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
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).
gro-pr | Research asia research news
Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg
Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH
A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.
In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...
A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.
By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...
Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
23.02.2018 | Physics and Astronomy
23.02.2018 | Health and Medicine
23.02.2018 | Physics and Astronomy