JCI online early table of contents: December 21, 2009

December 21, 2009

EDITOR'S PICK: What is the function of the protein CD20?

Antibodies directed against the protein CD20, which is expressed by immune cells known as B cells, are used to treat B cell non-Hodgkin lymphoma and rheumatoid arthritis. Despite this, the function of CD20 has not been determined. Now, a team of researchers led by René van Lier, at the Academic Medical Center, The Netherlands, has determined that CD20 has a nonredundant role in generating optimal B cell immune responses by analyzing a patient lacking the protein.

The patient was referred to the Academic Medical Center at four years of age, with a history of intermittent respiratory infections and recurrent bronchopneumonia. Detailed analysis of immune cells from the patient revealed that the B cells lacked CD20 expression due to a mutation in the CD20 gene. These CD20-deficient B cells failed to respond normally to certain stimuli in vitro, specifically those known as T-independent antigens. Further, vaccination of the patient with a T-independent antigen led to a markedly impaired B cell response. The authors therefore conclude that CD20 has an important role in enabling B cells to respond optimally to T-independent antigens and that absence of this protein causes an immunodeficiency characterized by a reduced capacity to make B cell responses to T-independent antigens.

TITLE: CD20 deficiency in humans results in impaired T cell-independent antibody responses

René A.W. van Lier
Academic Medical Center, Amsterdam, The Netherlands.
Phone: 31-20-5666303; Fax: 31-20-5669756; E-mail: r.vanlier@amc.uva.nl.

View this article at: http://www.jci.org/articles/view/40231?key=YsPY1tn296hkLJ0ksns0

EDITOR'S PICK: Gene therapy makes mice breath easier

Individuals with single-gene mutations that mean they have abnormally low levels of the protein alpha-1 antitrypsin are highly susceptible to emphysema, a progressive lung disease that causes severe shortness of breath. Previous attempts to correct single-gene defects that cause lung disease by gene transfer have failed to achieve sustained gene expression in the mouse lung. However, a team of researchers, at Boston University School of Medicine, has now developed an approach that enabled them to attain sustained in vivo expression of normal human alpha-1 antitrypsin at levels able to improve emphysema in mice.

The team, led by Darrell Kotton, introduced gene-carrying lentiviral vectors into the windpipe of mice and found that they selectively and efficiently transferred the genes they were carrying to resident cells known as alveolar macrophages. These cells were long-lived and continued to express the transferred genes for at least two years. In a mouse model of emphysema, introduction into the windpipe of lentiviral vectors carrying the gene responsible for making normal human alpha-1 antitrypsin led to sustained alpha-1 antitrypsin expression in the lung and reduced disease. The authors therefore conclude that targeting genes to alveolar macrophages provides a way to achieve sustained gene expression in the lung and suggest that this might provide a therapeutic approach for overcoming overcome lung diseases caused by single-gene defects, for example emphysema caused by alpha-1 antitrypsin deficiency.

TITLE: Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages

Darrell N. Kotton
Boston University School of Medicine, Boston, Massachusetts, USA.
Phone: (617) 638-4860; Fax: (617) 536-8093; E-mail: dkotton@bu.edu.

Gina Digravio
Boston University School of Medicine, Boston, Massachusetts, USA.
Phone: (617) 638-8480; E-mail: Gina.Digravio@bmc.org.

View this article at: http://www.jci.org/articles/view/36666?key=c1d002c27e68d71c8c88

HEMATOLOGY: Sensitizing leukemic cells to death-inducing compounds

Recent research has indicated that in the process of generating energy, leukemic cells use a cellular pathway known as fatty acid oxidation, rather than pyruvate oxidation, as had been previously thought. A team of researchers, at the University of Texas M.D. Anderson Cancer Center, Houston, and the University of Texas Houston Medical School, has now used this knowledge to develop a way to sensitize human leukemic cells to molecules that induce cell death by a process known as apoptosis. They hope that it might be possible to translate this approach to the clinic as a therapeutic strategy to treat leukemias.

The team, led by Michael Andreeff and Heinrich Taegtmeyer, found that inhibition of fatty acid oxidation with either etomoxir, a drug that was tested in clinical trials for the treatment of heart disease but never made it to market due to unacceptable toxicities, or ranolazine, a drug approved for the treatment of chronic angina, inhibited human leukemic cell proliferation in vitro. More importantly, etoxomir treatment sensitized human leukemic cells to the death-inducing compound ABT-737 both in vitro and in vivo, in a xenotransplant mouse model of leukemia. The authors therefore conclude that fatty acid oxidation is essential for human leukemic cell survival and suggest that inhibitors of fatty acid oxidation might provide a new approach to treating leukemias.

TITLE: Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Michael Andreeff
University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 792-7260; Fax: (713) 794-4747; E-mail: mandreef@mdanderson.org.

Heinrich Taegtmeyer
University of Texas Houston Medical School, Houston, Texas, USA.
Phone: (713) 500-6569; Fax: (713) 500-0637; E-mail: Heinrich.Taegtmeyer@uth.tmc.edu.

View this article at: http://www.jci.org/articles/view/38942?key=30WZqTtau09dbeoGpc7g

HEMATOLOGY: Seeing is believing: visualizing blood clot formation inside blood vessels

Inappropriate activation of the blood clotting process inside a blood vessel results in the formation of a clot known as a thrombus. Thrombus formation in blood vessels in the brain and heart can lead to stroke and heart attack, respectively. Drugs that prevent blood clot formation reduce the risk of these conditions. A team of researchers, at The University of Tokyo, Japan, and the International Medical Center of Japan, has now identified a role for the protein Lnk in stabilizing thrombus formation in mice, suggesting that it might provide a therapeutic target to prevent thrombus formation.

The team, led by Koji Eto and Satoshi Takaki, studied mice lacking Lnk and by imaging the process of thrombus formation in blood vessels found that Lnk played an essential role in stabilizing developing thrombi in blood vessels. Further analysis revealed the key signaling pathway regulated by Lnk. As Lnk-deficient mice did not have a spontaneous bleeding problem, the authors suggest that targeting Lnk or other proteins in the pathway might provide therapeutic targets that provide less risk for bleeding than those targeted by conventional drugs.

TITLE: Lnk regulates integrin alpha-IIb-beta-3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo

Koji Eto
The University of Tokyo, Tokyo, Japan.
Phone: 81-3- 6409-2342; Fax: 81-3-6409-2343; E-mail: keto@ims.u-tokyo.ac.jp.

Satoshi Takaki
Research Institute, International Medical Center of Japan, Tokyo, Japan.
Phone: 81-3-3202-7181; Fax: 81-3-3208-5421; E-mail: stakaki@ri.imcj.go.jp.

View this article at: http://www.jci.org/articles/view/39503?key=2635c6ddf170bf9248c1

CARDIOLOGY: Role for immune cells known as mast cells in Afib

Atrial fibrillation (Afib) is the most common type of abnormal heart beat. It is characterized by scarring of the atrial region of the heart (a hallmark known as atrial fibrosis). Although atrial fibrosis is thought to perpetuate Afib, exactly how it develops has not been determined. Some research has suggested a role for inflammation in the process. Consistent with this, a team of researchers led by Issei Komuro, at Chiba University Graduate School of Medicine, Japan, has now identified a role for immune cells known as mast cells in inducing atrial fibrosis and Afib in a mouse model of the condition.

Initial analysis indicated that in the mouse model of Afib, mast cells accumulate and become activated in the atria of the hearts, which are characterized by atrial fibrosis and enhanced susceptibility to induction of Afib. Stabilizing mast cells and generating mast cell-deficient mice reduced fibrotic atrial remodeling and susceptibility to Afib induction. Mechanistic studies determined that atrium-infiltrating mast cells increased production of the molecule PDGF-A and that this promoted atrial fibrosis and susceptibility to Afib induction. The authors therefore suggest that targeting the mast cell/PDGF-A axis might provide a way to prevent Afib in stressed hearts, although they caution that further studies are needed to determine whether the same mechanism operates upstream of Afib in large animals.

TITLE: Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts

Issei Komuro
Chiba University Graduate School of Medicine, Chiba, Japan.
Phone: 81-43-226-2097; Fax: 81-43-226-2557; E-mail: komuro-tky@umin.ac.jp.

View this article at: http://www.jci.org/articles/view/39942?key=GNQgwryfI73eUjM7U35H

CARDIOLOGY: Most plentiful cell type in the heart -- the fibroblast -- contributes to heart failure

Fibroblasts are the most numerous cell type in the heart, but they are considered to have a less important role in heart failure than heart muscle cells. However, a team of researchers, at the University of Tokyo Graduate School of Medicine, Japan, has now determined that fibroblasts are essential for the response of the mouse heart to conditions that mimic high blood pressure, a response that if sustained ultimately leads to heart failure.

The team, led by Ryozo Nagai and Ichiro Manabe, showed that mice lacking Klf5 only in heart muscle cells mounted a normal response to conditions designed to mimic moderate increases in blood pressure, whereas mice lacking Klf5 only in fibroblasts in the heart failed to respond to such conditions. Surprisingly, mice lacking Klf5 only in fibroblasts in the heart developed more severe heart failure than normal mice and died when subjected to conditions designed to mimic extreme increases in blood pressure. The authors therefore conclude that fibroblasts in the heart have a central role in the response of the heart to changes in blood pressure and suggest that modulating their function might provide a way to treat individuals with heart failure.

TITLE: Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload

Ryozo Nagai
University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Phone: 81-3-5800-6526; Fax: 81-3-3818-6673; E-mail: nagai-tky@umin.ac.jp.

Ichiro Manabe
University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Phone: 81-3-5800-6526; Fax: 81-3-3818-6673; E-mail: manabe-tky@umin.ac.jp.

View this article at: http://www.jci.org/articles/view/40295?key=e0QAHF50fX03CYWfBarV

JCI Journals

Related Blood Pressure Articles from Brightsurf:

Children who take steroids at increased risk for diabetes, high blood pressure, blood clots
Children who take oral steroids to treat asthma or autoimmune diseases have an increased risk of diabetes, high blood pressure, and blood clots, according to Rutgers researchers.

High blood pressure treatment linked to less risk for drop in blood pressure upon standing
Treatment to lower blood pressure did not increase and may decrease the risk of extreme drops in blood pressure upon standing from a sitting position.

Changes in blood pressure control over 2 decades among US adults with high blood pressure
National survey data were used to examine how blood pressure control changed overall among U.S. adults with high blood pressure between 1999-2000 and 2017-2018 and by age, race, insurance type and access to health care.

Transient increase in blood pressure promotes some blood vessel growth
Blood vessels are the body's transportation system, carrying oxygen and nutrients to cells and whisking away waste.

Effect of reducing blood pressure medications on blood pressure control in older adults
Whether the amount of blood pressure medications taken by older adults could be reduced safely and without a significant change in short-term blood pressure control was the objective of this randomized clinical trial that included 534 adults 80 and older.

Brain blood flow sensor discovery could aid treatments for high blood pressure & dementia
A study led by researchers at UCL has discovered the mechanism that allows the brain to monitor its own blood supply, a finding in rats which may help to find new treatments for human conditions including hypertension (high blood pressure) and dementia.

Here's something that will raise your blood pressure
The apelin receptor (APJ) has been presumed to play an important role in the contraction of blood vessels involved in blood pressure regulation.

New strategy for treating high blood pressure
The key to treating blood pressure might lie in people who are 'resistant' to developing high blood pressure even when they eat high salt diets, shows new research published today in Experimental Physiology.

Arm cuff blood pressure measurements may fall short for predicting heart disease risk in some people with resistant high blood pressure
A measurement of central blood pressure in people with difficult-to-treat high blood pressure could help reduce risk of heart disease better than traditional arm cuff readings for some patients, according to preliminary research presented at the American Heart Association's Hypertension 2019 Scientific Sessions.

Heating pads may lower blood pressure in people with high blood pressure when lying down
In people with supine hypertension due to autonomic failure, a condition that increases blood pressure when lying down, overnight heat therapy significantly decreased systolic blood pressure compared to a placebo.

Read More: Blood Pressure News and Blood Pressure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.