A team of researchers from the University of Alberta, the Yerkes National Primate Research Center of Emory University and the Emory Transplant Center has successfully transplanted insulin-producing neonatal porcine islet cells into monkeys, a procedure the researchers say represents a promising intermediate solution to the critical supply problem in clinical islet cell transplantation.
“Our work at the U of A and Emory, along with recent work at the University of Minnesota, is very exciting and shows that xenotransplantation in humans may soon be possible, thus solving the islet supply problem,” says one of the study authors Ray Rajotte, a professor of Surgery at the University of Alberta.
The paper appeared in an advanced on-line publication of Nature Medicine, February 26, entitled “Long-term survival of neonatal porcine islets in non-human primates by targeting co-stimulation pathways.” The work follows on the heels of similar work published last week by University of Minnesota researchers; those researchers used islets isolated from adult pig pancreases.
Neonatal islets were produced in Edmonton using a procedure Drs. Greg Korbutt and Rajotte developed in 1995. The pig islets were sent to the Yerkes Research Center for transplantation into diabetic rhesus macaques using an anti-rejection protocol developed by Drs. Christian Larsen and Kenneth Cardona of the Yerkes Research Center and the Emory Transplant Center. The isolation method developed by the U of A researchers is simple and reproducible with the neonatal pig islets having some growth potential post-transplant, considered a major advantage over adult pig islets.
The diabetic animals were treated with a CD28/CD154 co-stimulation blockade-based immunosuppressive regimen, and achieved sustained insulin independence (median survival >140 days with one animal now at 300 days) without evidence of porcine endogenous retrovirus (PERV) dissemination. “This represents a major step forward and proves neonatal porcine islets can correct diabetes long-term in primates,” said Drs. Korbutt and Rajotte.
“To meet the needs of the millions suffering from type 1 diabetes, we must find new donor sources to allow large-scale application of islet cell transplantation in humans,” said Dr. Larsen. “While there is much work to be done these studies suggest that the rejection response to porcine islets can be surmounted.”
“The next step is to prove that these neonatal porcine islet cells could become a source for human transplantation,” said Dr. Rajotte. “It’s hoped that within the next three to five years, we will be transplanting patients with pig islets once we prove that it is safe.”
Using a relatively simple and reproducible method of obtaining large numbers of islets from neonatal pig pancreata developed at the U of A, the researchers then transplanted islets comprised of endocrine and endocrine precursor cells into the monkeys. In vivo, these cells have been shown to proliferate, differentiate and reverse hyperglycemia in immunodeficient diabetic mice and allogeneic out-bred pigs.
However, humans and Old World primates have naturally occurring antibodies that are directed against antigens that can cause hyperacute or acute humoral rejection. To combat that, the researchers administered an anti-IL-2 receptor and anti-CD154 (H106) antibody, while maintaining immunosuppression using sirolimus and belatacept (a second-generation high affinity derivative of CTLA4-Ig)9-11 on diabetic rhesus macaques transplanted with neonatal porcine islets.
Other researchers involved in the work include: Zvonimir Milas1, James Lyon2, Jose Cano1, Wanhong Jiang1, Hameeda Bello-Laborn1, Brad Hacquoil2, Elizabeth Strobert3, Shivaprakash Gangappa1, Collin Weber1, and Thomas Pearson1. (1. Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta; 2. Surgical-Medical Research Institute, University of Alberta, Edmonton,; 3. Yerkes National Primate Research Center, Emory University, Atlanta.)
The research was supported by the Alberta Diabetes Foundation, Canadian Institutes of Health Research, Edmonton Civic Employees Charitable Assistance Fund, Canadian Diabetes Association, and University of Alberta Hospital Foundation MacLachlan Fund. Dr. Korbutt received a Career Development Award from the Juvenile Diabetes Research Foundation and a Senior Scholarship from the Alberta Heritage Foundation for Medical Research. The work at Emory was supported by National Institute of Health, the Juvenile Diabetes Research Foundation Center, Yerkes Research Center Base Grant P51-RR000165-45, the McKelvey Lung Transplant Center, and the Carlos and Marguerite Mason Trust.
The Islet Transplant Group at the University of Alberta is involved in all aspects of islet transplantation, from trying to develop an unlimited source of islets (this study) to developing transplant protocols that don’t need anti-rejection drugs or drugs that only need to be given for a short period of time (tolerance induction).
University of Alberta