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JCI online early table of contents: Feb. 7, 2008

EDITOR'S PICK: VEGF-B helps nerve cells cheat death without unwanted side effects

The prototypical member of the VEGF family of proteins, VEGF, has recently been shown to protect cells in the nervous system from death and degeneration. However, its clinical utility in this regard is limited, because it also induces blood vessel growth, a process known as angiogenesis. In a new study, Xuri Li and colleagues at the National Institutes of Health, Bethesda, have revealed that the VEGF family member VEGF-B acts as a potent inhibitor of murine retinal cell death while exerting minimal angiogenic effects.

In addition to inhibiting expression of cell-deathrelated genes, VEGF-B was shown to reduce the death of murine retinal cells in culture models of cellular injury and in mouse models of ocular neurodegenerative disorders. Furthermore, VEGF-B treatment inhibited brain cell death in a mouse model of stroke. As the concentration of VEGF-B required for retinal protection did not lead to angiogenesis in the mouse retina, the authors concluded that VEGF-B might provide a new therapeutic option for the treatment of neurodegenerative disease.

TITLE: VEGF-B inhibits apoptosis via VEGFR-1mediated suppression of the expression of BH3-only protein genes in mice and rats

Xuri Li
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-4103; Fax: (301) 480-2640; E-mail:

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EDITOR'S PICK: The key to survival and virulence for a fungal pathogen is autophagy

Autophagy is a process whereby cells recycle material during stress situations, such as when nutrients are scarce. Some cells also use this process as an immune defense mechanism to eliminate pathogens. However, new data, generated in mice by Peter Williamson and colleagues, at the University of Illinois at Chicago, has identified autophagy as a new virulence-associated trait and survival mechanism for Cryptococcus neoformans a fungal pathogen that commonly infects immunocompromised individuals, such as those with HIV.

In the study, a mutant form of C. neoformans that lacked the protein Vps34 PI3K (known as the vps34D mutant) was found to be less able to form autophagy-related 8labeled (Atg8-labeled) vesicles than normal C. neoformans. Furthermore, the vps34D mutant was less virulent in mice than normal C. neoformans. Consistent with a crucial role for autophagy in determining the extent of the disease caused by infection with C. neoformans, a strain of C. neoformans in which Atg8 expression was knocked down showed reduced virulence in mice. The authors therefore suggested that more detailed understanding of this virulence pathway might lead to new drugs for treating individuals who become infected with C. neoformans.

TITLE: PI3K signaling of autophagy is required for starvation tolerance and virulence of Cryptococcal neoformans

Peter R. Williamson
University of Illinois at Chicago, Chicago, Illinois, USA.
Phone: (312) 996-6070; Fax: (312) 413-1657; E-mail:

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ONCOLOGY: Straight to the tumor: fusion protein targets iNKT immune cells to tumors

A subset of immune cells known as iNKT cells have been shown to have antitumor activity. However, if mice are injected with a soluble form of a molecule that activates them (alpha-GalCer), the cells are only activated for a short time and then become dormant. Now, Alena Donda and colleagues at the University of Lausanne, Switzerland, have identified a way to activate mouse iNKT cells for longer periods of time and to target them to tumors.

In the study, mice were given a series of injections of alpha-GalCer bound to a soluble form of a protein known as CD1d (alpha-GalCer/sCD1d). This led to sustained iNKT cell activation as well as activation of other immune cell types important for antitumor immunity NK cells and DCs. Furthermore, when a form of the alpha-GalCer/sCD1d fused to a molecule (known as a scFv antibody fragment) that targeted the protein HER2 was administered to mice injected with tumor cells expressing HER2 two days earlier, the growth and metastasis of the tumor cells was inhibited. This antitumor activity was associated with the accumulation of iNKT cells, NK cells, and DCs at the site of the tumor. The authors therefore suggested that targeting iNKT cells to tumors could provide a new approach to treating many forms of cancer.

TITLE: Sustained activation and tumor targeting of NKT cells using a CD1danti-HER2scFv fusion protein induces antitumor effects in mice

Alena Donda
University of Lausanne, Epalinges, Switzerland.
Phone: 41-21-692-5737; Fax: 41-21-692-5705; E-mail:

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ONCOLOGY: Antitumor immune responses are boosted by TLR9-activated pDCs

The immune response mounted toward tumors is often very weak when compared with that mounted against invading viruses. It has been suggested that this difference is because the tumor microenvironment does not provide signals that activate immune cells known as pDCs through their Toll-like receptors (TLRs). Consistent with this, Patrick Hwu and colleagues were able to induce a potent tumor-specific CD8+ T cell immune response in mice bearing two tumors by injecting TLR9-activated pDCs directly into one of the tumors. Importantly, the tumor-specific CD8+ T cell immune response was not limited to the tumor into which the TLR9-activated pDCs had been injected. The TLR9-activated pDCs were shown to induce this antitumor immune response by recruiting and activating NK cells, which, in turn, activated cDCs, enabling them to activate tumor-specific CD8+ T cells. These data have provided insight into a cascade of immune cell activation that can result in antitumor immune responses, information that might lead to the development of new therapeutic antitumor approaches.

TITLE: Plasmacytoid dendritic cells induce NK celldependent, tumor antigenspecific T cell cross-priming and tumor regression in mice

Patrick Hwu
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 563-1727; Fax: (713) 745-1046; E-mail:

Gang Wang
US Food and Drug Administration, Rockville, Maryland, USA.
Phone: (301) 827-7123; Fax: (301) 827-3536; E-mail:

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IMMUNOLOGY: T cells stopped from reaching their destination

If immune cells known as T cells are to mount an effective immune response they must be able to migrate to and be retained in the tissue where the immune response is needed. New data, generated in mice by Federica Marelli-Berg and colleagues at Imperial College London, United Kingdom, have indicated that signaling through the protein PI3K p110-delta is important for T cells to localize in tissues where they are needed to mount an immune response.

In the study, when T cells from mice expressing an inactive form of PI3K p110-delta were transferred to normal mice they trafficked normally unless the mice were administered an inflammatory stimulus that induced a tissue to express the molecule (known as an antigen) that the T cells recognized. Under these conditions, the T cells from mice expressing an inactive form of PI3K p110-delta failed to migrate and to accumulate in the antigenic tissue, meaning that an immune response was not mounted. Consistent with this, normal T cells treated with a drug that inhibits PI3K p110-delta did not migrate to antigenic tissues activated by an inflammatory stimulus. The authors therefore suggested that drugs inhibiting PI3K p110-delta might be useful in preventing unwanted T cell accumulation in tissues, such as occurs in some autoimmune diseases and inflammatory disorders.

TITLE: T cell receptorinduced phosphoinositide-3-kinase p110-delta activity is required for T cell localization to antigenic tissue in mice

Federica Marelli-Berg
Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Phone: 44-0-2083831704; Fax: 44-0-2083832788; E-mail:

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GASTROENTEROLOGY: The soluble factor IL-10 has guts

Although it is known that the soluble factor IL-10 has an important role in preventing inflammation in the intestine of mice, the function of IL-10 in the human intestine is not well understood. By studying explant cultures of human colonic mucosa (the lining of the large intestine), Anne Jarry and colleague,s at INSERM U539, France, have now shown that IL-10 prevents a damaging inflammatory response being induced by bacteria living naturally in the human colon.

IL-10 was found to be constitutively expressed and secreted by human colonic mucosa. Depletion of IL-10 in explant cultures of human colonic mucosa led to increased expression of pro-inflammatory factors such as IFN-gamma, which was shown to cause damage to the colonic mucosa. The upregulation of IFN-gamma expression was eliminated if the bacterial product LPS was removed from the explant cultures. As IFN-gamma expression could be restored by the addition of a bacterium that lives naturally in the human colon, the authors suggested that IL-10 has a crucial role in maintaining the integrity of the human colonic mucosa.

TITLE: Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven, IFN-gammamediated epithelial damage in human colon explants

Anne Jarry
INSERM U539, Nantes, France.
Phone: 33-2-40-41-28-30: 33-2-40-41-28-37; E-mail:

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NEPHROLOGY: The CNRE region of the renin gene cant handle the blood pressure

The kidney protein renin has a crucial role in maintaining blood pressure. Transcription of the renin gene involves the decoding of its gene sequence to generate the protein. Keiji Tanomoto and colleagues at the University of Tsukuba, Japan, investigated the role of two portions of the renin gene known as RP-2 and CNRE in transcription of the renin gene and regulation of blood pressure. It was found that RP-2, but not CNRE, was essential for transcription of the renin gene and thereby expression of the renin protein in the kidneys of mice. Furthermore, the low blood pressure of renin-deficient mice was not restored to normal by a renin gene lacking the RP-2 region, but it was restored to normal by a renin gene lacking the CNRE region. The authors therefore concluded that RP-2, but not CNRE, is vital for the regulation of transcription of the renin gene and thereby the maintenance of blood pressure.

TITLE: A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation

Keiji Tanimoto
University of Tsukuba, Tsukuba, Ibaraki, Japan.
Phone: 81-29-853-6070; Fax: 81-29-853-6070; E-mail:

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ENDOCRINOLOGY: Oxygen deprivation makes the molecule D3 act locally to reduce thyroid hormone levels

The thyroid organ generates hormones that regulate a variety of functions in the body, including energy expenditure. The molecule D3 can inactivate thyroid hormones; however, D3 is typically found in only a few postnatal tissues, although its expression is reactivated in the liver and skeletal muscle of critically ill patients. In a new study, Stephen Huang and his colleagues at the Harvard Institutes of Medicine, Boston, have reported that a state of hypoxia (that is, low oxygen levels) can induce expression of D3 and lead to local inactivation of the thyroid hormone T3.

D3 production was induced following exposure of cultured cells from various species and organs to either hypoxic conditions or chemicals that altered the cellular chemistry to mimic hypoxia. Mechanistically, expression of the gene responsible for the generation of D3 protein was found to be regulated by a protein known as HIF-1. Functionally, inhibition of D3 activity in cultured cells resulted in increased energy expenditure. Finally, the clinical relevance of these data was highlighted by the observation that in a rat model of hypertrophic heart failure a disease that is associated with hypoxia in the heart muscle D3 was induced at the site of hypoxia, causing a localized reduction in T3 levels.

TITLE: Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats

Stephen A. Huang
Harvard Institutes of Medicine, Boston, Massachusetts, USA.
Phone: (617) 355-2452; Fax: (617) 730-0793; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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