Two recent research papers from the Emory Transplant Center describe research on pancreatic islet transplantation, an experimental procedure that could help people with type I diabetes live without daily insulin injections.
As with other types of transplantation, the challenge with islet transplantation is to avoid rejection of the donated organ and to balance that goal against side effects from the drugs needed to control the immune system. These papers illustrate how that balancing act is especially complex.
In the last decade, transplant specialists developed a method for islet transplantation named the â€œEdmonton protocolâ€ after pioneers at the University of Alberta. While the emergence of this method was a major step forward, there are limitations:
Around 90 percent of patients lose insulin independence within five years, multiple islet donors are often required, and the immunosuppressive drugs used tend to damage the kidneys and worsen cardiovascular health.Â Emory scientists have been trying alternative tactics that avoid some of the most toxic immunosuppressive drugs, such as calcineurin inhibitors.
Both of the research papers report on tests of a possible strategy to control memory T cells,Â a part of the immune system that has been confounding transplant specialists because of the cells’ resistance to other drugs. The strategy researchers use here is to interfere with a molecule on T cells called LFA-1.
One recent paper, in the September 2010 issue of the American Journal of Transplantation, outlines a clinical study led by Emory transplant surgeon Nicole Turgeon, which compared the Edmonton protocol with a regimen based on efalizumab, an antibody that blocks LFA-1. Until 2009, efalizumab had been approved by the FDA for the treatment of the skin disease psoriasis. This study was cut short when efalizumabâ€™s manufacturer withdrew it from the U.S. market because of safety concerns.
Out of roughly 40,000 patients who were treated with efalizumab for psoriasis over a several year period, four cases were reported of progressive multifocal leukoencephalopathy (PML), three of which were fatal.
No cases of PML were reported in islet transplant recipients. Actually, the results were promising, at least for the period when the study ran according to plan, the authors report:
All patients treated with the efalizumab-based regimen achieved insulin independence with normal hemoglobin A1c [a sign of good blood sugar control] after a single islet cell infusion and remained insulin independent while on efalizumab.
Researchers tried to replace efalizumab with another drug, abatacept, but unfortunately, three of the four patients who were on efalizumab and then had to stop experienced rejection of their islet grafts.
The authors argue that the risk of PML, while relatively low, may be inappropriate for patients with psoriasis, since that disease is not life-threatening and alternative treatments are available. However, the risk may be justifiable for people with “brittle” type 1 diabetes and possibly other transplant recipients, they write.
Another recent Emory paper, in the December 2010 issue of theÂ Journal of Clinical Investigation, describes experiments with rhesus macaques, performed in cooperation with Yerkes National Primate Research Center. Here a team of researchers, led by Emory Transplant Center director Chris Larsen, combined short-term treatment with an antibody against LFA-1 with other drugs. The results add to evidence that LFA-1 may be a valuable target when seeking to control memory T cell activity.