News From The Journal Of Clinical Investigation March 20, 2008

Main Category: Biology / Biochemistry
Also Included In: Immune System / Vaccines;  Genetics;  Cancer / Oncology
Article Date: 24 Mar 2008 - 1:00 PDT

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Antibodies protect against bacteria in the blood

In developed countries, infection with nontyphoidal strains of Salmonella bacteria (NTS) usually occurs through eating contaminated food and causes gastroenteritis. By contrast, in Africa, children under the age of 2 and HIV-infected adults usually develop an infection in the blood (bacteremia), which is fatal in almost a quarter of affected children. There is currently no vaccine against NTS and understanding the immune response that protects against NTS bacteremia is crucial if one is to be developed. New data, generated by Calman MacLennan and colleagues, has now identified a role for antibody in protection against NTS bacteremia in children from Malawi, leading to the suggestion that effective vaccines against NTS should induce the generation of protective antibody.

TITLE: The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children

AUTHOR CONTACT:
Calman A. MacLennan
University of Birmingham, Birmingham, United Kingdom.

Take heed: HOXB4 gene therapy causes leukemia in large animals

Individuals with a number of life-threatening genetic diseases of the immune system have been successfully treated by gene therapy - that is, they were infused with early precursors of immune cells that had the correct form of the defective gene delivered into them by agents known as retroviral vectors. However, some patients later developed leukemia. This slowed progress in the field and has led to detailed studies seeking to determine the mechanisms underlying the cause of leukemia and whether other genes that are candidates for gene therapy approaches might pose a similar risk. A new study, carried out by Hans-Peter Kiem and colleagues, at the Fred Hutchinson Cancer Research Center, Seattle, has now indicated that early precursors of immune cells that had the gene HOXB4 delivered into them by a gammaretroviral vector became leukemic in 2 of 2 dogs and 1 of 2 macaques. In vitro analysis established a clear link between HOXB4 expression and leukemia, leading the authors to conclude that the use of HOXB4-based gene therapy would probably carry a high risk of leukemia and that extreme caution is needed when considering gene therapy approaches. The need for caution is echoed in an accompany commentary by Andre Larochelle and Cynthia E. Dunbar, at the National Institutes of Health, Bethesda, who discuss how important large animal studies, such as those reported by Hans-Peter Kiem and colleagues, are to minimize the risk of adverse events in humans receiving gene therapy in the future.

TITLE: High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector

AUTHOR CONTACT:
Hans-Peter Kiem
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

ACCOMPANYING COMMENTARY

TITLE: HOXB4 and retroviral vectors: adding fuel to the fire

AUTHOR CONTACT:
Cynthia E. Dunbar
National Institutes of Health, Bethesda, Maryland, USA.

Antitumor immune cells seen taking it slow

In human clinical trials and mouse models of cancer, the transfer of large numbers of immune cells known as CTLs into patients with cancer and mice, respectively, can cause tumor destruction. However, the mechanisms by which CTLs eliminate tumors in this setting remain largely unknown. But now, Philippe Bousso and colleagues, at the Institut Pasteur, France, have provided insight into these mechanism by visualizing tumor cell destruction in real-time in a mouse model of solid tumors.

In the study, transferred CTLs were seen to directly kill tumor cells, with only minimal effects on nontumor cells in the surrounding environment. As an individual CTL was shown to take, on average, 6 hours to destroy a single tumor cell, the authors suggest that directly observing the dynamics of the interaction between tumor cells and CTLs has enabled them to determine one of the factors limiting the efficiency of antitumor CTL responses - time.

TITLE: Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

AUTHOR CONTACT:
Philippe Bousso
Institut Pasteur, Paris, France.

Man versus rat: same type of drug, different response

A phase I clinical trial to test the drug TGN1412 ended only hours after it began in March 2006, when the six healthy volunteers who were administered the drug developed severe clinical symptoms that led to multiple organ failure. The devastating consequences of the drug in humans had not been predicted by studies in animals, in which similar drugs had shown tremendous efficacy in rodent models of autoimmune diseases. New data generated by Holger M. Reichardt and colleagues at the University of Goettingen Medical School, Germany, has now provided more insight into the effects of drugs similar to TGN1412 in rats, but as with the preclinical trials no evidence of the devastating consequences in humans were observed. As pointed out in an accompanying commentary by William St. Clair, at Duke University Medical Center, Durham, these data serve to highlight the different responses of rodents and humans to drugs like TGN1412, and raise "questions about how best to design preclinical studies that can better predict the risks of novel immunotherapeutics in humans.?

TITLE: A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats

AUTHOR CONTACT:
Holger M. Reichardt
University of Goettingen Medical School, Goettingen, Germany.

ACCOMPANYING COMMENTARY

TITLE: The calm after the cytokine storm: lessons from the TGN1412 trial

AUTHOR CONTACT:
E. William St. Clair
Duke University Medical Center, Durham, North Carolina, USA.

The protein TM4SF5 lets tumor cells grow out of control

A characteristic of tumor cells is that they grow in an uncontrolled manner. One reason for this is that although normal cells stop growing when they contact one another (a process known as contact inhibition), tumor cells do not. New data, generated by Jung Weon Lee and colleagues, at Seoul National University, Republic of Korea, has now indicated that the protein TM4SF5 has a crucial role in the ability of human hepatocarcinoma cells to overcome contact inhibition and grow in an uncontrolled manner.

In the study, TM4SF5 was found to be overexpressed in human hepatocarcinoma tissue. This overexpression mediated cellular effects that caused the tumor cells to undergo a process known as epithelial-mesenchymal transition, and resulted in uncontrolled growth, both in vitro and when the cells were injected into mice. The importance of these data, which imply TM4SF5 has a crucial role in cancer progression, is discussed in an accompanying commentary by Ruth Muschel and Annamaria Gal from the University of Oxford, United Kingdom.

TITLE: Tetraspanin TM4SF5 mediates loss of contact inhibition through epithelial-mesenchymal transition in human hepatocarcinoma

AUTHOR CONTACT:
Jung Weon Lee
Seoul National University, Seoul, Republic of Korea.

ACCOMPANYING COMMENTARY

TITLE: Tetraspanin in oncogenic epithelial-mesenchymal transition

AUTHOR CONTACT:
Ruth J. Muschel
University of Oxford, Oxford, United Kingdom.

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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