JDRF Research
Pigs May Help Relieve Islet Shortage
The biggest challenge to making islet transplantation a widely available cure for people with juvenile (type 1) diabetes is the limited supply of insulin producing islet tissue. In recent years, researchers have been investigating the use of islets from pigs, which may provide a temporary solution to the human islet shortage. Pig insulin has been used successfully in humans for years, and the organs of pigs are similar to those of humans. Now two JDRF-funded studies published in the April issue of Diabetes provide encouraging results about the feasibility of using pig islets in humans.
While any transplant between species (xenotransplant) is difficult because it can trigger acute rejection by the immune system, researchers think they may be able to overcome this hurdle with immunosuppressive drugs or by encasing the islets in a protective capsule.
The first of the two studies, involving a transplant between pigs, suggests that islets from neonatal pigs may offer advantages over islets from adults. The second study, involving xenotransplantation between pigs and mice, demonstrates a possible new approach to prevent islets from being rejecte prevent islets from being rejected.
Advantages of Neonatal Islets
Although islets from adult pigs have worked well when transplanted into mice and monkeys, adult pig islets are difficult and expensive to isolate and hard to maintain in cell culture before transplantation. Neonatal islets offer two potential advantages:
1) They are more capable of multiplying and growing inside the recipient after the transplant due to flexibility early in life, and
2) Because they are less developed, they are less likely to set off a defensive immune system response in the recipient’s body that would damage them.
JDRF-funded researchers at the University of Alberta in Edmonton, Canada, led by Ray Rajotte, Ph.D., are investigating how well neonatal pig islets actually perform after transplant. In previous investigations, they had shown that neonatal pig islets could reverse high blood sugar in diabetic mice. In a new study, the researchers wanted to prove that neonatal pig islets could restore blood sugar control in a larger animal—the pig itself.
They removed the pancreas of each of the 13 adult pigs to make them diabetic and then implanted islets isolated from multiple newborn pigs. Six of the pigs received drugs to suppress their immune response to the islets, while seven did not.
All the pigs receiving immunosuppression achieved normal blood sugar levels after 14 days, with some in this group remaining insulin independent for up to 69 days. Among the pigs receiving no immunosuppression, four out of the 6 achieved normal blood sugar levels within 6-14 days after the transplant, with two of those pigs remaining insulin-independent for more than 49 days.
These results suggest that neonatal pig islets show promise for transplant into humans. Especially encouraging was how quickly the pigs in the study regained control of blood sugar levels—about two weeks, compared with six to eight weeks in the previous experiments using pig islets in mice.
A Dual Approach to Helping Islets Survive
In the second study, JDRF-funded researchers at King’s College in London took a novel approach to prevent pig islets from being rejected after transplantation into mice. The researchers used the species difference—normally a hurdle in xenotransplantation—to design a precise combination therapy for blocking rejection.
The main hurdle for implanting pig islets into humans is a reaction involving T-cells, master controllers of the immune system, which can lead to rejection of the transplant. When the human T-cells recognize foreign antigens from the pig cells presented to them on the surface of specialized immune cells called antigen- antigen-presenting cell presenting cells (APCs), they move into action and launch an attack against the perceived threat. Without the presentation from the APCs, the T cells will not attack the pig cells.
In an experiment transplanting pig islets into mice, the King’s College researchers, led by Robert Lechler, Ph.D., decided to try blocking the antigen-presentation stage in each animal by using two distinct antibodies. One antibody, given within a few days of the transplant, would selectively bind to (and neutralize) the APCs in the pig tissue. Later, a second antibody, given 12-14 days after the transplant, would selectively bind to (and neutralize) APCs in the mouse tissue. With APC cells’ receptors plugged by the antibodies, the T cells would not receive the necessary signal and would be unable to initiate the immune response that causes rejection.
This two-antibody approach allowed the pig islets to survive in the mice even though no immunosuppressive drugs were given. Because the antibodies selectively targeted specific APCs (leaving most APCs unhindered), they did not compromise the normal immune function of the mice receiving the transplant.
These results suggest that a similar approach might work well for preventing rejection of pig islets in human patients. However, the success of this method will need to be duplicated in animals more closely resembling humans, such as monkeys, before it can be attempted in human clinical trials.