JCI online early table of contents: May 16, 2011

(Press-News.org) EDITOR'S PICK: Stem cells reverse disease in a model of Parkinson disease

A team of researchers — led by Sang-Hun Lee, at Hanyang University, Republic of Korea, and Kwang-Soo Kim, at Harvard Medical School, Belmont, — has now compared the ability of cells derived from different types of human stem cell to reverse disease in a rat model of Parkinson disease and identified a stem cell population that they believe could be clinically relevant.

Parkinson disease results from the progressive loss of a specific subpopulation of nerve cells. Current treatments provide only relief from the symptoms of the disease and cannot reverse the nerve cell loss. Stem cells are considered by many to be promising candidate sources of cells to reverse nerve cell loss in individuals with Parkinson disease through their ability to regenerate and repair diseased tissues. There are two types of stem cell considered in this context: embryonic stem (ES) cells, which are derived from early embryos; and induced pluripotent stem (iPS) cells, which are derived by reprogramming cells of the body such that they have the ability to generate any cell type. In turn, cells of the body can be reprogrammed to become iPS cells in one of two ways: the reprogramming proteins can be transferred directly into the cells (protein-based iPS cells) or viruses can be used to deliver to the cells the genetic information necessary for producing the reprogramming proteins (virus-based iPS cell). Lee, Kim, and colleagues found several problems with cells derived from virus-based human iPS cells that precluded their use in the Parkinson disease model but found that nerve cells derived from protein-based human iPS cells reversed disease when transplanted into the brain of rats modeling Parkinson disease. They therefore conclude that protein-based human iPS cells could be used in the treatment of individuals with Parkinson disease.

TITLE: Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease

AUTHOR CONTACT:
Sang-Hun Lee
Hanyang University, Seoul, Republic of Korea.
Phone: 82.2.2220.0625; Fax: 82.2.2294.6270; E-mail: leesh@hanyang.ac.kr.

Kwang-Soo Kim
McLean Hospital and Harvard Medical School, Belmont, Massachusetts, USA.
Phone: 617.855.2024; Fax: 617.855.2220; E-mail: kskim@mclean.harvard.edu.

View this article at: http://www.jci.org/articles/view/45794?key=972c7c1fb96f33f1d948

EDITOR'S PICK: An APT(amer) approach to preventing HIV transmission

The HIV epidemic is continuing spread and efforts to develop a vaccine that protects against infection are still showing limited promise. Therefore, researchers are seeking to develop alternative approaches to block HIV transmission. One such strategy is vaginal application of an agent known as a microbicide, which works to kill the virus at the site of entry into the body. A team of researchers, led by Judy Lieberman, at Harvard Medical School, Boston, has now developed a new agent that they hope could be used as the active ingredient in a microbicide to prevent HIV transmission.

HIV infects cells in the body that express the protein CD4. Lieberman and colleagues generated CD4 aptamers (a structured RNA that binds CD4 with high affinity) fused to small inhibitory RNAs targeting the HIV gag or vif genes (which template essential HIV proteins) or the human CCR5 gene (which templates a protein key to HIV entry into cells). These chimeric aptamers were taken up by CD4+ cells, where they knocked down expression of their target genes. More importantly, they inhibited HIV infection of primary CD4+ cells in vitro and of CD4+ cells in polarized human cervicovaginal explants. Furthermore, when applied vaginally to humanized mice they protected against vaginal transmission of HIV. Although additional studies are required to determine how long gene silencing and protection lasts, these data suggest that microbicides containing CD4 aptamers fused to defined small inhibitory RNAs could provide a new tool in the fight against HIV/AIDS.

TITLE: Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras

AUTHOR CONTACT:
Judy Lieberman
Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.713.8600; Fax: 617.713.8620; E-mail: lieberman@idi.harvard.edu.

View this article at: http://www.jci.org/articles/view/45876?key=f00cbc583fd015db1899

TECHNICAL ADVANCE: Mosaics model degenerative disease

Degenerative disorders such as type 1 diabetes and Parkinson disease result from the gradual loss of a particular cell type. The conditions are only diagnosed after cell loss reaches such a level that symptoms are detectable; for example, approximately 80% of pancreatic beta-cells are lost before symptoms of type 1 diabetes arise. Thus, diagnosis is preceded by a nonsymptomatic phase. Current models of degenerative diseases do not allow partial cell ablation, meaning that researchers are unable to study the early nonsymptomatic stages of the disease. However, a team of researchers, led by Albert Edge, at Harvard Medical School, Boston, has now generated a line of transgenic mice that can be crossed with other mouse strains to ablate only a fraction of cells of a given type. Using these mice, Edge and colleagues have modeled a condition similar to the nonsymptomatic phase of type 1 diabetes and studied the effects of partial ablation of inner ear hair cells. Their results indicate that the new line of transgenic mice will be of use for studying degenerative diseases, assessing the regenerative capacity of a tissue, and developing regenerative therapies.

TITLE: Generating mouse models of degenerative diseases using Cre/lox-mediated in vivo mosaic cell ablation

AUTHOR CONTACT:
Albert S.B. Edge
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.573.4452; Fax: 617.720.4408; E-mail: albert_edge@meei.harvard.edu.

View this article at: http://www.jci.org/articles/view/45081?key=1c1295f79c9fb1a15454

IMMUNOLOGY: All new immune response to tuberculosis

Tuberculosis, which is caused by the bacterium Mycobacterium tuberculosis, causes almost 2 million deaths annually. Current vaccine strategies fail to provide strong, long-lasting protection and new approaches are needed. A team of researchers, led by Ajit Lalvani, at Imperial College London, United Kingdom, has now analyzed patients with tuberculosis and generated data that suggest a way to develop an improved tuberculosis vaccine.

Current tuberculosis vaccine strategies stimulate immune cells that target proteins expressed by Mycobacterium tuberculosis. The team found large numbers of immune cells that target mycolic acid, the predominant lipid (fat) in the wall of Mycobacterium tuberculosis, in patients with active tuberculosis. These cells were absent in individuals not infected with the bacterium but who had been vaccinated against tuberculosis. Importantly, although numbers of these cells declined as the patients were successfully treated, the remaining cells remembered seeing mycolic acid and responded rapidly when exposed to mycolic acid in vitro long after successful treatment. The authors therefore conclude that immune cells that target mycolic acid are an important part of the immune system's protective response against Mycobacterium tuberculosis. Vaccines that include the ability to stimulate immune cells that target Mycobacterium tuberculosis lipids might therefore provide stronger and longer-lasting protection than current ones.

TITLE: A mycolic acid–specific CD1-restricted T cell population contributes to acute and memory immune responses in human tuberculosis infection

AUTHOR CONTACT:
Ajit Lalvani
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Phone: 44.20.7594.0883; Fax: 44.20.7262.8913; E-mail: a.lalvani@imperial.ac.uk.

View this article at: http://www.jci.org/articles/view/46216?key=65d650dc73765efe5e64

PULMONARY: Smoking out a new therapeutic target for emphysema

Cigarette smoking is considered the most important cause of emphysema, a chronic lung condition characterized by loss of cells in the air sacs (alveoli). Loss of these cells impairs gas exchange in the lungs, causing the symptoms of the disease, e.g., shortness of breath and fatigue. Recent data indicate that the death of structural alveolar cells, via a process known as apoptosis, has a major role in the development of emphysema. A team of researchers, led by Irina Petrache, at Indiana University, Indianapolis, has now generated data in a mouse model of cigarette smoke–induced emphysema that implicate the molecule EMAPII as a mediator of lung damage through its ability to induce cell death in alveoli of the lung. Importantly, antibodies that neutralized EMAPII reduced alveolar cell apoptosis and improved lung function. As current smokers were found to have increased levels of EMAPII in fluid from the lungs compared with that from the lungs of nonsmokers, the team suggests that neutralizing antibodies targeted to EMAPII might provide a way to treat individuals with emphysema.

TITLE: Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

AUTHOR CONTACT:
Irina Petrache
Indiana University, Indianapolis, Indiana, USA.
Phone: 317.278.2894; Fax: 317.278.7030; E-mail: ipetrach@iupui.edu.

View this article at: http://www.jci.org/articles/view/43881?key=9498f9473b932447211f

GENE THERAPY: Increasing the efficacy of gene therapy

Successful gene therapy requires the efficient targeted delivery of the therapeutic gene to the defective cells. Adeno-associated viruses (AAVs) have been intensively investigated as the backbone for delivery vehicles (also known as vectors) in this context. Vectors based on AAV9 have shown considerable promise for in vivo gene delivery to several organs, including the heart and lungs. However, the molecule to which AAV9 binds before entering cells has not been determined. Identifying this could suggest ways to improve the efficacy of AAV9-based gene therapy.

A team of researchers, led by James Wilson, at the University of Pennsylvania, Philadelphia, has now determined that AAV9 binds molecules known as glycans if they have a terminal galactose. When an AAV9 vector was administered to mice together with an agent (neuraminidase) that exposed terminal galactose on glycans on cells lining the airways, the airway lining cells were targeted by the AAV9 vector far more efficiently than in the absence of neuraminidase. The team hopes that these data will help improve the efficiency with which AAV9-based vectors deliver their gene load to the target cell by increasing receptor abundance.

TITLE: The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice

AUTHOR CONTACT:
James M. Wilson
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.898.0226; Fax: 215.898.6588; E-mail: wilsonjm@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/57367?key=8313c81bc02325bb4b9a

METABOLIC DISEASE: The protein PKC-delta is sensitive to insulin

Obesity, type 2 diabetes, and the metabolic syndrome are related health problems that are now major health problems worldwide. They arise as a result of environmental and genetic factors. Studies in mice have identified a region of DNA containing the Pkcd gene as contributing to both genetic and diet-induced resistance to the hormone insulin, a key risk factor for developing type 2 diabetes and the metabolic syndrome. A team of researchers, led by Ronald Kahn, at Harvard Medical School, Boston, has now extended these observations and determined that the protein PKC-delta is a regulator of both insulin sensitivity in the liver and fatty liver (a component of the metabolic syndrome) in mice and humans. The data generated by Kahn and colleagues through analysis of genetically modified mice and obese humans leads them to suggest that PKC-delta could be a good target for improving insulin sensitivity and preventing the development of type 2 diabetes and fatty liver in individuals with diet-induced obesity.

TITLE: PKC-delta regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

AUTHOR CONTACT:
C. Ronald Kahn
Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.732.2635; Fax: 617.732.2487; E-mail: c.ronald.kahn@joslin.harvard.edu.

View this article at: http://www.jci.org/articles/view/46045?key=53056e177a46577f8bf2

IMMUNOLOGY: A new way to think about macrophage activation syndrome (MAS)

Macrophage activation syndrome (MAS) is a severe, potentially life-threatening condition characterized by a cytokine storm, overwhelming inflammation, and multiorgan dysfunction. It is closely related to a number of other conditions, including hemophagocytic lymphohistiocytosis (HLH), that are characterized by a cytokine storm. Most animal models of HLH/MAS require infectious agents to trigger disease, making it difficult to separate the damage caused by the infection from that caused by the cytokine storm itself. A team of researchers, led by Edward Behrens, at the University of Pennsylvania, Philadelphia, has now determined that activation of the innate immune system via stimulation of the molecule TLR9 causes a MAS-like syndrome in mice in the absence of infection. These data are at odds with the current paradigm that MAS-like syndromes result from overstimulation of the adaptive immune system and thereby provide a new way to think about these conditions, in particular forms of MAS in which there is chronic activation of the innate immune system and no genetic defects in cells of the adaptive immune system known as cytotoxic T cells.

TITLE: Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice

AUTHOR CONTACT:
Edward M. Behrens
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 267.426.0142; Fax: 215.590.1258; E-mail: behrens@email.chop.edu.

View this article at: http://www.jci.org/articles/view/43157?key=369a5ea19342ffb7502a

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