JCI online early table of contents: May 2, 2011

(Press-News.org) EDITOR'S PICK: Skin sensitivity to food allergens explained

Atopic dermatitis is a form of eczema that is caused by an inappropriate inflammatory response in the skin. Many children with atopic dermatitis also have food allergies, and skin contact with food allergens can make their atopic dermatitis worse. It is unclear why this occurs, but it has been suggested that immune cells known as T cells that are sensitized by exposure to food allergens in the gut are responsible. Raif Geha and colleagues, at Harvard Medical School, Boston, have now generated data in a mouse model of food allergen–induced atopic dermatitis that support this idea. Specifically, their data indicate that skin contact with food allergens can lead to the reprogramming of gut-homing T cells into skin-homing T cells that mediate allergic skin inflammation. These data have important implications for the prevention and treatment of atopic dermatitis in patients with food allergy.

TITLE: Epicutaneous challenge of orally immunized mice redirects antigen-specific gut-homing T cells to the skin

AUTHOR CONTACT:
Raif S. Geha
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.919.2482; Fax: 617.730.0528; E-mail: raif.geha@childrens.harvard.edu.

View this article at: http://www.jci.org/articles/view/43586?key=ac0a2a02b9e4913fdcde

EDITOR'S PICK: Cells derived from different stem cells: same or different?

Stem cells are considered by many to be promising candidate sources of cells for therapies to regenerate and repair diseased tissues. There are two types of stem cell considered in this context: embryonic stem (ES) cells, which are derived from early embryos; and induced pluripotent stem (iPS) cells, which are derived by reprogramming cells of the body such that they have the ability to generate any cell type. Recent data indicate that ES and iPS cells are molecularly different, raising the possibility that cells derived from these two sources could be distinct.

A team of researchers, led by Darrell Kotton and Gustavo Mostoslavsky, at Boston University School of Medicine, Boston, has now, however, determined that mouse iPS and parental ES cells show highly similar capacity to be differentiated in vitro into definitive endoderm progenitors — the cells from which thyroid, lung, liver, and pancreas are derived. Importantly, there was considerable overlap between the genetic programs of definitive endoderm derived from ES and iPS cells in vitro and definitive endoderm isolated from mouse embryos. The authors therefore conclude that their data support the notion that iPS cells could be used for the development of cell-based therapies for diseased endoderm-derived tissues.

TITLE: Mouse ES and iPS cells can form definitive endoderm despite differences in imprinted genes

AUTHOR CONTACT:
Darrell N. Kotton
Boston University School of Medicine, Boston, Massachusetts, USA.
Phone: 617.638.4860; Fax: 617.536.8063; E-mail: dkotton@bu.edu.

Gustavo Mostoslavsky
Boston University School of Medicine, Boston, Massachusetts, USA.
Phone: 617.638.6532; Fax: 617.638.7785; E-mail: gmostosl@bu.edu.

View this article at: http://www.jci.org/articles/view/43853?key=1acccf69de7b78a41298

HEMATOLOGY: TIF(f)1 between blood cell progenitors leads to leukemia

Proteins whose normal function helps prevent the development of tumors are known as tumor suppressors. Tumors arise when expression of these proteins is reduced. A team of researchers, led by Laurent Delva and Jean-Noël Bastie, at the University of Burgundy, France, has now identified the protein TIF1-gamma as a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML).

To analyze the function of TIF1-gamma in blood cells, Delva, Bastie, and colleagues generated mice lacking TIF1-gamma only in blood cells. Upon reaching 6 months of age, the mice progressively developed a disorder that recapitulated the essential characteristics of a form of leukemia known as chronic myelomonocytic leukemia (CMML). The clinical relevance of these data was highlighted by the researchers' observations that TIF1-gamma is downregulated in the leukemic cells of approximately 35% of patients with CMML. Downregulation was a result of modification of the structure of the TIF1G gene that templates TIF1-gamma protein and not a result of genetic mutations. These data lead the authors to suggest that changes in TIF1-gamma expression could act as a marker of response to modifiers of genetic structure, which are currently being developed for the treatment of CMML.

TITLE: Transcription intermediary factor 1-gamma is a tumor suppressor in mouse and human chronic myelomonocytic leukemia

AUTHOR CONTACT:
Laurent Delva
Inserm UMR 866, University of Burgundy, Dijon, France.
Phone: 33.0.380393440; Fax: 33.0.380393434; E-mail: Laurent.Delva@u-bourgogne.fr.

Jean-Noël Bastie
Inserm UMR 866, University of Burgundy, Dijon, France.
Phone: 33.0.380393440; Fax: 33.0.380393434; E-mail: jean-noel.bastie@chu-dijon.fr.

View this article at: http://www.jci.org/articles/view/45213?key=e227eccbb68079d7c3ca

IMMUNOLOGY: Characterizing key defenders against influenza infection

CD8+ T cells play a key role in defending the body against infection with viruses. In the human lung, CD8+ T cells can be detected in several different locations, but whether cells in different locations have the same or distinct functions has not been determined. A team of researchers, led by Berber Piet, at Academic Medical Centre, The Netherlands, has now begun to investigate this question by isolating T cells from fresh lung resection tissue.

The team found that most CD8+ T cells expressing the protein CD103 were located in amongst the cells lining the small airways, as has been previously published. These cells were analyzed further and it was found that CD103 was expressed by lung CD8+ T cells specific for influenza (a virus that affects the lungs) but not those specific for viruses that do not affect the lungs (e.g., EBV and CMV). The functional and molecular characteristics of the CD8+CD103+ T cells indicated that they likely provide a rapid and efficient response to protect against influenza infection but are restrained from damaging the delicate lining of the airways when patrolling for viruses.

TITLE: CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung

AUTHOR CONTACT:
Berber Piet
Academic Medical Centre, Amsterdam, Netherlands.
Phone: 31.20.5668041; Fax: 31.20.5669756; E-mail: b.piet@amc.nl.

View this article at: http://www.jci.org/articles/view/44675?key=2504e877ec43eddc6146

AUTOIMMUNITY: Alternative pathways to autoimmune disease

Autoimmune diseases arise when an individual's immune system attacks specific cell types in the body. For example, type 1 diabetes arises when the immune system targets beta-cells in the pancreas. Understanding what triggers the immune system to attack an individual's own cells could lead to new strategies to prevent autoimmune diseases. In this context, Keith Elkon and YuFeng Peng, at the University of Washington, Seattle, have now generated new data in mice regarding one mechanism that underlies autoimmunity.

Increasing data indicate that defective clearance of cells that have died by a process known as apoptosis can trigger autoimmunity. Elkon and Peng set out to investigate how defective clearance of apoptotic cells leads to autoimmunity by studying mice lacking the protein MFG-E8, which binds to apoptotic cells and facilitates their removal by immune cells such as dendritic cells. Their data indicate that the defective uptake of intact apoptotic cells in MFG-E8–deficient mice leads to the accumulation of apoptotic cell debris that is then taken up by dendritic cells and processed differently to ingested intact apoptotic cells. This alternative processing causes dendritic cells to activate other immune cells (CD8+ T cells) that go on to attack and destroy cells in the mouse, leading to autoimmune diseases.

TITLE: Autoimmunity in MFG-E8–deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens

AUTHOR CONTACT:
Keith B. Elkon
University of Washington, Seattle, Washington, USA.
Phone: 206.543.3415; Fax: 206.685.9397; E-mail: elkon@u.washington.edu.

YuFeng Peng
University of Washington, Seattle, Washington, USA.
Phone: 206.616.5636; Fax: 206.685.9397; E-mail: pengyf@u.washington.edu.

View this article at: http://www.jci.org/articles/view/43254?key=11e0e978fbf915f7e75a

ONCOLOGY: Linking the immune system to lung cancer development

Lung cancer is the leading cause of death from cancer. Chronic lung inflammation, which is induced by both cigarette smoke and asbestos, is a major contributing factor to the development of lung cancer. Despite this, most models of lung cancer rely on genetic manipulation of known oncogenes or tumor suppressors. To investigate more clearly the role of inflammation in the development of lung cancer, a team of researchers, led by Glenn Dranoff, at Harvard Medical School, Boston, developed a mouse model of lung cancer initiated by alterations in immune response genes in the absence of mutations in known oncogenes or tumor suppressors. The mice developed chronic lung inflammation and lung tumors at a high frequency. Detailed analysis indicated that the tumors arose through a combination of tumor-promoting inflammation and failure of spontaneous antitumor immunity. Future studies separating these two components of inflammation-induced lung tumor development should provide new avenues of research for those seeking to develop immune-based therapies for lung cancer.

TITLE: A dual role for the immune response in a mouse model of inflammation-associated lung cancer

AUTHOR CONTACT:
Glenn Dranoff
Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.632.5051; Fax: 617.632.5167; E-mail: glenn_dranoff@dfci.harvard.edu.

View this article at: http://www.jci.org/articles/view/44796?key=336bfd21508ce66c22d0

ONCOLOGY: CD73 has a cooperative approach to promoting tumor cell growth

The protein CD73 is overexpressed in many types of cancer. Recent data suggest that it might promote tumor growth. Now, a team of researchers, led by Bin Zhang, at the University of Texas Health Science Center, San Antonio, has determined that both CD73 on tumor cells and CD73 on host cells promote tumor growth in multiple mouse tumor models. Further, CD73 on host blood cells and nonblood cells were shown to promote tumor growth in different ways. Consistent with these data, the optimal antitumor effect of CD73 blockade required inhibiting CD73 on both tumor and host cells. The authors therefore conclude that tumor and host CD73 cooperate to promote tumor growth and that CD73 is a viable target for anticancer immunotherapy.

TITLE: CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice

AUTHOR CONTACT:
Bin Zhang
University of Texas Health Science Center, San Antonio, Texas, USA.
Phone: 210.562.5243; Fax: 210.562.5292; E-mail: Zhangb3@uthscsa.edu.

View this article at: http://www.jci.org/articles/view/45559?key=ebd2540136ad009d75d4

CARDIOLOGY: TGF-beta handles the pressure for heart muscle cells

High blood pressure (hypertension) is a leading cause of heart disease. This is because heart muscle cells react to sustained pressure overload in such a way that they become dysfunctional. One of the many factors that triggers this response is the multi-functional molecule TGF-beta. However, its pleiotropic nature and the fact that it is generated by and interacts with several cell types means that its role in heart disease has remained ambiguous. Now, a team of researchers, led by David Kass, at Johns Hopkins Medical Institutions, Baltimore, has found that preventing TGF-beta from acting on mouse heart muscle cells protects against the deleterious effects of pressure overload (a model of high blood pressure). The authors therefore suggest that cell-selective targeting of anti–TGF-beta strategies may have to be targeted to selective cell populations if they are to be effective.

TITLE: Pivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload

AUTHOR CONTACT:
David A. Kass
Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Phone: 410.955.7153; Fax: 410.502.2558; E-mail: dkass@jhmi.edu.

View this article at: http://www.jci.org/articles/view/44824?key=506899241861541d7af6

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