Using a mouse model, scientists from the RIKEN-Max Planck Joint Research Center for Systems Chemical Biology and a number of other institutes have identified a sugar molecule that reduced the inflammatory response and progress of emphysema, a common component of chronic obstructive pulmonary disease (COPD). According to Naoyuki Taniguchi, the leader of the group, this discovery could lead to the development of drugs based on glycans—biological sugar molecules—for the treatment of diseases such as COPD, which is the fourth leading cause of death worldwide.
As part of the research group’s work to explore the roles of sugar molecules in health and disease, they found that keratan sulfate, a large negatively charged saccharide found in the small airway of the lung, is decreased in mice that have been exposed to cigarette smoke. They wondered if this decrease might be associated with the damage that smoking causes to the lung. Taniguchi says, “We are not absolutely sure of the mechanism through which smoking leads to a reduction in keratan sulfate, but felt that clearly the reduction is important in thinking about glycan-based strategies for combating emphysema and COPD.”
They wondered whether the keratan sulfate might be playing a protective role in COPD. To test the hypothesis, they prepared a repeating disaccharide element of keratan sulfate, named L4, and administered it into two mouse models of emphysema—one a model of emphysema triggered by the enzyme elastase, and the other an exacerbation of smoking-induced emphysema triggered by LPS, a toxin found in bacterial cell walls.
In the first model, they found that that treatment with L4 prevented destruction of the alveoli—the small air sacs in lungs that are used to exchange gases, and in addition that it reduced the infiltration of a type of white blood cell called neutrophils, which is symptomatic of an inflammatory response, as well as levels of inflammatory cytokines and tissue-degrading enzymes. Although L4 was shown to inhibit these enzymes, they did not find any ability of L4 to directly reduce the production of cytokines or reactive oxygen species, so concluded that the action was also being done indirectly, through mechanisms involving the neutrophils.
In the exacerbation model, they found that the L4 administration prevented the influx of neutrophils. According to Taniguchi, “We found that L4 was as effective as dexamethasone in reducing neutrophil infiltration. This is very exciting, because dexamethasone, the treatment currently used for COPD, is a steroid medication that can have serious side effects and can in some cases make the outcome worse. It will be exciting if we can show that L4—a sugar molecule which we found had no adverse effects in the mice even at high doses—can be used as a treatment for this condition, which exerts a tremendous health burden.”
According to Taniguchi, there is still work to be done in the area. “We plan now to try to determine exactly how L4 blocks neutrophil migration, by finding a target receptor protein, and how L4 can suppress inflammation in vivo, as this could give us important insights into the mechanism of COPD progression and how it can be halted.”
Researchers at the RIKEN Center for Developmental Biology (CDB) have successfully transplanted retinal pigment cells derived from stem cells of one monkey into the eyes of other monkeys without rejection and without the need for immunosuppressant drugs. Published in Stem Cell Reports, the study shows that this procedure is possible as long as a set of cells called the MHC are genetically matched between the host monkey and the new retinal cells.
A realistic hope of modern medicine is to replace damaged tissue with healthy cells grown in the lab. Currently, adult cells can be reprogrammed into stem cells, and then re-differentiated and grown into desired cell types. The researchers at RIKEN CDB led by Masayo Takahashi have already begun a clinical transplant trial in people with age-related macular degeneration. The team grew retinal pigment cells from induced pluripotent stem cells (iPSCs) and transplanted them into the damaged retina of a human participant. In order to avoid tissue rejection, they used autologous iPSCs—iPSCs that were created from the recipient’s own skin cells.
While this method is sound, producing autologous iPSCs is costly. Additionally, because the cells must grow at the same rate as they do during normal development, a person would have to wait more than a year before a transplant could be performed.
Notes lead author Sunao Sugita, “In order to make iPSC transplantation a practical reality, the current goal is to create banks of iPSC-derived tissues that can be transplanted into anyone as they are needed. However, immune responses and tissue rejection are big issues to overcome when transplanting tissue derived from other individuals.”
The new study tested a technique called MHC matching as a way to overcome this issue. Major histocompatibility complexes (MHCs) are a sets of cell-surface proteins found in all cells that function in the immune system. In humans, MHCs are also called human leukocyte antigens (HLAs). There are many genetic variations of MHCs, and after transplantation, if the MHCs of the transplanted cells are not recognized by the T cells of the host immune system, there is an immune response and the tissue is rejected.
To test whether MHC matching is a viable method, the team used retinal pigment cells that were grown from monkey iPSCs in the iPS cell bank at the Center for iPS Cell Research and Application, Kyoto University. They transplanted the cells into the subretinal space in monkeys with either genetically matched or non-matched MHCs.
The researchers found that these transplanted cells survived without rejection for at least 6 months in MHC-matched monkeys, without using any of the usually necessary immunosuppressant drugs. In contrast, rejection was relatively quick in the MHC-mismatched monkeys. Immunohistochemical examination showed that infiltration by inflammatory cells was only present in the transplanted grafts of MHC-mismatched monkeys. In vitro, the team saw that T cells failed to respond to the iPSC-derived retinal pigment cells if they were from an MHC-matched monkey.
In a separate study published in the same issue of Stem Cell Reports, the researchers saw similar results when they repeated this last experiment with human T cells and HLA-matched or unmatched retinal pigment cells grown from IPSCs.
Now that we have established the lack of immune response in monkeys and in human cells in vitro,” explains Sugita, “using the iPS cell bank appears to be a viable solution, at least in the case of retinal pigment epithelial cell transplantation.”
“In the next clinical trial,” continues Sugita, “we plan to use allogeneic iPS-retinal pigment epithelial cells from HLA homozygote donors. The clinical data after the transplantation will allow us to see if the iPS cell bank is truly useful or not. If so, I think this type of transplantation can become standard treatment within 5 years.”
An international team of physicists has published ground-breaking research on the decay of subatomic particles called kaons – which could change how scientists understand the formation of the universe.
Professor Christopher Sachrajda, from the Southampton Theory Astrophysics and Gravity Research Centre at the University of Southampton, has helped to devise the first calculation of how the behaviour of kaons differs when matter is swapped out for antimatter, known as direct “CP” symmetry violation.
Should the calculation not match experimental results, it would be conclusive evidence of new, unknown phenomena that lie outside of the Standard Model-physicists’ present understanding of the fundamental particles and the forces between them.
The target of the present calculation is a phenomenon that is particularly elusive: a one-part-in-a-million difference between the matter and antimatter decay strengths.
The calculation determines the size of the symmetry violating effect as predicted by the Standard Model.
RIKEN (理研?) is a large STEM research institute in Japan.
Founded in 1917, it now has approximately 3000 scientists on seven campuses across Japan, the main one in Wako, just outside Tokyo. RIKEN is an Independent Administrative Institution whose formal name in Japanese is Rikagaku Kenkyūsho (理化学研究所?) and in English is the Institute of Physical and Chemical Research.
RIKEN conducts research in many areas of science, including physics, chemistry, biology, medical science, engineering and computational science, and ranging from basic research to practical applications. It is almost entirely funded by the Japanese government, and its annual budget is approximately ¥88 billion (US$760 million).
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RIKEN research articles from Innovation Toronto
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- A blueprint for clearing the skies of space debris – April 18, 2015
- A repulsive material – December 31, 2014
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