Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Multiple sclerosis blocked in mouse model

08.03.2011
Barring immune cells from brain prevents symptoms

Scientists have blocked harmful immune cells from entering the brain in mice with a condition similar to multiple sclerosis (MS).

According to researchers from Washington University School of Medicine in St. Louis, this is important because MS is believed to be caused by misdirected immune cells that enter the brain and damage myelin, an insulating material on the branches of neurons that conduct nerve impulses.

New insights into how the brain regulates immune cell entry made the accomplishment possible. Washington University scientists had borrowed an anti-cancer drug in development by the company ChemoCentryx simply to test their theories.

“The results were so dramatic that we ended up producing early evidence that this compound might be helpful as a drug for MS,” says Robyn Klein, MD, PhD, associate professor of pathology and immunology, of medicine and of neurobiology. “The harmful immune cells were unable to gain access to the brain tissue, and the mice that received the highest dosage were protected from disease.”

ChemoCentryx is now testing the drug in Phase I safety trials. The study is published in The Journal of Experimental Medicine.

Klein and her colleagues discovered a chemical stairway that immune cells have to climb down to enter the brain. Immune cells that exit the blood remain along the vessels on the tissue side, climbing down from the meninges into the brain where they can then cross additional barriers and attack myelin on the branches of neurons.

“The effect of immune cell entry into the brain depends on context,” Klein says. “In the case of viral infection, immune cell entry is required to clear the virus. But in autoimmune diseases like multiple sclerosis, their entry is associated with damage so we need to find ways to keep them out.”

The stairway is located on the tissue side of the microvasculature, tiny vessels that carry blood into the central nervous system. The steps are made of a molecule called CXCL12 that localizes immune cells, acting like stairs that slow them down so that they can be evaluated to determine if they are allowed to enter the brain. Klein's lab previously discovered that the blood vessel cells of the microvasculature display copies of this molecule on their surfaces.

Klein also found that MS causes CXCL12 to be pulled inside blood vessel cells in humans and mice, removing the stairway’s steps and the checkpoints they provide. In the new paper, she showed that blocking the internalization of the molecule prevented immune cells from getting into the brain and doing harm.

Work by another lab called Klein’s attention to CXCR7, a receptor that binds to CXCL12. She showed that the receptor is made by the same cells in the microvasculature that display CXCL12. They watched the receptor take copies of CXCL12 and dump them in the cells' lysosomes, pockets for breakdown and recycling of molecules the cell no longer needs.

“After it dumps its cargo in the lysosome, the receptor can go right back to the cell surface to pull in another copy of CXCL12,” Klein says. “There likely exists an equilibrium between expression and disposal of CXCL12. Some of the proteins expressed by the immune cells in MS patients affect CXCR7 expression and activity, disrupting the equilibrium and stripping the steps from this immune cell stairway we're studying.”

Klein contacted researchers at ChemoCentryx, who were developing a blocker of the CXCR7 receptor as a cancer treatment. When they gave it to the mouse model of MS, immune cells stopped at the meninges.

Klein also found that immune factors could cause microvasculature cells to make more or less of CXCR7, ramping up or down the number of steps on the chemical stairway. She is currently investigating additional immune factors that impact on CXCR7 activity within the blood vessel cell. Whether a given factor promotes or suppresses the receptor may also differ depending upon what part of the brain is being considered.

“One of the biggest questions in MS has been why the location, severity and progression of disease varies so much from patient to patient,” Klein says. “Getting a better understanding of how these factors regulate immune cell entry will be an important part of answering that question.”

Cruz-Orengo L, Holman DW, Dorsey D, Zhou L, Zhang P, Wright M, McCandless EE, Patel JR, Luker GD, Littman DR, Russell JH, Klein RS. CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. The Journal of Experimental Medicine, Feb. 7, 2011.

Funding from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Michael C. Purdy | EurekAlert!
Further information:
http://www.wustl.edu

More articles from Life Sciences:

nachricht When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short
23.03.2017 | Institut für Pflanzenbiochemie

nachricht WPI team grows heart tissue on spinach leaves
23.03.2017 | Worcester Polytechnic Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short

23.03.2017 | Life Sciences

Researchers use light to remotely control curvature of plastics

23.03.2017 | Power and Electrical Engineering

Sea ice extent sinks to record lows at both poles

23.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>