JCI table of contents: Oct. 2, 2006

EDITOR'S PICK: Looking for new approaches to target antibiotic-resistant bacteria

Infection with Entercoccus faecalis can cause bacterial endocarditis, an infection of the heart valves that if not treated with antibiotics results in death. The number of infections with antibiotic-resistant E. faecalis is increasing. So, researchers are looking for alternative strategies for treating individuals who become infected with this bacterium. Now, in a study appearing in the October issue of the Journal of Clinical Investigation, researchers from University of Texas Medical School at Houston have identified proteins that are required for E. faecalis to cause endocarditis in rats and that might make good vaccine candidates.

Barbara Murray and colleagues found that E. faecalis expresses four proteins that are required for the bacteria to form protein structures on their surface known as pili. The pili were required for the bacteria to aggregate and form biofilms. More importantly, rats infected with E. faecalis lacking expression of any one of these proteins suffered less severe bacterial endocarditis. This study, identifying E. faecalis proteins required for the bacterium to cause endocarditis in rats, might lead to the development of new strategies to treat individuals who become infected with E. faecalis.

In an accompanying commentary, Jonathan Budzik and Olaf Schneewind from the University of Chicago agree with this suggestion when they comment that, "This information may enable new vaccine strategies for the prevention of E. faecalis infections."

TITLE: Endocarditis and biofilm-associated pili of Entercoccus faecalis.

AUTHOR CONTACT:
Barbara E. Murray
University of Texas Medical School at Houston, Houston, Texas, USA.
Phone: (713) 500-6745; Fax: (713) 500-6766; E-mail: bem.asst@uth.tmc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29021

ACCOMPANYING COMMENTARY
TITLE: Pili prove pertinent to enterococcal endocarditis

AUTHOR CONTACT:
Olaf Schneewind
University of Chicago, Chicago, Illinois, USA.
Phone: (773) 834-9060; Fax: (773) 834-8150; E-mail: oschnee@bsd.uchicago.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30088


ONCOLOGY: Anti-tumor immune responses bring about their own demise

In the early stages of cancer an individual's immune system mounts an anti-tumor response to try and rid the body of the tumor. However, this immune response becomes blunted with time and the tumor is able to grow unimpeded. Understanding why the immune response becomes ineffective is a major goal of many researchers looking for ways to treat individuals with cancer. Now, in a mouse study appearing in the October issue of the Journal of Clinical Investigation, researchers from the Instituto Oncologico Veneto, Italy, have identified one pathway by which tumors suppress the anti-tumor response, providing new avenues of research for the development of anti-cancer drugs.

Previous studies have shown that tumors release soluble factors that recruit a population of cells known as myeloid suppressor cells (MSCs) because of their ability to suppress an immune response. Vincenzo Bronte and colleagues have now shown that MSCs marked by their expression of a protein known as IL-4R-alpha produce two soluble factors (IFN-gamma and IL-13) that are required for MSC suppression of the immune response. Ironically, IL-4R-alpha–expressing MSCs were activated to produce these soluble factors by the anti-tumor immune response going on at their time of recruitment to the tumor. This study describes one pathway by which the anti-tumor immune response can be blunted with time and provides researchers with new potential therapeutic strategies to prevent this occurring.

In an accompanying commentary, Alan Frey from the New York University School of Medicine discusses how this pathway might intersect with other immunosuppressive mechanisms and the potential therapeutic targets that this study has brought to light.

TITLE: Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells

AUTHOR CONTACT:
Vincenzo Bronte
Instituto Oncologico Veneto, Padua, Italy.
Phone: +39-049-8215897; Fax: +39-049-8072854; E-mail: enzo.bronte@unipd.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28828

ACCOMPANYING COMMENTARY
TITLE: Myeloid suppressor cells regulate the adaptive immune response to cancer

AUTHOR CONTACT:
Alan B. Frey
New York University School of Medicine, New York, New York, USA.
Phone: (212) 263-8129; Fax: (212) 263-8139; E-mail: freya01@med.nyu.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29906


ONCOLOGY: Blood vessels refill their old shoes after treatment with VEGF inhibitors is stopped

Inhibitors of the protein VEGF are currently being used to treat individuals with certain cancers. As tumors grow they develop their own blood vessels, which supply the tumor cells with the nutrients and oxygen that they need to survive, and VEGF inhibitors exert their anti-cancer effect by destroying blood vessels in the tumor. Current VEGF inhibitors work by blocking the function of any VEGF in the individual, but little is known about the reversibility of their effects.

Now, in a study appearing in the October issue of the Journal of Clinical Investigation, Donald McDonald and colleagues from UCSF, show that it takes the blood vessels in tumors in mice 7 days to regrow after treatment with VEGF inhibitors is withdrawn. The new blood vessels grew along the tracks left behind by the old blood vessels destroyed by the VEGF inhibitors. This study indicates that although VEGF inhibitors destroy blood vessels in a tumor, the development of approaches that combine VEGF inhibitors with agents that destroy blood vessel tracks might be more effective at preventing blood vessel re-growth in a tumor.

In an accompanying commentary, Kristy Red-Horse and Napoleone Ferrara explain how important these findings are for the future development of strategies aimed at destroying the blood vessels that feed a tumor.

TITLE: Rapid vascular regrowth in tumors after reversal of VEGF inhibition

AUTHOR CONTACT:
Donald M. McDonald
University of California San Francisco, San Francisco, California, USA.
Phone: (415) 476-2118; Fax (415) 476-4845; E-mail: donald.mcdonald@ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=24612

ACCOMPANYING COMMENTARY
TITLE: Imaging tumor angiogenesis

AUTHOR CONTACT:
Napoleone Ferrara
Genentech Inc., South San Francisco, California, USA.
Phone: (650) 225-2968; Fax: (650) 225-6327; E-mail: nf@gene.com.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30058


IMMUNOLOGY: VSIG4 helps keep T cells under control

Inappropriate activation of cells of the immune system known as T cells can cause immune-mediated disorders such as the autoimmune disease rheumatoid arthritis. As a result, activation of T cells is a tightly regulated process that occurs only when a T cell receives exactly the right amount of stimulation. The level of stimulation that a T cell receives is a combination of lots of positive and negative signals. In a study appearing in the October issue of the Journal of Clinical Investigation researchers from Cytos Biotechnology AG, Switzerland have identified VSIG4 as a previously unknown negative regulator of human T cell activation in vitro and mouse T cell activation in vivo.

Martin Bachmann and colleagues showed that stimulation with VSIG4 impaired the activation of both human and mouse T cells in vitro. Similarly, administration of VSIG4 to mice impaired their ability to mount immune responses. As VSIG4 was expressed by another immune cell type, the macrophage, only in the absence of inflammation, the authors suggest that VSIG4 might be important for maintaining T cells in an inactive state in healthy tissues.

In an accompanying commentary, Xingxing Zang and James Allison from Memorial Sloan-Kettering Cancer Center, New York, discuss this function of VSIG4 in light of another recent publication showing that VSIG4, under the alterego of CRIg, is important for the removal of bacteria from the blood by macrophages.

TITLE: VSIG4, a B7 family–related protein, is a negative regulator of T cell activation

AUTHOR CONTACT:
Martin F. Bachmann
Cytos Biotechnology AG, Zürich-Schlieren, Switzerland.
Phone: +41-1-733-47-07; Fax: +41-1-733-47-57; E-mail: martin.bachmann@cytos.com.

View the PDF of this article at: https://www.the-jci.org/article.php?id=25673

ACCOMPANYING COMMENTARY
TITLE: To be or not to be B7

AUTHOR CONTACT:
James P. Allison
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (646) 888-2332; Fax: (646) 422-0470; E-mail: allisonj@mskcc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30103


GASTROENTEROLOGY: Two steps to TNF-induced diarrhea

OKT3 is an immunotherapeutic drug that has been developed successfully for the treatment of transplant rejection. One of the side effects of OKT3 is diarrhea, which is thought to be caused by the soluble factors released by the immune cells (T cells) activated by OKT3. Exactly how these soluble factors cause diarrhea has not been clearly established. Now, in a study appearing in the October issue of the Journal of Clinical Investigation, researchers at the University of Chicago have shown that the soluble factor TNF causes diarrhea in mice by affecting two separate processes, enabling researchers to understand more about the regulation of water absorption and secretion in the intestine.

Jerrold Turner and colleagues found that although the barrier of the intestine was dysfunctional in both mice injected with TNF and those injected with the related soluble factor LIGHT, only mice injected with TNF had diarrhea. Importantly, TNF, but not LIGHT, was found to inhibit the absorption of sodium ions. However, this effect of TNF alone was not sufficient to cause diarrhea, it was the combined effect of TNF on the barrier of the intestine and the absorption of sodium ions that resulted in diarrhea. This study indicates that TNF can cause diarrhea by affecting two distinct processes and might explain why diarrhea is a side effect of excessive T cell activation, not only after OKT3 treatment but also during graft-versus-host disease.

However, in an accompanying commentary, Michael Field from Columbia University puts forward the opinion that TNF must also affect other processes to cause such dramatic water loss and diarrhea.

TITLE: Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo

AUTHOR CONTACT:
Jerrold R. Turner
University of Chicago, Chicago, Illinois, USA.
Phone: (773) 702-2433; E-mail: jturner@bsd.uchicago.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=29218

ACCOMPANYING COMMENTARY
TITLE: T cell activation alters intestinal structure and function

AUTHOR CONTACT:
Michael Field
Columbia University, New York, New York, USA.
E-mail: mf9@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29985


HEMATOLOGY: CXCL12 blocks the way to the bone marrow

Hematopoietic stem cells (HSCs) are the cells that give rise to all the different cell types in the blood and HSC transplantation is used to treat a number of blood disorders, including some cancers of the blood. These cells are mostly found in the bone marrow, although they can also be detected in umbilical cord blood, the placenta, and the fetal liver. The processes that control the recruitment and retention of HSCs in the bone marrow are not well understood, particularly during development.

Now, in a study appearing in the October issue of the Journal of Clinical Investigation, Connie Eaves and colleagues at the Terry Fox Laboratory in Vancouver, have shown that until mice reach 3 weeks of age all their HSCs are proliferating, but that by 4 weeks of age most of their HSCs have stopped proliferating. Proliferating HSCs from mice less than 3 weeks old expressed high levels of a protein known as CXCL12 and this prevented them being recruited and retained in the bone marrow when transplanted to other mice; only if recipient mice were treated with a drug that blocks CXCL12 were the proliferating HSCs recruited and retained in the bone marrow.

This study has clinical implications because human HSCs that are proliferating at the time of transplantation are not efficiently incorporated into the bone marrow of recipients. So, the authors suggest that treating recipients of HSC transplants with inhibitors of CXCL12 might help improve the efficiency of HSC transplantation. This sentiment is echoed in an accompanying commentary by David Williams and colleagues, from Cincinnati Children's Hospital, when they state that, 'Such agents [CXCL12 inhibitors] are currently clinically available, suggesting that this approach could be used to improve stem cell transplantation and engraftment.'

TITLE: Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect

AUTHOR CONTACT:
Connie J. Eaves
Terry Fox Laboratory, Vancouver, British Columbia, Canada.
Phone: (604) 675-8122; Fax: (604) 877-0712; E-mail: ceaves@bccrc.ca.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28310

ACCOMPANYING COMMENTARY
TITLE: Children are not little adults: just ask their hematopoietic stem cells

AUTHOR CONTACT:
David A. Williams
Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: (513) 636-0364; Fax: (513) 636-3768; E-mail: david.williams@cchmc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30083

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Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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