Although there has been much excitement surrounding the transplantation of insulin-producing islets for the treatment of patients with diabetes, many patients fail to achieve insulin independence with a single transplant, owing to rapid rejection of the donor islets. To explore the mechanism of islet rejection, Yasunami et al. studied a mouse model of islet transplantation, and they report that natural killer T (NKT) cells might be behind such early graft loss.

NKT cells have a key role in immediate immune responses and, mainly through their ability to produce large amounts of interferon-γ (IFN-γ), function as a bridge between innate and adaptive immune responses. Because IFN-γ has been shown to be an important factor in the destruction of islet β cells, the authors proposed that NKT cells might be involved in early islet-graft failure.

Diabetes, as measured by hyperglycaemia, was induced in C57BL/6 mice by intravenous injection of streptozotocin. A transplant of 400 islets harvested from 2 syngeneic mice and injected into the liver of the diabetic mice was required to restore normal blood-glucose levels; mice that received 200 islets remained hyperglycaemic and had few intact islets. But if the diabetic mice lacked NKT cells, a transplant of only 100 islets was sufficient to restore normal blood-glucose levels, indicating that NKT cells might be responsible for the loss of the transplanted islets.

Next, tetramers of CD1d complexed with α-galactosylceramide (α-GalCer) were used to analyse NKT-cell numbers in mice that showed islet-graft destruction. Although NKT-cell numbers seemed to decrease immediately after transplantation (consistent with activation-induced downregulation of their antigen receptors), NKT-cell numbers increased markedly 24 hours after transplantation. As a consequence of NKT-cell activation, neutrophils infiltrated the transplanted islets and were induced to produce high levels of IFN-γ, indicating that they might mediate destruction of the islets.

On the basis of the observation that a single dose of α-GalCer induces NKT-cell activation but repeated stimulation with α-GalCer inhibits IFN-γ production by NKT cells, the authors tested whether graft loss could be prevented by repeated injection of α-GalCer. Diabetic mice that received 400 islets and were treated with a single injection of α-GalCer remained hyperglycaemic and had increased IFN-γ production by neutrophils and NKT cells. By contrast, when diabetic mice were pretreated three times with α-GalCer, a transplant of only 200 islets was sufficient to restore normal blood-glucose levels and reduce IFN-γ production.

So, in vivo modulation of NKT-cell activation to prevent this collaboration between NKT cells and neutrophils might be a novel approach for improving the efficiency of islet transplantation.