Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find new way to block destructive rush of immune cells

16.01.2008
Detailed Images of Fast-Moving T Cells Provide First Experimental Evidence of Theory

Researchers have found a way to selectively block the ability of white blood cells to “crawl” toward the sites of injury and infection when such mobility drives disease, according to a study published today in The Journal of Experimental Medicine. The results suggest a new treatment approach for autoimmune diseases like rheumatoid arthritis, lupus and multiple sclerosis, and for conditions made worse by misplaced inflammation, like atherosclerosis, stroke and transplant rejection, researchers said.

Where a single-celled amoeba moves to find food, human cells migrate as part of complex bodily functions like immunity. Disease-fighting cells for instance move toward bacteria and cells infected with viruses, which they target for destruction. Unfortunately, the same cells can mistakenly attack the body’s own cells or drive inflammation too far, worsening the problem they rushed in to solve.

A team of researchers at the University of Rochester Medical Center has been studying proteins called integrins that enable T cells, a major subset of immune cells, to migrate. The integrin-related mechanisms described for the first time in the current paper suggest a way to shut down only those T cells currently in the act of disease-related migration, while leaving in place reserves needed in the likely event that another infection occurs during treatment. Making the mechanistic discoveries possible was a successful effort by the team to capture on video the first detailed images of fast-migrating T cells and the behavior of key proteins related to migration, which had been tagged with fluorescence. Twelve videos of T cells, and their key migration proteins, in action are part of the publication and are available online.

“There are many cases where it would be incredibly useful to precisely block integrin activation, and thus T cell migration,” said Minsoo Kim, Ph.D., assistant professor of Microbiology and Immunology within the David H. Smith Center for Vaccine Biology and Immunology at the Medical Center, and lead author of the article. “Good examples include when our immune system attacks our own cells, or rejects a lifesaving transplant or clogs our blood vessels by mistake. The problem is that past, system-wide attempts that block all integrin activation, like the multiple sclerosis drug Tysabri, shut down not only unwanted inflammation in one locale, but also vital immune defenses elsewhere, leaving patients vulnerable to infection.”

The Great Migration

Two mechanisms make cell migration, or programmed directional movement, possible. The first, called chemotaxis, tells the cell which direction to move in. Cell surface proteins sense and follow chemicals and molecules they are attracted to toward wherever those attractants are most concentrated. T cells, named after the thymus (T) where they mature, move toward the byproducts of bacteria and viruses.

The second migratory mechanism is propulsion. In between infections and injuries, inactive T cells ride along with the bloodstream. T cells “realize” when they pass by part of a blood vessel wall close to the site of an injury or infection. Integrins on their surfaces unfold and grab onto key proteins on the surface of blood vessel wall cells (e.g. ICAM), resisting the surrounding blood flow. The T cells then pass through the vessel wall, and once outside the bloodstream, crawl along the tissue scaffolding toward the site of injury.

In a T cell at rest, integrins are distributed evenly over the entire surface of the T cell. When the cell gets ready to move, however, activated integrins cluster on the leading edge of the cell in the direction the cell wants to move in. They bind to their counterpart adhesion proteins like ICAM on the surface that the T cell is moving across. The T cell then contracts using its cell skeleton to pull itself over the leading edge integrins. Finally, the integrins on the trailing edge of the cell let go. Without precise changes that enable the front end to gain traction, and the tail to let go, the cell cannot migrate.

Kim’s team found that a subset of integrins, including lymphocyte function–associated antigen-1 (LFA-1), control whether or not the tail end of the T cell can “let go” (de- adhesion). Data revealed for the first time that a protein called non-muscle myosin heavy chain-IIA (MyH9) is recruited to LFA-1 at the trailing end of migrating T lymphocytes. Experiments that interfered with the association between MyH9 and the LFA-1 integrin were found to prevent the trailing edge of the crawling T cell from letting go, dramatically reducing the ability of T cells to move. Myosins are motor proteins that expend energy to enable cell skeletons to contract. That contraction creates force that is used in many cases to move muscle fibers, but in the case of MyH9, to rip the trailing end of a migrating T cell foot away from the surface it is migrating across by breaking integrin-ICAM bonds. The results provide the first evidentiary support of the longstanding theory that cell skeleton contractile force is used to drive T cell migration, with MyH9 as the mechanical link. Captured images show fluorescently tagged actin (which partners with LFA-1 to grip the surface) gathering at the front end of the cell, and fluorescently tagged MyH9 gathering at the tail end in cycles, each time the cell takes a “step.”

The study was a joint effort by the Department of Surgery at Rhode Island Hospital, Brown Medical School, the Department of Physics at Brown University, the CBR Institute for Biomedical Research at Harvard Medical School and the departments of Chemical Engineering, Biomedical Engineering and Department of Microbiology and Immunology at the University of Rochester. The project was supported by the American Heart Association, the Rhode Island Foundation, the National Institutes of Health, the National Science Foundation and the Brown University Seed Grant.

In the next phase, the team will seek to develop better-targeted, anti-integrin therapies, with MyH9 among the rational targets for new classes of drugs. Toward that end, experiments currently underway are designed to determine which molecules regulate MyH9 activity during T cell migration.

“Initial clinical studies on T cell migration focused on overall blocking of migration, but general inhibition is a blunt tool,” said Tim Mosmann, Ph.D., director of the David H. Smith Center for Vaccine Biology and Immunology. “As studies such as Dr. Kim’s help us to understand the process more precisely, we should be able to design much more precise methods to block migration in the selected circumstances that cause problems, without crippling the essential immune responses to infections.”

Greg Williams | EurekAlert!
Further information:
http://www.urmc.rochester.edu

More articles from Health and Medicine:

nachricht Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Safe glide at total engine failure with ELA-inside

On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded after a glide flight with an Airbus A320 in ditching on the Hudson River. All 155 people on board were saved.

On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded...

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

New pop-up strategy inspired by cuts, not folds

27.02.2017 | Materials Sciences

Sandia uses confined nanoparticles to improve hydrogen storage materials performance

27.02.2017 | Interdisciplinary Research

Decoding the genome's cryptic language

27.02.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>