News From The Journal Of Clinical Investigation

Main Category: Eye Health / Blindness
Also Included In: Biology / Biochemistry;  Cancer / Oncology;  Genetics
Article Date: 20 Aug 2007 - 10:00 PST

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Eyeing up a role for S1P2R in abnormal blood vessel formation

Many millions of individuals worldwide suffer from vision loss as a result of the formation of an abnormal network of blood vessels in the eye. This abnormal blood vessel network forms in response to damage to the retina and often occurs in individuals who are diabetic. Understanding the molecular mechanisms controlling the development of the network of blood vessels in the retina under normal and pathological conditions is therefore an area of intensive research.

In a study appearing online in advance of publication in the September print issue of the Journal of Clinical Investigation, Timothy Hla and colleagues from the University of Connecticut School of Medicine, Farmington, show that under normal conditions, blood vessel development is indistinguishable in wild-type mice and in mice lacking a protein known as sphingosine 1-phosphate receptor 2 (S1P2R). By contrast, damage to the retina, in the form of low levels of oxygen, induces the formation of an abnormal network of blood vessels in the eyes of wild-type mice, but not in the eyes of S1P2R-deficient mice. The absence of pathological blood vessel formation in S1P2R-deficient mice was associated with decreased inflammatory cell infiltration of the retina and decreased expression of the proinflammatory enzyme cyclooxygenase-2. This demonstration that S1P2R-driven inflammation is an important event in pathological blood vessel formation in the eye led the authors to suggest that inhibiting S1P2R activation in the retina might provide a new therapeutic approach to treating diseases of the eye caused by the presence of an abnormal blood vessel network.

TITLE: Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina

AUTHOR CONTACT: Timothy Hla University of Connecticut School of Medicine, Farmington, Connecticut, USA.

Christopher DeFrancesco Office of Communications University of Connecticut Health Center, Farmington, Connecticut, USA.

A winning combination for the treatment of cancer

The immune system does not destroy tumors even though they express molecules that should activate immune cells. The immune system is therefore said to be tolerant of the tumors. Several molecules and cell types have been implicated in the induction of immune system tolerance to tumors, including, in mice, a small population of immune cells known as plasmacytoid dendritic cells (pDCs) that produce the enzyme indoleamine 2,3-dioxygenase (IDO) and that are isolated from the lymph nodes that drain the site of the tumor. Now, researchers from the Medical College of Georgia, Augusta, have identified how these mouse IDO-expressing pDCs induce tumor-specific immune tolerance.

In the study, which appears online in advance of publication in the September print issue of the Journal of Clinical Investigation, David Munn and colleagues found that mouse IDO-expressing pDCs from tumor-draining lymph nodes directly activate the suppressive function of a population of regulatory immune cells characterized as CD4+CD25+Foxp3+ and known as Tregs. Suppression by Tregs activated by IDO-expressing pDCs was mediated by interactions between programmed cell death 1 (PD1) and its ligands. This mechanism of suppression is distinct from that used by Tregs activated by other stimuli. Importantly, immune suppression in tumor-draining lymph nodes was abrogated by treating mice with both a chemotherapeutic drug and a chemical inhibitor of IDO, but not either agent alone, leading the authors to suggest that combining IDO inhibitors with chemotherapeutic agents might improve the efficacy of chemotherapeutics in individuals with cancer.

TITLE: Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3,-dioxygenase

AUTHOR CONTACT: David H. Munn Medical College of Georgia, Augusta, Georgia, USA.

Toni Baker Director of Media Relations Medical College of Georgia, Augusta, Georgia, USA.

How tumors prevent immune cell entry

For a number of cancers the presence of immune cells known as an NKT cells in the tumor is associated with a better prognosis. It has therefore been suggested that more aggressive tumors have developed strategies to prevent them from being infiltrated by NKT cells. A new study, which appears online in advance of publication in the September print issue of the Journal of Clinical Investigation, shows that this is the case. The pathway used by tumors to prevent NKT cell infiltration might provide researchers with new targets for the development of new treatments for cancer.

In the study, Leonid Metelitsa and colleague from Childrens Hospital Los Angeles show in vitro that expression of a protein known as MYCN, which has been associated with many different types of cancer, by neuroblastoma cells decreases their secretion of a soluble factor (CCL2) that attracts NKT cells. Similarly, in mice, NKT cells were largely inhibited from invading neuroblastomas overexpressing MYCN. Furthermore, individuals with neuroblastomas that expressed high levels of MYCN and whose cancer had spread to the bone marrow had substantially fewer NTK cells in their bone marrow than individuals with neuroblastomas that expressed low levels of MYCN and whose cancer had spread to the bone marrow. The authors therefore suggest that enhancing NKT cell localization to the tumor should be considered when designing new cancer therapeutics.

TITLE: Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma

AUTHOR CONTACT: Leonid S. Metelitsa Childrens Hospital Los Angeles, Los Angeles, California, USA.

Steve Rutledge Director of Communications Childrens Hospital Los Angeles, Los Angeles, California, USA.

1, 2, 3: third gene responsible for genetic disorder identified

Tumoral calcinosis is an inherited disorder that is characterized by the presence of lumps of calcium at inappropriate sites in the body, such as around the hip, elbow, shoulder, and knee joints. Previously, mutations in two genes (FGF23 and GALNT3) had been shown to cause this disease. Now, researchers from Indiana University School of Medicine have identified in a third gene a mutation that causes tumoral calcinosis.

In the study, which appears online in advance of publication in the September print issue of the Journal of Clinical Investigation, Michael Econs and colleagues show that a 13 year old girl with tumoral calcinosis has a mutation in both copies of her KL gene. In vitro analysis revealed that the KL protein resulting from this mutation was expressed and secreted at lower levels than normal KL and that it was unable to help FGF23 mediate its functions. This study provides insight into why mutations in the KL gene cause tumoral calcinosis and gives clinicians a new candidate gene to consider when attempting to determine the etiology of tumoral calcinosis.

TITLE: A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis

AUTHOR CONTACT: Michael J. Econs Indiana University School of Medicine, Indianapolis, Indiana, USA.

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Article adapted by Medical News Today from original press release.
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Source: Karen Honey
Journal of Clinical Investigation