BMP type I receptor inhibition reduces heterotopic ossification

Nature Medicine pp 1363 - 1369

Inflammation is a key step in the progression of heterotopic ossification -- where soft tissue turns into bone -- according to research in Nature Medicine this week. The study shows that an inhibitor of the disease gene's protein product is partially therapeutic, and therefore offers hope for this devastating condition.

In a reverse of the ancient myth of Pygmalion and Galatea, where a statue comes to life, sufferers of heterotopic ossification have their fibrous tissue 'ossified'. A major form of heterotopic ossification is fibrodysplasia ossificans progressiva (FOP), which in about 98% of cases results from a mutation in a specific bone morphogenetic protein receptor.

A mouse model of FOP involving the same mutation found in people has yet to be made, but Paul Yu and colleagues have now developed a mouse model of the general phenomenon by expressing a related version of the mutated receptor. They found that just expressing the mutant version of the protein receptor was not sufficient to cause the disease -- an inflammatory stimulus was also needed. Yu's team also show that inhibiting inflammation with glucocorticoids -- a treatment commonly used in the clinic -- helps reduce the incidence of heterotopic ossification in their model.

Importantly, the authors also show that a small molecule inhibitor of the protein receptor likewise reduced the incidence of disease progression. This form of treatment represents a potential breakthrough, as long-term use of glucocorticoids causes severe side-effects. The authors caution, however, that much more research is needed before the drug could be considered for human trials.

BMP type I receptor inhibition reduces heterotropic ossification pp 1363 - 1369

Paul B Yu, Donna Y Deng, Carol S Lai, Charles C Hong, Gregory D Cuny, Mary L Bouxsein, Deborah W Hong, Patrick M McManus, Takenobu Katagiri, Chetana Sachidanandan, Nobuhiro Kamiya, Tomokazu Fukuda, Yuji Mishina, Randall T Peterson & Kenneth D Bloch

Published online: 30 November 2008 | doi 10.1038/nm.1888

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A role for leukocyte-endothelial adhesion mechanisms in epilepsy

Nature Medicine pp 1377 - 1383

A possible link between epileptic seizures and an interaction between immune cells and brain blood vessels is reported online this week in Nature Medicine. The study indicates that these interactions might be a target for the prevention and treatment of epilepsy.

Although epilepsy affects about 1% of the world population, its underlying mechanisms are poorly understood. Gabriela Constantin and colleagues show that seizures induce the expression of adhesion molecules in blood vessels of mice brains, holding immune cells called leukocytes in the circulatory system of the brain. Stopping the interactions of these cells with blood vessels or depleting certain immune cells known as neutrophils markedly reduced seizures.

The authors also found that seizures caused the barrier between the blood and the brain to become leaky, a phenomenon known to enhance the tendency of neurons to become active. However, blocking the binding of leukocytes to brain vessels prevented such a leak, linking leukocyte-blood vessel interactions, damage to the blood-brain barrier and seizure generation. Finally, the team found that leukocytes were more abundant in brains of people with epilepsy than in healthy subjects, a finding consistent with a potential leukocyte involvement in human epilepsy.

A role for leukocyte-endothelial adhesion mechanisms in epilepsy pp 1377 - 1383

Paolo F Fabene, Graciela Navarro Mora, Marianna Martinello, Barbara Rossi, Flavia Merigo, Linda Ottoboni, Simona Bach, Stefano Angiari, Donatella Benati, Asmaa Chakir, Lara Zanetti, Federica Schio, Antonio Osculati, Pasquina Marzola, Elena Nicolato, Jonathon W Homeister, Lijun Xia, John B Lowe, Rodger P McEver, Francesco Osculati, Andrea Sbarbati, Eugene C Butcher & Gabriela Constantin

Published online: 23 November 2008 | doi 10.1038/nm.1878

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Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases

Nature Medicine pp 1357 - 1362

Targeting specific fat molecules normally found on the inside of the cell membrane could be a therapeutic strategy against viral diseases, reports a paper published online this week in Nature Medicine

Therapies against multiple classes of viruses might be achieved by targeting molecules that are widely expressed on infected cells, as opposed to targeting individual viruses. Philip Thorpe and colleagues reasoned that events occurring during virus replication -- for example, changes immediately before an infected cell dies -- might lead to the extracellular exposure of fat molecules, known as phospholipids, that are normally on the inner surface of the cell membrane.

The team used a specific antibody, bavituximab, to target these potentially exposed molecules in cells infected with Pichinde virus. This virus is used as a model for Lassa fever virus -- a potential bioterrorism agent. They found that infection led to the exposure of phospholipids, and that bavituximab treatment cured guinea pigs lethally infected with the virus. The authors found a similar therapeutic effect of bavituximab in mice with lethal cytomegalovirus infections. These results represent a new strategy for the generation of antiviral agents.

Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases pp 1357 - 1362

M Melina Soares, Steven W King & Philip E ThorpeM Melina Soares, Steven W King & Philip E Thorpe

Published online: 23 November 2008 | doi 10.1038/nm.1885

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Souped-up T cells

Nature Medicine pp 1363 - 1369

Researchers have engineered killer T cells that are better able to limit the spread of HIV in cell culture. The study published this week in Nature Medicine finds that the enhanced cells can also recognise virus that has mutated to try and escape this response.

T cells are alerted to the presence of HIV by the T-cell receptor (TCR), which recognises fragments of virus proteins displayed as warning flags on the surface of infected cells. Current methods to isolate specific T cells that recognise HIV rely on cloning cells from HIV patients - a slow and painstaking process - and often these cells have TCRs that only weakly detect virus-infected cells. The virus can also mutate to avoid being detected.

James Riley and colleagues used 'phage display' technology to isolate a TCR from T cells from an HIV infected patient, which identified a fragment of the virus particularly well. The team then engineered the TCR to be much better at finding the virus. Putting this TCR into T cells created killer cells that were better at restricting the spread of HIV in cell culture. It remains to be seen whether these T cells can control virus infection in animals or patients and therefore become a practical form of therapy.

Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor pp 1363 - 1369

Angel Varela-Rohena, Peter E Molloy, Steven M Dunn, Yi Li, Megan M Suhoski, Richard G Carroll, Anita Milicic, Tara Mahon, Deborah H Sutton, Bruno Laugel, Ruth Moysey, Brian J Cameron, Annelise Vuidepot, Marco A Purbhoo, David K Cole, Rodney E Phillips, Carl H June, Bent K Jakobsen, Andrew K Sewell & James L Riley

Published online: 9 November 2008 | doi 10.1038/nm.1779

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