine’s annual Marshall J. Orloff Lecture last month on his work to determine the effectiveness of combining genetic modification with immune suppression to conduct kidney xenotransplantation, or transplantation from one species to another (in this case, from pigs to Rhesus macaques).
Established in honor of the UC San Diego Department of Surgery’s founder, Dr. Marshall J. Orloff, the Orloff Lecture series features leaders in the field of surgery and surgical science presenting on the latest issues and innovations in research.
Dr. Orloff, who passed away in November 2018, was recruited from Harbor-UCLA at just 39 years old, named chair of the Department in September 1966 and assumed his new duties in January 1967. Core to Orloff's vision was a department that would become both a clinical and research powerhouse.
"The best results in terms of quality and accuracy of care," Orloff said, "come from those who practice and teach. Teaching and research keep physicians on the leading edge for patients."
Xenotransplant research was once thought to be the leading edge for patients before it fell out of favor in 2001 with the discovery that a porcine virus can infect human cells. Now new technologies have revived interest in transplantation between species, especially in light of its potential to solve the organ shortage.
In his lecture, Dr. Tector -- one of the leading researchers in xenotransplantation – noted the similarities between the mechanisms of baboon heterograft rejection and that of humans, and also pointed out that the mechanisms of rejection are the same for both xenotransplantation and allogeneic transplantation (the transplantation of an organ from a genetically non-identical donor of the same species). Dr. Tector added that T-cell proliferation is similar in allo- and xeno-transplants and that organ rejection in both cases is dependent on donor-specific antibody levels, further suggesting “the need to turn discordant reaction into concordant reaction using genome editing.”
For their most recent study, Dr. Tector and his team used the CRISPR-Cas9 gene editing tool to block pig cells from creating alpha-gal as well as two other genes thought to be implicated in organ rejection. They theorized that for about 30 percent of people, the organs from these “triple-knockout pigs” would not cause hyperacute rejection, and that patients who received these pig organs could then be treated with Tacrolimus, the same immunosuppressant drugs that recipients take after human-to-human transplants.
To test this theory, Dr. Tector’s team then conducted pig-to-rhesus macaque renal xenografts on a select group of monkeys with low amounts of anti-pig antibodies and suppressed immune function. This method improved survival of these monkeys significantly, with the treatment leading to a 235-day survival time as compared with the less than 100-day survival time of previous models (and the six-day survival time of control subjects).
The researchers also discovered that suppressing CD4+ T cells (but not CD8+ T cells) led to long-term survival, with the average survival time of CD4+ suppressed monkeys surpassing 400 days – a first for a pig-to-non-human primate model. This suggests that CD4+ T cells may have a more prominent role in xenograft rejection compared with CD8+ T cells.
paper about the study, published in March in the American Journal of Transplantation, the researchers refer to their results as “the longest‐reported life‐sustaining xenotransplants to date.”
Dr. Tector’s talk marked the first Orloff Memorial Lecture since the passing of Dr. Orloff.
Noted Brian Clary, chair of the UC San Diego Department of Surgery: “The lecture was made all the more special by the fact that also in attendance were Dr. Orloff’s children, Dr. Susan Orloff and Dr. Mark Orloff, who are transplant surgeons in their own right at Oregon Health Sciences University and the University of Rochester, respectively. We’re very grateful for their ongoing support.”