News Release

JCI table of contents: Feb. 1, 2007

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: New role in asthma for old drug

The results of a study in mice by researchers from Erasmus University, The Netherlands, have indicated that an inhaled drug currently used to treat individuals with pulmonary arterial hypertension (raised blood pressure in the blood vessels in the lungs that leads to shortness of breath, dizziness, and fainting) might provide a new therapeutic to treat individuals with asthma.

Iloprost is a stable analog of the naturally occurring soluble factor PGI2. It is used to treat pulmonary arterial hypertension because it causes blood vessels to widen, thereby increasing blood flow and reducing blood pressure. However, recent studies have indicated that PGI2, and therefore iloprost, might also have anti-inflammatory properties. In a study that appears in the February issue of the Journal of Clinical Investigation, Bart Lambrecht and colleagues show that inhalation of iloprost inhibits the Th2 cell inflammatory response that causes disease in a mouse model of allergic asthma. Inhalation of iloprost inhibited this response in two ways. First, it prevented the immune cells in the lungs that activate the Th2 cell response (known as dendritic cells [DCs]) from leaving the lungs and going to the site at which they activate the allergic Th2 cell response. Second, it blocked the DCs becoming activated enough to stimulate an allergic Th2 cell response. This study therefore indicates that targeting DCs in the lungs can suppress allergic asthma in mice and might lead to studies determining whether such targeting by iloprost can provide a new treatment for individuals with asthma.

TITLE: Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function

AUTHOR CONTACT:

Bart N. Lambrecht
Erasmus University Medical Center, Rotterdam, The Netherlands.
Phone: 31-10-408-7703; Fax: 31-10-408-9453; E-mail: b.lambrecht@erasmusmc.nl.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28949


EDITOR'S PICK: Tumor-reactive T cells boosted by hematopoietic stem cell transplantation

Although treatment regimens involving the infusion of tumor-reactive T cells into patients with skin cancer (melanoma) have shown clinical benefit, there is plenty of room to improve the protocols to increase therapeutic benefit. Regimens currently being investigated in humans involve pre-treatment with agents that transiently decrease the number of immune cells (and that are known as nonmyeloablative agents), enabling the subsequently infused tumor-reactive T cells to increase in number in vivo.

In a study that appears in the February issue of the Journal of Clinical Investigation, Nicholas Restifo and colleagues from the National Institutes of Health show that in mice, pre-treatment with more intense immune cell–depleting strategies (known as myeloablative strategies) and a hematopoietic stem cell (HSC) transplantation enabled infused tumor-reactive CD8+ T cells to increase in number more than pre-treatment with nonmyeloablative agents. Importantly, this increased expansion of the CD8+ T cell population correlated with increased tumor regression. Further analysis showed that it was the HSC transplantation, and not the increased immune cell depletion, that made the myeloablative agents more effective at inducing the infused tumor-reactive T cell population to expand and that it was the effector CD8+ T cell population, rather than the naïve T cell population, that expanded. This study has important implications for the future development of treatment regimens involving the infusion of tumor-reactive T cells into patients with melanoma.

In an accompanying commentary, Claudio Anasetti and James J. Mulé from the H. Lee Moffitt Comprehensive Cancer Center, Tampa, discuss the issues that are raised by these data and the implications that these issues have for the development of cell-based immunotherapies for cancer.

TITLE: Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8+ T cells

AUTHOR CONTACT:

Nicholas P. Restifo
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-4904; Fax: (301) 496-0011; E-mail: restifo@nih.gov

Claudia Wrzesinski
National Cancer Institute, NIH, Bethesda, Maryland, USA.
Phone: (301) 451-6948; Fax: (301) 496-0011; E-mail: wrzesinc@mail.nih.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=30414

ACCOMPANYING COMMENTARY

TITLE: To ablate or not to ablate? HSCs in the T cell driver's seat

AUTHOR CONTACT:

James J. Mulé
H. Lee Moffitt Comprehensive Cancer Center, Tampa, Florida, USA.
Phone: (813) 745-1536; Fax: (813) 745-6188; E-mail: mulejj@moffitt.usf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30973


VIROLOGY: p21 stops HIV-1 in its tracks in hematopoietic stem cells

Hematopoietic stem cells (HSCs) are one of the few cell types able to resist infection with HIV-1 despite expressing the cell surface molecules to which HIV-1 binds before entering a cell. In a study that appears in the February issue of the Journal of Clinical Investigation, researchers from Harvard Medical School, Boston, show that HSC expression of a protein known as p21Waf1/Cip1/Sdi1 (p21) is required for HSCs to be resistant to infection with HIV-1.

David Scadden and colleagues showed that HSCs in which expression of p21 was decreased were more susceptible to infection with HIV-1 than cells expressing normal levels of p21. Further analysis showed that p21 did not inhibit HIV-1 entering the cells, rather it prevented the viral DNA integrating into the host cell genome by binding to the HIV-1 integrase complex and preventing it from mediating chromosomal integration. This protective mechanism was specific for HIV-1, as decreased expression of p21 in HSCs did not allow a related virus (SIVmac-251) to productively infect the HSCs. This study therefore identifies p21 as a protective factor that prevents HSCs being infected with HIV-1.

In an accompanying commentary, Paul D. Bieniasz from the Aaron Diamond AIDS Research Center, New York, discusses how this study adds p21 to an ever-growing list of cellular proteins that alter the sensitivity of a cell to infection with HV-1, but cautions that "it would seem premature to dub p21 a bona fide restriction factor." (a protein whose major, and perhaps only, role is to prevent retrovirus replication).

TITLE: Primitive hematopoietic cells resist HIV-1 infection via p21Waf1/Cip1/Sdi1

AUTHOR CONTACT:

David T. Scadden
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-5615; Fax: (617) 724-2662; E-mail: scadden.david@mgh.harvard.edu.

Clyde S. Crumpacker
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 667-5863; Fax: (617) 667-5541; E-mail: ccrumpac@caregroup.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28971

ACCOMPANYING COMMENTARY

TITLE: An intrinsic host defense against HIV-1 integration?

AUTHOR CONTACT:

Paul D. Bieniasz
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.
Phone: (212) 448-5070; Fax: (212) 725-1126; E-mail: pbienias@adarc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31290


PHYSIOLOGY: What makes epithelial cells change their identity?

During development and during pathological processes in the adult, cells are constantly changing their function. One, well-characterized, cellular transition that occurs during development, as well as during wound healing, tissue fibrosis, and tumor metastasis, is the transition from an epithelial cell to a mesenchymal cell (often a fibroblast). This change in cell type and function is known as epithelial-mesenchymal transition (EMT) and it has been shown that a protein known as FSP1 is important for this transition. However, the proteins that direct the change in the pattern of genes expressed, so that epithelial cells can undergo EMT, have not been completely defined.

In a study appearing in the February issue of the Journal of Clinical Investigation, Eric Neilson and colleagues from Vanderbilt University, Nashville, identify two proteins, CBF-A and KAP-1, as crucial for initiating EMT. CBF-A and KAP-1 were shown, by two independent mechanisms, to bind a regulatory region of DNA in the gene encoding FSP1. This regulatory region of DNA is known as FTS-1 and the binding of proteins to FTS-1 has previously been shown to drive the expression of FSP1. Further analysis by Neilson and colleagues showed that in kidney epithelial cells engineered to express CBF-A a complex composed of CBF-A, KAP-1, and FST-1 formed and that this triggered EMT. This study indicated that the CBF-A/KAP-1/FTS-1 complex is an early regulator of EMT and the authors suggest that it might be the master regulatory complex in this important process.

In an accompanying commentary, Raghu Kalluri and colleagues from Harvard Medical School, Boston, clarify the importance of this study for our understanding of EMT and suggest that the CBF-A/KAP-1/FTS-1 complex might be a good therapeutic target for the treatment of diseases in which EMT features prominently, such as tissue fibrosis.

TITLE: A proximal activator of transcription in epithelial-mesenchymal transition

AUTHOR CONTACT:

Eric G. Neilson
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: (615) 322-3146; Fax: (615) 343-9391; E-mail: eric.neilson@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29544

ACCOMPANYING COMMENTARY

TITLE: Transcriptional regulation of epithelial-mesenchymal transition

AUTHOR CONTACT:

Raghu Kalluri
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 667-0445; Fax: (617) 975-5663; E-mail: rkalluri@bidmc.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31200


DEVELOPMENT: NOTCHing up heart development

Defects in the heart and/or blood vessels (cardiovascular defects) in both humans and mice can result from mutations in any one of a number of genes encoding proteins that are part of the Notch signaling cascade. However, it has not been determined which cell type these mutations affect to cause these cardiovascular defects.

In a study that appears in the February issue of the Journal of Clinical Investigation, Jonathan Epstein and colleagues from the University of Pennsylvania, Philadelphia, show that mice in which the Notch signaling cascade is only inhibited in cells of the neural crest lineage (which includes both smooth and skeletal muscle cells) develop cardiovascular defects. Further analysis showed that during cardiac development the Notch signaling cascade is active in the developing vascular smooth muscle cells and that when this signaling cascade is inhibited few cells express markers of developing vascular smooth muscle cells. Consistent with this, inhibition of the Notch signaling cascade in neural crest cells in vitro prevented them from differentiating into smooth muscle cells. This study therefore identifies cells of the neural crest lineage as the cells in which Notch signaling is important for cardiovascular development in mice and might provide a cellular mechanism for the cardiovascular defects observed in humans with the hereditary disorder Alagille syndrome, which has been linked to mutations in genes encoding proteins that are part of the Notch signaling cascade.

In an accompanying commentary, Leonard Anderson and Gary Gibbons from the Morehouse School of Medicine, Atlanta, discuss the intriguing possibility that defects in the Notch signaling cascade might also be important in adult vascular diseases; something that Epstein and colleagues also suggest.

TITLE: An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation

AUTHOR CONTACT:

Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-8731; Fax: (215) 573-9306; E-mail: epsteinj@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30070

ACCOMPANYING COMMENTARY

TITLE: Notch: a mastermind of vascular morphogenesis

AUTHOR CONTACT:

Gary H. Gibbons
Morehouse School of Medicine, Atlanta, Georgia, USA.
Phone: (404) 752-1545; Fax: (404) 752-1042; E-mail: ggibbons@msm.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31288


NEUROBIOLOGY: Stress response prevents neurodegeneration

Multiple sclerosis (MS) is a debilitating immune-mediated disease of the brain and spinal cord (the central nervous system [CNS]). It is characterized by infiltration of the CNS by inflammatory cells and destruction of cells that reside in the CNS, known as oligodendrocytes (ODCs). The soluble factor IFN-gamma has a detrimental effect on disease in patients with MS. However, studies using the mouse model of MS, known as EAE, indicate that IFN-gamma can also have a protective effect. In a study appearing in the February issue of the Journal of Clinical Investigation, researchers from the University of Chicago describe a mechanism by which IFN-gamma protects mice from developing EAE.

Brian Popko and colleagues showed that if IFN-gamma is expressed in the brain before EAE is induced it protects mice from neurodegeneration. IFN-gamma–mediated protection was associated with an increased survival of ODCs and activation of the integrated stress response in ODCs. The ODC integrated stress response, which is triggered in cells by non-optimal environmental conditions, was mediated by PERK, as the beneficial effects of IFN-gamma were lost in PERK-deficient mice. This study describes a mechanism by which IFN-gamma can protect mice from developing EAE and leads the authors to suggest that the timing of IFN-gamma expression in the brain and the extent of the stress response in the ODCs are factors determining whether or not IFN-gamma has a protective or detrimental effect on EAE. Furthermore, they suggest that therapies designed to activate the integrated stress response in ODCs might be beneficial to individuals with MS. However, in an accompanying commentary, Jason Lees and Anne Cross sound a note of warning, saying that "an understanding of these relationships [between the level of IFN-gamma in the brain and the extent of the integrated stress response in ODCs] would be required before attempting to alter ODC stress responses in MS patients for therapeutic benefit."

TITLE: The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage

AUTHOR CONTACT:

Brian Popko
The University of Chicago, Chicago, Illinois, USA.
Phone: (773) 702-4953; Fax: (773) 702-5577; E-mail: bpopko@uchicago.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29571

ACCOMPANYING COMMENTARY

TITLE: A little stress is good: IFN-gamma, demyelination, and multiple sclerosis

AUTHOR CONTACT:

Anne H. Cross
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-3293; Fax: (314) 747-1345; E-mail: crossa@neuro.wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31254


METABOLIC DISEASE: 4E-BP1 and 4E-BP2 stop mice getting fat

Obese individuals often suffer from the metabolic syndrome, which is a combination of medical disorders that increase an individual's risk for cardiovascular disease and type 2 diabetes. Deregulation of a protein known as mTOR (which is a nutrient sensor that when activated increases energy expenditure by the cell's of the body) has been implicated in the development of obesity and the metabolic syndrome in humans. Further evidence for this idea is now provided by researchers from McGill University, Canada, who show that mice lacking two proteins known to be effectors of some mTOR functions (4E-BP1 and 4E-BP2) are more obese than normal mice.

In their study, which appears in the February issue of the Journal of Clinical Investigation, Nahum Sonenberg and colleagues show that mice lacking both 4E-BP1 and 4E-BP2, when fed either a normal or high-fat diet, weigh more than wild-type mice. The increased weight gain after being on a high-fat diet was a result of increased fat accumulation, associated with decreased energy expenditure, decreased fat degradation, increased differentiation of fat cells, and increased insulin resistance (one of the main triggers of type 2 diabetes and a contributing factor to the metabolic syndrome). This study indicates that two effectors of mTOR functions are crucial for preventing mice from becoming obese and suggests that 4E-BP1 and 4E-BP2 might provide therapeutic targets for the treatment of obesity and the metabolic syndrome.

In an accompanying commentary, Liangyou Rui from the University of Michigan Medical School, Ann Arbor, puts these observations into the bigger picture of how other mTOR effectors also affect body weight and how this pathway intersects with other molecules known to regulate obesity.

TITLE: Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2

AUTHOR CONTACT:

Nahum Sonenberg
McGill University, Montréal, Québec, Canada.
Phone: (514) 398-7274; Fax: (514) 398-1287; E-mail: nahum.sonenberg@mcgill.ca.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29528

ACCOMPANYING COMMENTARY

TITLE: A link between protein translation and body weight

AUTHOR CONTACT:

Liangyou Rui
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 615-7544; Fax: (734) 647-9523; E-mail: ruily@umich.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31289

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