JCI table of contents, March 1 2004


Vaccine nips breast cancer in the bud

Preneoplastic lesions, detectable by breast cancer screening, are made up of altered cells that are not themselves cancerous but indicate an increased likelihood that a benign or cancerous tumor may subsequently form. In the March 1 issue of the Journal of Clinical Investigation, Federica Cavallo and colleagues from the University of Turin, Italy, evaluated vaccine strategies for treating neoplastic lesions. The authors designed a combined approach consisting of a primary vaccination with plasmids encoding portions of the oncogenic protein rp185neu and a booster vaccination one week later with cells expressing this protein and also engineered to release IFN-gamma. Of mice that received the combined vaccine, 48% remained tumor free for the duration of the study, a significant improvement over untreated mice and mice receiving only the primary vaccine. Both morphologic analysis of the lesions and microarray analysis of gene expression in parallel revealed that the immune reaction halted carcinogenesis and reverted neoplastic lesions to an early stage. This study highlights the potential of a combinatorial approach to vaccination for the prevention and suppression of neoplastic lesions.

TITLE: Concordant morphologic and gene expression data show that a vaccine halts HER-2/neu preneoplastic lesions

Federica Cavallo
University of Turin, Orbassano, Italy.
Phone: 39 –11-670-8119
Fax: 39-11-236-8117
E-mail: federica.cavallo@unito.it

View the PDF of this article at: https://www.the-jci.org/press/19850.pdf


Gene therapy for a broken heart

Despite significant ad-vances in the treatment of cardiac disease, chronic heart failure remains a leading cause of morbidity and mortality. Gene therapy represents a potential new strategy for the treatment of cardiac dysfunction. In the March 1 issue of the Journal of Clinical Investigation John Ross, Jr., and colleagues from the University of California, San Diego, report that gene delivery to express a modified form of the phospholamban protein, S16EPLN, to chronically failing rat hearts after a heart attack exerted many beneficial effects. The report suggests that S16EPLN gene delivery shows promise as a novel strategy for the treatment of chronic heart failure.

The presence of S16EPLN upregulated the activity of the enzyme SERCA2 in transduced cells and compensated for defects in calcium uptake during heart failure. Echocardiographic and hemodynamic measurements showed improvements in global heart function and contractility in rats that received S16EPLN treatment. In addition, the formation of scar tissue was suppressed in these animals. Although further long-term studies are necessary to clarify the effects of modifying phospholamban on arrhythmias, gene transfer of S16EPLN shows promise as a novel therapeutic strategy.

TITLE: Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats

John Ross Jr.
University of California, San Diego, La Jolla, California, USA.
Phone: 858-822-2267
Fax: 858-534-1626
E-mail: jross@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/press/18716.pdf


Viral immunosuppression: not just a game of hide and go seek

When facing an immune response, viruses can either attempt to elude them or confront them. Dendritic cells (DCs) play a pivotal role in bringing forth the immune response by stimulating T cells. In the March 1 issue of the Journal of Clinical Investigation, Noemi Sevilla and colleagues from the Scripps Research Institute demonstrate that a lymphocytic choriomeningitis virus (LCMV) strain can suppress immune responses by targeting both the development and activation of DCs. Ironically, the release of type I interferon in response to LCMV infection, which normally contributes to the immune response, actually helped block DC development. This new mechanism provides us with a new perspective regarding therapeutic strategies associated with immunosuppression.

In an accompanying commentary, Marco Colonna from Washington University discusses the paradoxical role of type 1 interferon in the immune suppression following LCMV infection and the novel way in which this virus not only eludes specific immune surveillance, but actively suppresses the immune response.

TITLE: Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion

Noemi Sevilla
Universidad Autónoma de Madrid, Madrid, Spain.
Phone: 34-91-397-8477
Fax: 34-91-397-4799
E-mail: nsevilla@cbm.uam.eds

View the PDF of this article at: https://www.the-jci.org/press/20243.pdf

ACCOMPANYING COMMENTARY: Viral immunosuppression: disabling the guards

Marco Colonna
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314-362-0367
Fax: 314-362-4096
E-mail: mcolonna@pathology.wustl.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21166.pdf


Boosting antitumor immunity

Despite the initial excitement over cancer vaccines, the clinical effectiveness of immunotherapy has been disappointing. It is believed that defective presentation of tumor antigens by dendritic cells (DCs) to T cells and the subsequent defective stimulation of the immune response, may be the cause. In the March 1 issue of the Journal of Clinical Investigation, Edgar Engleman and colleagues from Stanford University report that the number and activation state of intratumoral DCs are critical factors in the host immune response to tumors. They also describe a method for manipulating both the number of local DCs and the local environment, that resulted in effective tumor immunity in mice. The expression of chemokine ligand 20 (CCL20) in the tumor site attracted large numbers of DCs into the tumor mass and led to complete tumor regression.

In an accompanying commentary, Howard Kaufman and Mary Disis from Columbia University and the University of Washington discuss the mechanisms involved in manipulating the local tumor environment in order to promote DC activation and enhance the host immune response. They state "this represents an exciting new strategy for the treatment of human cancer and warrants renewed interest in clinical trials to determine the full potential for these approaches in cancer patients."

TITLE: Induction of potent antitumor immunity by in situ targeting of intratumoral DCs

Edgar Engleman
Stanford University School of Medicine, Palo Alto, California, USA.
Phone: 650-723-7960
Fax: 650-725-0592
E-mail: edengleman@stanford.edu

View the PDF of this article at: https://www.the-jci.org/press/19762.pdf

ACCOMPANYING COMMENTARY: Immune system versus tumor: shifting the balance in favor of DCs and effective immunity

Howard Kaufman
Columbia University Medical Center, Ithaca, New York, USA.
Phone: 212-342-6042
Fax: 212-342-0234
E-mail: hlk2003@columbia.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21148.pdf


B7-H1 loves me, loves me not

B7-H1 is expressed in many tissue types and has been shown to inhibit the T cell response. This observation led Yang-Xin Fu, Maria-Luisa Alegre, and colleagues from the University of Chicago to investigate the ability of B7-H1 to inhibit the T cell response in order to generate immune tolerance during transplants and in the treatment of autoimmune diseases such as diabetes. In the March 1 issue of the Journal of Clinical Investigation they report that B7-H1 actually promotes rather than inhibits T cell–mediated immune responses, and can direct positive or negative signals depending on its specific cellular setting.

The authors generated transgenic mice expressing B7-H1 in pancreatic islet_b cells to study the immunomodulatory effects of local B7-H1 expression in nonlymphoid tissues. When B7-H1–expressing islets were transplanted, mice had accelerated graft rejection, signifying an upregulation of the immune response. Moreover, mice developed T cell–dependent autoimmune diabetes, supporting the notion that B7-H1 can promote rather than inhibit T cell–mediated responses. These findings lead us to question the development of B7-H1–targeted immune response strategies.

TITLE: Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection

Yang-Xin Fu
The University of Chicago, Chicago, Illinois, USA.
Phone: 773-702-0929
Fax: 773-834-8940
E-mail: yfu@midway.uchicago.edu

View the PDF of this article at: https://www.the-jci.org/press/19210.pdf


Cartilage reconstruction for ailing knees

Nearly half of the elderly population suffers from osteoarthritis, a degenerative joint disorder characterized by degradation of articular cartilage. Because this disorder is so widespread, finding a regenerative source of cartilaginous tissue would prove invaluable to the orthopedic field. In the March 1 issue of the Journal of Clinical Investigation, in an effort to regenerate cartilage, Sakae Tanaka and colleagues from the University of Tokyo determined the signaling pathways involved in cartilage-specific gene expression in synovial fibroblasts that line the surfaces of joints.

The authors were able to analyze the signaling cascades involved in the differentiation of synovial fibroblast cells into chondrocytes – the cells responsible for secreting cartilage material – by expressing constitutively active forms of activin receptor–like kinases (ALK3CA, ALK5CA, and ALK6CA) in synovial fibroblasts. Transplantation of these cells into mice induced differentiation and cartilage matrix formation. Further experiments elucidated critical roles for both the Smad and p38 downstream signaling pathways in chrondrogenic differentiation of synovial fibroblasts, whereby balance of these two signals will be critical in engineering chondrocytes for cartilage reconstruction.

TITLE: Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts

Sakae Tanaka
The University of Tokyo, Tokyo, Japan.
Phone: 81-3-3815-5411 ext. 33376
Fax: 81-3-3818-4082
E-mail: TANAKAS-ORT@h.u-tokyo.ac.jp

View the PDF of this article at: https://www.the-jci.org/press/19899.pdf


Langerhans cells: I've got you under my skin

All dendritic cells (DCs) share the capacity to present foreign antigens to T cells. Langerhans cells (LCs) are a special subset of DCs that reside in the skin – specifically the epidermis. CD1a and langerin are specific markers expressed by LCs that distinguish them from other DCs, however their immunological functions have remained mostly unknown. In the March 1 issue of the Journal of Clinical Investigation, Robert Modlin and colleagues from the University of California, Los Angeles, demonstrate that LCs are able to present non-peptide antigens of Mycobacterium leprae – the bacterium that causes leprosy – to T cells and that this presentation is associated with CD1a and dependent on the presence of langerin, which facilitates uptake of bacterial fragments and perhaps their delivery to a specialized subcellular compartment.

In an accompanying commentary, Akira Takashima from the University of Texas discusses the orchestration of lipid antigen presentation by LCs.

TITLE: Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells

Robert L. Modlin
University of California Los Angeles, Los Angeles, California, USA.
Phone: 310-825-5420
Fax: 310-206-9878
E-mail: rmodlin@mednet.ucla.edu

View the PDF of this article at: https://www.the-jci.org/press/19655.pdf

ACCOMPANYING COMMENTARY: CD1a and langerin: acting as more than Langerhans cell markers

Akira Takashima
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214-648-3419
Fax: 214-648-3472
E-mail: akira.takashima@utsouthwestern.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21140.pdf


TGF-b1 is the cause of bone marrow fibrosis in hairy cell leukemia

In the March 1 issue of the Journal of Clinical Investigation Josef Schwarzmeier and colleagues from the University of Vienna provide an explanation for the presence of extensive bone marrow fibrosis in hairy cell leukemia (HCL) – a distinctive feature of this malignancy. The authors found that TGF-beta1 was present in high concentrations in bone marrow, serum, and plasma of HCL patients in comparison with healthy donors, and active TGF-beta1 significantly correlated with the extent of bone marrow fibrosis and infiltration with leukemic cells. The authors went on to demonstrate that TGF-beta1 significantly enhanced the production and deposition of collagen fibers associated with the fibrotic process. Finally, this fibrogenic activity could be blocked by neutralizing anti– TGF-beta1 antibodies confirming that TGF-beta1 is directly involved in bone marrow fibrosis in HCL. The report also suggests that the levels of circulating TGF-beta1 should be considered as a non-invasive indicator for the ongoing fibrogenic processes of the bone marrow and the extent of marrow infiltration with leukemic cells.

TITLE: TGF-beta1 induces bone marrow reticulin fibrosis in hairy cell leukemia

Josef Schwarzmeier
Vienna University, Vienna, Austria.
Phone: 43-40400-5459
Fax: 43-40400-4461
E-mail: Josef.schwarzmeier@akh-wien.ac.at

View the PDF of this article at: https://www.the-jci.org/press/19540.pdf


Understanding the cause of vascular spasm and cardiomyopathy

Evidence suggests that mutations in diverse components of the dystrophin-sarcoglycan complex can cause cardiomyopathy. Previous studies have shown that delta-sarcoglycan is expressed in both heart cells and smooth muscle cells (SMCs) and has raised the question as to whether it is the absence of this protein in heart cells or SMCs that can cause cardiomyopathy. Previous studies have shown that there is vascular spasm, which can acutely reduce the supply of blood and oxygen reaching tissues, in mice lacking delta-sarcoglycan in SMCs. In the March 1 issue of the Journal of Clinical Investigation, Elizabeth McNally and colleagues from the University of Chicago use transgenic mice to demonstrate that the restoration of the sarcoglycan complex in heart cells was sufficient to correct the cardiac degeneration associated with the absence of sarcoglycan, and also eliminated coronary artery vascular spasm. Furthermore, restoration of SMC sarcoglycan in sacroglycan-null mice did not effect this rescue. The authors conclude that, in contrast to previous suggestions, cardiomyopathy and associated vascular spasm in delta-sarcoglycan–knockout mice arises from a primary requirement for this protein in heart cells rather than in SMCs.

TITLE: Smooth muscle cell–extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy

Elizabeth McNally
University of Chicago, Chicago, Illinois, USA.
Phone: 773-702-2672
Fax: 773-702-2681
E-mail: emcnally@medicine.bsd.uchicago.edu

View the PDF of this article at: https://www.the-jci.org/press/20410.pdf


Increased CD36 levels result in defective macrophage insulin signaling and promote atherosclerosis

Individuals with diabetes show an increased susceptibility for the development of accelerated atherosclerosis, however the root causes of this progression are not well understood. Some evidence suggests that insulin resistance, commonly seen in overweight individuals, is an important cause of both diabetes and increased atherosclerosis risk. In the March 1 issue of the Journal of Clinical Investigation, Chien-Ping Liang and colleagues from Columbia University report that macrophages from obese mice are insulin resistant, have enhanced levels of CD36, and an increased capacity to bind and take up oxidized low-density lipoprotein (LDL) – a carrier for fats and cholesterol in the bloodstream that is considered a risk factor for coronary artery disease. Their data indicate that defective insulin signaling is the cause for increased CD36 levels. The report suggests a new mechanism that predisposes to the formation of fat laden macrophages in insulin-resistant states.

TITLE: Increased CD36 protein as a response to defective insulin signaling in macrophages

Chien-Ping Liang
Columbia University School of Medicine, New York, New York, USA.
Phone: 212-305-4899
Fax: 212-305-5052
E-mail: CL534@columbia.edu

View the PDF of this article at: https://www.the-jci.org/press/19528.pdf


Researchers uncover physiological significance of two proteins, I kappa B alpha and I kappa B beta, previously thought to possess redundant properties in liver injury

The NF-kappa B family of proteins orchestrates cellular responses to injury by regulating immune function, inflammation, cell growth, and cell death. Induction of NF-kappa B is tightly controlled by two I kappa B proteins, I kappa B alpha and I kappa B beta, which prevent NF-kappa B from binding to DNA in the nucleus. Stimulation of NF-kappa B in response to injury involves activation of the I kappa B complex that phosphorylates both I kappa B alpha and I kappa B beta causes their degradation, thereby freeing NF-kappa B to move into the nucleus to bind DNA. Previous studies have uncovered divergent activities of I kappa B alpha and I kappa B beta which influence their ability to regulate NF-kappa B in the liver.

In their report in the March 1 issue of the Journal of Clinical Investigation, John Engelhardt and colleagues from the University of Iowa observed that mice in which I kappa B alpha has been replaced by I kappa B beta have identical levels of liver NF-kappa B activation in response to lipopolysaccharide-induced injury, while a significantly reduced level of liver NF-kappa B activation was observed in response to liver ischemia and reperfusion. The data suggest that while either I kappa B alpha and I kappa B beta can mediate responses to lipopolysaccharide, I kappa B alpha is essential for mediating liver ischemia/reperfusion injuries.

Further studies suggested that the specificity of I kappa B alpha, but not I kappa B beta, in the regulation of NF-kappa B induction during ischemia/reperfusion injury is due to the injury-context–specific activation of c-Src and subsequent phosphorylation of an I kappa B alpha tyrosine residue, Tyr42. While this signaling pathway was previously known, the authors have uncovered the pathway's physiological significance. The authors also suggest that down-regulation of I kappa B alpha expression following liver ischemia/reperfusion injury may be therapeutically beneficial.

TITLE: I kappa B alpha and I kappa B beta possess injury context–specific functions that uniquely influence hepatic NF-kappa B induction and inflammation

John F. Engelhardt
University of Iowa, Iowa City, Iowa, USA.
Phone: 319-335-7744
Fax: 319-335-6581
E-mail: john-engelhardt@uiowa.edu

View the PDF of this article at: https://www.the-jci.org/press/17337.pdf


Inactivating the fatty acid transport protein FATP1 prevents fat-induced insulin resistance

Insulin resistance in skeletal muscle plays a major role in the development of type 2 diabetes, yet the underlying factors causing insulin resistance remain unknown. Fatty acid transport protein (FATP1) is expressed in cells and tissues such as skeletal muscle, adipose tissue, and the heart, which have high levels of fatty acid uptake for metabolism and storage. To investigate the role of FATP1 in insulin resistance, Jason Kim and colleagues from Yale University examined the effect of a high-fat diet on insulin action in mice lacking FATP1. In the March 1 issue of the Journal of Clinical Investigation the authors report that mice lacking FATP1 that were fed a regular chow diet experienced no changes in whole-body adiposity or insulin sensitivity. FATP1-knockout mice fed a high-fat diet were actually protected from fat-induced insulin resistance and intramuscular fat accumulation. The data suggest that intramuscular fatty acid metabolites play an important role in causing insulin resistance and that FATP1 may be a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.

TITLE: Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle

Jason Kim
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-6716
Fax: 203-785-6753
E-mail: jason.k.kim@yale.edu

View the PDF of this article at: https://www.the-jci.org/press/18917.pdf


The anatomy of an arrhythmia

Computer simulations are potentially effective approaches to unraveling the causes of lethal heart rhythm disorders. In the March 1 issue of the Journal of Clinical Investigation, Alan Garfinkel and colleagues from the University of California, Los Angeles, describe an anatomically realistic computer model of the development of arrhythmia in the heart.

In an accompanying commentary, Robert Gilmour from Cornell University, discusses the known mechanisms underlying ventricular fibrillation and sudden cardiac death that may result from arrhythmia and how the evolution of computer models of the heart will help researchers answer important questions that remain about these conditions.

TITLE: A simulation study of the effects of cardiac anatomy in ventricular fibrillation

Alan Garfinkel
University of California Los Angeles, Los Angeles, California, USA.
Phone: 310-794-7214
Fax: 310-206-9133
E-mail: agarfinkel@mednet.ucla.edu

View the PDF of this article at: https://www.the-jci.org/press/17341.pdf

ACCOMPANYING COMMENTARY: The anatomy of an arrhythmia

Robert Gilmour
Cornell University, Ithaca, New York, USA.
Phone: 607-253-3856
Fax: 607-253-3851
E-mail: rfg2@cornell.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21223.pdf

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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