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News and issues that affect organ and tissue transplantation

Three years ago, the field of xenotransplantation was revitalized after groups in Minneapolis and Atlanta/Edmonton reported in Nature Medicine that pig islet transplantation had successfully corrected diabetes in monkeys.1,2 Although it appeared that human clinical trials were just around the corner, a cloud still hung over the celebration. The researchers had used an experimental anti-CD154 costimulation pathway blocker that caused elevated incidents of thromboembolism in humans. For those researchers and others, it was time to look at alternatives. The question was, which immunosuppressant could substitute for the anti-CD154 antibody that both the Atlanta/Edmonton and Minneapolis groups had used in the trials reported in Nature Medicine, says Bernhard Hering, MD, scientific director of the Schulze Diabetes Institute, University of Minnesota, Minneapolis and lead author of the Minneapolis study. “Since 2006, in the pig-to-monkey islet model, we have studied the critical immune recognition and rejection pathways and currently approved immunosuppressants that can substitute for anti-CD154 antibody when combined with baseline immunosuppression with CD28 antagonist and rapamycin,” he says. He also says that the approach has led to significant progress in developing a safe, efficacious and clinically applicable immunosuppressive protocol for taking a first-generation pig islet cell therapy product to the clinic. CD154 is just one way of doing this, according to David Sutherland, MD, PhD, director of the Schulze Diabetes Institute. “There are other immunosuppressant approaches, such as targeting lymphocyte functionassociated antigen-1 (LFA-1) and CD40,” he says. New generation strategies are likely going to involve privileged microenvironments for islet implantation, such as the bioengineered omentum instead of the portal vein, according to Drs. Hering and Sutherland. For example, researchers from Miami and France recently reported in the American Journal of Transplantation the successful implantation of non-human primate islets in an omental pouch on a biodegradable scaffold.3 The Minnesota group is also refining pre-transplant islet immunomodulation and investigating the possibility of local immunosuppression. Christian Larsen, MD, PhD, chief of the Division of Transplantation at Emory University School of Medicine in Atlanta says, “Our priorities are to develop cocktails that avoid CD154. This might include targeting the other side of the pathway, CD40. We’re also looking at CD28 pathway blockers such as belatacept, and antibodies against LFA-1.” Additionally, there may be approaches that would still allow targeting of CD154. “If you make the therapy duration short enough, perhaps just a few doses, you could anti-coagulate around the time of the procedure,” says Dr. Larsen.