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Pig islet transplantation research points to future success in humans
NEW ORLEANS — Clinical, pig-to-human xenotransplantation could provide a viable substitute for human pancreatic islet cell transplantation, according to a speaker at the American Diabetes Association Scientific Sessions.
Barriers to xenotransplantation are more complex than allotransplantation, said David K.C. Cooper, MD, PhD, FRCS, professor of surgery at the Thomas E. Starzi Transplantation Institute at the University of Pittsburgh School of Medicine, and include issues with innate immune response, adaptive immune response, coagulation dysfunction and persistent inflammation.
David K.C. Cooper
Genetic engineering of the pig, Cooper said, could potentially address each of those problems.
“The more we can modify the donor, the less problems for the recipient,” Cooper said during his presentation. “I think the potential here is enormous.”
Cooper said two approaches are being investigated in pig islet xenotransplantation. One method is to encapsulate the islets using biomaterials, putting a barrier around the islets so rejecting cells, such as lymphocytes, cannot damage the islet. This method would not require immunosuppressive therapy, he said.
“But obviously the barrier [around the islets] has to have some holes in it to let the insulin come out,” Cooper said. “If you could let insulin come out, there’s a very good chance you’re going to let antibodies or cytokines come in. I don’t see any way that this will be resolved.”
The alternative, Cooper said, involves injecting “free” or “naked” islets that are not encapsulated, which would require immunosuppressive therapy to prevent rejection. Studies in animal models have shown successful xenotransplantation using free islets. Cynomolgus monkeys made diabetic with streptozotocin who received immunosuppressant drug therapy experienced survival rates of more than 1 year without insulin injections or complications; in Seoul researchers achieved similar results with monkeys for 2 years. The results were achieved using both wild-type and genetically engineered pigs.
“We can’t do this routinely,” Cooper said. “We can do it in about one-third of the monkeys. The others lose the graft very early on, and that’s a different problem.”
The problem, Cooper said, likely stems from injecting the islets directly into the blood in the portal vein, where antibodies damage the islet.
Cooper and colleagues are considering the gastric submucosal space as an alternative site, where islets could be injected endoscopically.
For a clinical trial, researchers would need “clean” pigs, raised in biosecure housing, or isolated, tested pig islets, and a clinically acceptable immunosuppressive regimen, as well as consistent graft survival for at least 6 months in monkeys, Cooper said. As improvements in pig islet xenotransplantation continue, he said, the possibility of an FDA trial with transplantation into humans with diabetes may not be far off.
“One day, in the not too distant future, allotransplantation will be of historic interest only,” Cooper said. – by Regina Schaffer
Reference:
Cooper DK. Pig Islet Xenotransplantation. Presented at: American Diabetes Association 76th Scientific Sessions; June 10-14, 2016; New Orleans.
Disclosure: Cooper reports no relevant financial disclosures.