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Skepticism surrounds diabetes xenograft experiment

The news that a team of researchers has because the procedure has not been ratified pression of exogenous needs with- ‘cured’ a patient with using in non-human primates, or other large an- out immunosuppression.” pig islet cells transplanted within a proto- imal models. “The experimental data If the transplanted islet cells are not type device has roused the diabetes, trans- showing efficacy of sertoli cells in prevent- functioning, how then are patients able to plant and comm- ing autoimmune rejection is not strong. It reduce their external insulin dependency? unities. While all are united in the hope works in small animal models but has been According to experts, alternative possibili- that the results are bona fide, the lack of very hard to replicate in large animal mod- ties exist. For example, the patients may hard data from the study is generating in- els,” says one researcher. have been at an early, incomplete stage of tense skepticism. And the fact that the trial The detail that most engages the skeptics Type 1 diabetes, since patients sometimes was carried out in Mexico, outside interna- is the production, or lack thereof, of present with severe hyperglycemia that tionally recognized regulatory conditions, porcine C peptide. When a molecule of pig goes into remission. This ‘honeymoon’ pe- is also causing concern. At best, the scien- insulin is produced, a molecule of porcine riod could last for several months. tific community has expressed a guarded C peptide is also made. Thus, if a cell But many members of the community reaction to the potentially groundbreaking is functioning, circulating pig C peptide remain adamant that porcine C peptide is work. should be detectable in the bloodstream of the definitive test of a functioning islet David White of the Robarts Research patients, and should rise after ingestion of xenotransplant. Hugh Auchincloss, Institute, University of Western Ontario, food. Professor of Surgery at Harvard Medical and Rafael Valdes of the Children’s The abstract presented in Miami by School, told Nature Medicine, “This group Hospital in Mexico City, presented details White states that five patients had “func- has been repeatedly asked to provide of the study at the XIXth International tioning grafts as defined by…production of porcine C peptide and histologic data to http://www.nature.com/naturemedicine Congress of the Transplantation Society in porcine C peptide in response to intra- support their claim that they have Miami in August. Speaking at a press con- venous glucose.” However, the team is achieved meaningful survival and function ference, Valdes announced that one of 12 known to have found extremely low, of pig islets. Not having seen these data, I adolescents in the trial has been insulin- where detectable, levels of the peptide in do not believe that this group has accom- free for over 12 months, and 5 others have patient plasma. Moreover, an independent plished successful xenotransplantation.” reduced their insulin requirement. The re- group lead by Gordon Weir at the Joslin Another point of controversy is the use mainder have experienced no change in Diabetes Center, Boston, has also failed to of sertoli cells to protect the transplanted insulin use. find a strong peptide signal in samples. islet cells and the concomitant lack of James Shapiro, Director of the Clinical “The measurements we’ve made thus far treatment with anti-rejection drugs. As Islet Transplant Program at the University are inconclusive,” Weir told Nature Shapiro explains, “Sertoli cells produce a of Alberta, who pio- Medicine, adding, “I thousand different products in the testes to neered the successful think it’s a bold set prevent auto-reactivity of sperm. When Edmonton Protocol— of experiments and they are transplanted together with islets,

© Group 2002 Nature Publishing whereby donor human we all hope that the concept is that they secrete Fas ligand islet cells are trans- something like this and other inhibitory molecules [to prevent planted into the liver— will work. We’re destruction]. But it’s not been tried before says of the work, looking forward to in people.” In fact, sertoli cell protection of “There are a lot of firsts. resolving the linger- islet transplants has not proved effective in It’s a leap of faith.” ing questions about large animal models to-date. Valdes’ technique in- what is happening Similarly, the delivery cylinder used by volves the implanta- with these patients, Valdes has not been described in preclini- Courtesy of Diatranz tion of a cylindrical Can a sertoli/islet cell mixture (inset) cure and I’m very sup- cal models. And there are reservations steel tube, containing diabetes? portive of the work.” about its subcutaneous placement. “All an inner teflon bung, Sir Roy Calne, who previous attempts to use a subcutaneous in a subcutaneous pocket in the area of the is establishing an Islet Transplant study site to transplant islets have failed miser- abdomen. Two months later, once the im- group at the National University of ably in animal models,” says one investiga- plant has become embedded in a growth of Singapore, explains that the C peptide tor. “This is because of the poor dynamics collagen, the teflon insert is removed and assay is difficult to perform, and that it suf- of glucose and insulin absorption in the porcine islet cells (pancreatic cells that pro- fers from cross-reactivity with human C surrounding milieu of an s.c. site.” duce insulin) and sertoli cells (cells that peptide from human islets. However, the Ethically, such an experiment cannot provide immune protection for germ cells 12 patients in the Mexican study were de- be balanced by control data. For example, developing in the testis) are injected into fined as having “C peptide-negative Type 1 it is not possible to remove the device and the tube. The cells were derived from new- diabetes” on enrollment. show that diabetes returns. For this reason born, special pathogen-free pigs, produced Valdes told Nature Medicine that his the community is pressuring the group to by the New Zealand company, Diatranz. group is examining the reasons for their test the approach in non-human pri- Islets are mixed in a ratio of 1:35–50 sertoli difficulty in detecting porcine C peptide mates, dog or rabbit. Valdes has agreed, cells. Patients are not treated with im- but he remains resolute: “We stand by our but has also begun trials in a further 24 munosuppressant drugs. results based on the potential therapeutic patients. The trial has generated concern largely success, which is reduction, or even sup- Karen Birmingham, London

NATURE MEDICINE • VOLUME 8 • NUMBER 10 • OCTOBER 2002 1047