JCI online early table of contents: Dec. 13, 2010

December 13, 2010

EDITOR'S PICK: A benefit of 'flu: protection from asthma?

The number of people with asthma has increased sharply over the past few decades. It has been suggested that this is a result of decreased childhood exposure to microorganisms. A team of researchers -- led by Dale Umetsu, at Harvard Medical School, Boston; Michio Shimamura, at the University of Tsukuba, Japan; and Petr Illarionov, at the University of Birmingham, United Kingdom -- has now provided concrete evidence in mice to support this idea and identified an underlying mechanism to explain this protection, which the team hope could be exploited to develop ways to prevent asthma.

In the study, infection of suckling mice with influenza A virus protected the mice as adults in a model of asthma. Protection was associated with the expansion of a subset of immune cells known as NKT cells. Importantly, NKT cell-mediated protection in the model of asthma studied could also be induced by treating suckling mice with a molecule derived from the bacterium Helicobacter pylori. The authors therefore suggest that treating children with therapeutics that activate the NKT cell population might prevent the development of asthma.

TITLE: Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity

Dale T. Umetsu
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.919.2439; Fax: 617.730.0384; E-mail: dale.umetsu@childrens.harvard.edu.

Michio Shimamura
University of Tsukuba, Ibaraki, Japan.
Phone: 81.29.853.4527; Fax: 81.29.853.4507; E-mail: michio@chem.tsukuba.ac.jp.

Petr Illarionov
University of Birmingham School of Biosciences, Birmingham, United Kingdom.
Phone: 44.121.4158123; Fax: 44.121.4145925; E-mail: illar@yahoo.com.

View this article at: http://www.jci.org/articles/view/44845?key=a64000b8748341132a37

EDITOR'S PICK: New approaches needed for treating chronic myeloid leukemia

Chronic myeloid leukemia (CML) was transformed from a fatal disease to a chronic condition by the development of a drug known as imatinib, which targets the protein that drives this disease (BCR-ABL). However, imatinib does not cure patients, they must take the drug lifelong, as disease recurs if they stop taking it. This is because imatinib does not kill all the CML cells; some, which are known as CML stem cells, persist. A key to therapeutically targeting CML stem cells is knowing whether they rely on BCR-ABL to persist. Answers to this will determine whether more effective BCR-ABL inhibitors are likely to be effective treatments or whether new approaches to targeting these cells need to be developed.

A team of researchers, led by Brian Drucker and Michael Deininger, at Oregon Health and Science University, Portland, has now shown clearly that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. As noted by the authors and, in an accompany commentary, Alexander Perl and Martin Carroll, at the University of Pennsylvania, Philadelphia, the data indicate that therapeutics targeting BCR-ABL will not improve CML treatment and that new approaches are needed if further advances in patient care are to be made.

TITLE: Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity

Michael W. Deininger
Oregon Health and Science University, Portland, Oregon, USA.
Phone: 503.494.1091; Fax: 503.494.3688; E-mail: deinginge@ohsu.edu.

Brian J. Druker,
Oregon Health and Science University, Portland, Oregon, USA.
Phone: 503.494.1288; Fax: 503.494.3688; E-mail: drukerb@ohsu.edu.

View this article at: http://www.jci.org/articles/view/35721?key=1602b640084adb5cfcdc

TITLE: BCR-ABL kinase is dead; long live the CML stem cell

Martin Carroll
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.573.5217; Fax: 215.573.7049; E-mail: carroll2@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/43605?key=1da0d8726712d0c91c88

DEVELOPMENT: Linking heart valve and blood vessel abnormalities

One of the most common congenital defects is a defect in the aortic heart valve -- the structure that opens and closes to ensure that blood flows in one direction from the heart to the main blood vessel (the aorta). Such abnormalities are associated with problems in the aorta that complicate patient management and increase morbidity and mortality. These complications have been attributed to the turbulent blood flow caused by the aortic valve defects. However, a team of researchers, led by Jonathan Epstein, at the University of Pennsylvania School of Medicine, Philadelphia, has now generated data in mice that suggest that there is another explanation for the association between aortic valve defects and blood vessel complications. Specifically, their data suggest that a developmental defect in a single tissue, the cardiac neural crest, leads to the faulty aortic valves and abnormalities in the aorta.

TITLE: Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves

Jonathan A. Epstein
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.898.8731; Fax: 215.573.2094; E-mail: epsteinj@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/44244?key=54f3d4229d52a06ffe59

IMMUNOLOGY: Protein fragment activates immune cells known as NKT cells

Immune cells known as NKT cells have been linked with protection against autoimmune diseases (conditions in which the immune system attacks the body's own tissues) and other inflammatory disorders. In the mouse, NKT cells are activated by lipids (fats) bound to CD1d molecules on the surface of other immune cells. However, a team of researchers, led by Shohreh Issazadeh-Navikas, at the University of Copenhagen, Denmark, has now determined that mouse NKT cells can be activated by a fragment of the collagen type II protein bound to CD1d molecules. Furthermore, NKT cells activated by this CD1d-bound fragment of collagen type II suppressed disease in various models of inflammatory conditions, including models of the autoimmune diseases multiple sclerosis and rheumatoid arthritis. The team therefore suggests that activation of these NKT cells with protein fragments might provide a new approach to treating certain inflammatory conditions.

TITLE: Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice

Shohreh Issazadeh-Navikas
University of Copenhagen, Denmark.
Phone: 45.3532.5649; Fax: 45.3532.5669; E-mail: shohreh.issazadeh@bric.ku.dk.

View this article at: http://www.jci.org/articles/view/43964?key=68bc5923aa7b827fb484

INFLAMMATION: Tone down the emergency response to prevent tissue damage

Immune cells known as granulocytes are key components of the inflammatory response, defending the body against invading microorganisms and repairing damaged tissue, e.g., after transplantation. However, if too many accumulate at one site, they cause tissue damage. Therefore, numbers of granulocytes are normally kept low; it is only when they are needed, under inflammatory conditions, that large numbers are produced. This demand-driven production of granulocytes is known as emergency granulopoiesis.

A team of researchers, led by Andrew Gelman, at Washington University School of Medicine, St. Louis, has now determined in mice, that the protein Bcl3 has a key role in limiting the production of granulocytes under inflammatory conditions. Importantly, in a clinically relevant mouse model of transplant-mediated lung injury, expression of Bcl3 in transplant recipients inhibited emergency granulopoiesis and limited acute graft damage. The team therefore suggests that it might be possible to target emergency granulopoiesis as a therapeutic strategy for preventing inflammatory lung injury.

TITLE: Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis

Andrew E. Gelman
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314.362.8382; Fax: 314.361.8706; E-mail: gelmana@wudosis.wustl.edu.

View this article at: http://www.jci.org/articles/view/42596?key=8ec344e115c54a5d45e6

HEMATOLOGY: Identifying the cells initiating leukemia is a tricky business

Human leukemic stem cells were originally defined as a rare subpopulation of immature cells selectively able to initiate leukemia. The presence of such cells is demonstrated by the ability of the defined subpopulation to cause leukemia upon transfer into mice with a compromised immune system (NOD/SCID mice). However, work in other types of tumors using NOD/SCID/IL2R-gamma-c-deficient mice as recipients has challenged the cancer stem cell model, suggesting that most tumor cells expressing any molecule can initiate tumor formation. Now, a team of researchers, led by Martin Carroll, at the University of Pennsylvania, Philadelphia, has determined that for human acute myelogenous leukemia (AML), stem cells are indeed rare cells, as assayed in NOD/SCID/IL2R-gamma-c-deficient recipient mice. However, this team found that the AML leukemic stem cells were not restricted to immature cell populations but could be detected in a number of different populations. Thus, these data provide some support for the original leukemic stem cell hypothesis (the cells are indeed rare) but refute the idea that leukemic stem cells must be immature cells.

TITLE: Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2R-gamma-c-deficient mice

Martin Carroll
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.573.5217; Fax: 215.573.7049; E-mail: carroll2@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/41495?key=d8ea39374262e29eb224

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