Deactivating the alarm

For patients with insulin-dependent diabetes mellitus, the only route to full recovery without daily injections of insulin is by transplantation of pancreatic islet cells. This can be achieved non-surgically via injection of donor cells into the liver, but such treatment also elicits a vigorous negative response from the body.

“Transplantation tolerance can be controlled by immunosuppressive drugs such as FK506,” says Masaru Taniguchi of the RIKEN Research Center for Allergy and Immunology in Yokohama. “However, transplanted islets are rejected soon after transplantation even with the use of FK506.” The mechanism for this rejection is unknown, and patients must typically receive several injections from multiple donors for transplantation to succeed.

High-mobility group box 1 (HMGB1) was first identified as a DNA-binding factor in the cell nucleus, but it is also secreted by immune cells as an apparent trigger for inflammation in response to tissue damage. Taniguchi’s team recently joined forces with Yohichi Yasunami at Fukuoka University to demonstrate the impact of this protein on transplanted islet survival.

They produced diabetic mice by treating the animals with an islet-killing drug, and then transplanted varying numbers of donor islet cells. Animals receiving 200 cells normally developed diabetic symptoms, but these could be averted by simultaneous treatment with HMGB1-blocking antibodies. This treatment also prevented accumulation of immune cells in the liver and countered the production of inflammatory cytokines—typical outcomes of islet transplantation.

The researchers were surprised to note that HMGB1 expression was highly specific to islet cells, with protein levels 20-fold higher than any other organ or tissue examined, further supporting its particular role in islet rejection. In fact, they noted two strong peaks in plasma levels of HMGB1 in transplant recipients: one 24 hours after chemical destruction of islets, and another 6 hours after islet injection. These results suggest that islet stress or damage directly triggers HMGB1 secretion, which in turn activates the inflammatory response pathways that initiate destruction of the transplanted cells.

These findings provide strong hope for improving transplant efficiency. “We can use antibodies in humans without any side effects, because HMGB1 is not present in the serum under physiological conditions,” says Taniguchi, who adds that Yasunami’s team is now exploring clinical strategies based on this approach. However, Taniguchi also hopes to develop chemical inhibitors that preemptively block HMGB1 secretion by donor cells prior to transplantation. “This is ideal,” he says, “because then we do not need to treat patients with any drugs or antibodies.”

The corresponding author for this highlight is based at the Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology

Journal information

1. Matsuoka, N., Itoh, T., Watarai, H., Sekine-Kondo, E., Nagata, N., Okamoto, K., Mera, T., Yamamoto, H., Yamada, S., Maruyama, I. et al. High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice. The Journal of Clinical Investigation 120, 735–743 (2010).