Using a molecular switch to turn on cancer vaccines
The immune system is capable of recognizing tumor growth, and naturally mounts an anti-cancer defense. Dendritic cells (DCs) can take up tumor-derived molecules (antigens) and present them to T cells, and those "primed" T cells are then able to recognize and kill tumor cells. In recent years, researchers have attempted to capitalize upon these natural immune responses to develop new therapies- namely, by generating a pool of tumor antigen-pulsed DCs that might be used as vaccines to augment the T-cell responses of cancer patients. In clinical trials, these DC vaccines have had limited success, in part because the protocols to generate mature and active DCs in vitro are imperfect. Specifically, generation of mature DCs requires activation of Toll-Like receptors (TLRs), usually achieved by administration of lipopolysaccharide, which can cause toxic shock in humans and can promote apoptosis.
In this paper, David Spencer and colleagues, of Baylor University in Houston, Texas, addressed this problem by looking to the adaptor molecule downstream of the TLR, MyD88. They engineered a form of MyD88 that could induce downstream signaling in response to a drug, and expressed this inducible MyD88 (iMyD88) in DCs. Further, the researchers combined iMyD88 with a second pathway required for optimal activation of DCs- CD40 signaling- so that they could control both pathways with administration of a single drug. This combination improved DC-mediated tumor antigen-specific T cell responses in mouse cancer models and T cell responses to human tumor antigens. The researchers hope that this "switch" might be broadly applicable to the design of DC vaccines.
A composite MyD88/CD40 "switch" synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy
Baylor College of Medicine, Houston, TX, USA
Phone: 713-798-6475; Fax: 713-798-3033; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/44327?key=56347f1f6448c0426b53
Tie-ing up loose ends: new hope for atherosclerosis therapy?
Atherosclerosis is a buildup of fatty deposits in the walls of blood vessels that can predispose patients to heart attacks. Notably, these deposits most often form at locations within the vascular system where vessel branching occurs and blood flow may be disturbed. This disturbed blood flow increases the amount of shear stress exerted on the underlying endothelial cells; in response to that stress, the endothelium activates a number of proteins, including the tyrosine kinase Tie1. Overexpression of Tie1 is known to lead to increased levels of inflammatory markers, suggesting that Tie1 mediates the pro-inflammatory response to shear stress.
In new research, H. Scott Baldwin and colleagues, of Vanderbilt University in Nashville, Tennessee, investigated the role of Tie1 in a mouse model of atherosclerosis, and found that reduction of Tie1 levels attenuated the development of lesions. In addition, genetic deletion of Tie1 increased the expression of endothelial nitric oxide synthase, which is known to be protective of blood vessel integrity. The researchers believe that these findings highlight Tie1 as a potential new target for the development of atherosclerosis therapy.
Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stressspecific manner
Kel Vin Woo
Vanderbilt University Medical Center, Nashville, TN, USA
Phone: 615-351-6342; Fax: 615-322-6541; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/42040?key=cc0c8d7b85909aaf4ede
Using oncolytic viruses to put a Chk on cancer growth
In order to proliferate rapidly, cancer cells dysregulate the so-called cell cycle checkpoints that control cell division. In so doing, the integrity of the genome can be compromised, leading to aberrant DNA replication, double strand breaks, and other forms of DNA damage. Cells respond to this damage in part by upregulating Checkpoint Kinase 1 (Chk1), which in turn acts to inhibit cell division.
Oncolytic viruses preferentially infect and destroy tumor cells; considerable research has been aimed at engineering and optimizing these for cancer therapy. In this paper, Iain A. McNeish and colleagues, at the Queen Mary University of London, UK, found that sensitivity to oncolytic virus infection in ovarian cancer cells correlated with the extent of cell cycle dysregulation and DNA damage. They further demonstrated that inhibiting Chk1 increased the level of DNA damage following viral infection in cancer cells, and increased the ability of the virus to kill cancer cells. The researchers hope that their findings might translate into clinical medicine, and suggest that combining oncolytic viruses- already in clinical trials- with inhibition of Chk1 might be a viable strategy in cancer treatment.
Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells
Barts and The London School of Medicine, LONDON, GBR
Phone: +44 20 7882 3840; Fax: +44 20 7882 3884; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/43976?key=7cb739dff1bcf0ec7cbe
IL-2 alleviates the sting of the WASp
Wiskott-Aldrich syndrome (WAS) is an immunodeficiency syndrome marked by susceptibility to infection, bleeding, and dermatitis. The causative gene encodes for WAS protein (WASp), which is expressed in hematopoietic cells and is known to be involved in controlling the actin cytoskeleton. WAS patients are susceptible to blood cancers and to infection with herpesviruses; both of these features suggest that the Natural Killer (NK) cells of the immune system may be dysfunctional in this disease. However, it has previously been shown that when NK cells are isolated from WAS patients and put into culture, they regain their cytotoxicity.
In this paper, Jordan Orange, Rahul Pandey and their team at the Children's Hospital of Philadelphia and the University of Pennsylvania describe that a molecule in the culture medium called IL-2 is responsible for restoring the cytotoxicity of NK cells from WAS patients. They found that IL-2 induces the expression of a protein related to WASp called WAVE2, which can function in the absence of WASp to control cytoskeletal changes. Importantly, the researchers found that administration of IL-2 improved NK cell function in a WAS patient, suggesting that this molecule might be a viable therapeutic for WAS patients.
IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function
University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Phone: 267-426-5622; Fax: 267-426-5727; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/44862?key=f589aa119f7538b8b7b5
Clustering gene expression changes reveals pathways toward glaucoma prevention
Glaucoma is the second-most common cause of blindness in the US, and occurs due to loss of retinal ganglion cells and degeneration of the optic nerve. Although it is known that high levels of pressure within the eye predispose individuals to the development of glaucoma, the molecular mechanisms involved are poorly defined.
In new research from the Jackson Laboratory in Bar Harbor, Maine, Simon John and colleagues analyzed gene expression patterns in the retina and optic nerves of mice that develop age-related glaucoma. Using a method that involved the clustering of samples that showed similarity in expression profiles, the researchers were able to identify molecular signatures of early events in glaucoma progression- events that were detectable before there was morphological evidence of damage. Activation of part of the innate immune system called the complement cascade, and upregulation of endothelin 2- a protein that can increase blood pressure- were among these early changes. Notably, the researchers found that genetically and pharmacologically interfering with these changes protected mice from developing glaucoma. The researchers believe that they have identified pathways that might be targeted in the development of new glaucoma therapeutics, and hope that their method of clustered gene expression analysis will be useful in uncovering the early molecular events that underlie other diseases.
Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma
The Jacson Laboratory, Bar Harbor, Maine, USA
Phone: +1 207 288 6475; Fax: ; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/44646?key=c20d6c7052869a8b5a9a
A new target for chronic pain therapy
Although the neural pathways and molecules that transmit pain signals have been studied for decades, the molecular mechanisms that result in chronic pain are incompletely understood. AMPA receptors, which respond to the neurotransmitter glutamate, are thought to be involved in the pain-sensing pathway. However, AMPA receptors are multi-protein complexes, and the effect of signaling through them depends on the inclusion or exclusion of particular subunits.
In this paper, Rohini Kuner and his team at the University of Heidelberg, in Germany investigated the role of AMPA receptor subunits in chronic pain by genetically deleting them in specific areas of the brains of mice. Their results reveal that one of these subunits, called GluA1, is critically important in the hyperexcitability state that occurs in neurons during chronic pain, suggesting that this might be a novel target for the development of pain therapeutics.
Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice
University of Heidelberg, Heidelberg, DEU
Phone: 49 6221 54 8289; Fax: ; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/44911?key=4f9eac3bca23b948b3ef
Hope for a sticky situation in sickle cell disease
Sickle Cell Disease (SCD) is a genetic form of anemia that results from mutations to the β globin gene. SCD patients are often treated with repeated blood transfusions, but this can result in immunological responses called hemolytic transfusion reactions (HTR). HTR can induce vaso-occlusion (VOC), where the misshapen red blood cells characteristic of SCD lodge in capillaries and block blood flow, but the mechanism that explains this connection has not been established.
In new research, Paul Frenette and his team at Albert Einstein College of Medicine in the Bronx, New York induced HTR in a mouse model of SCD, and analyzed the effect on levels of inflammatory molecules in the blood. One such molecule, called CXCL1, was dramatically elevated after HTR, and the group found that injecting CXCL1 into SCD mice was sufficient to induce VOC. The researchers believe that this occurs because CXCL1 attracts white blood cells to the sickle-shaped red blood cells, which then block blood flow through small vessels. The researchers hope that their results will benefit SCD patients, as drugs that inhibit CXLC1 might prevent the development of this serious reaction to transfusion.
CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions
Albert Einstein College of Medicine, New York, NY, USA
Phone: 718.678.1255; Fax: ; E-mail: firstname.lastname@example.org
View this article at: http://www.jci.org/articles/view/45336?key=bcb7b3899e959a577bed
New insight into the pathology of ulcerative colitis
Ulcerative colitis (UC) is a form of inflammatory bowel disease related to interaction between the bacteria of the colon and immune cells. In the healthy intestine, bacteria are protected from immune attack by the epithelium and two layers of mucus. The mucus is made up primarily of mucin proteins that are glycosylated, meaning that have special sugar molecules called O-glycans attached. The synthesis of these glycoproteins is complex and highly regulated. UC patients have a deterioration of the mucus layer and impaired glycosylation in the distal colon, where the inflammation is localized.
In this paper, Lijun Xia and colleagues, at the University of Oklahoma Health Sciences Center, derived mice that were unable to produce O-glycans in the intestine. These mice spontaneously developed colitis, suggesting that proper glycosylation of mucin proteins is required to protect the epithelium. The researchers also demonstrated that some human UC patients carry a mutation in an enzyme required for production of glycosylated proteins. Xia and his team believe that these findings help explain the mechanism of pathogenesis in this mysterious disease.
Loss of intestinal core 1derived O-glycans causes spontaneous colitis in mice
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Phone: 405-271-7892; Fax: 405-271-3137; E-mail: email@example.com
View this article at: http://www.jci.org/articles/view/45538?key=98950db1fa671a24687c
|Contact: Kathryn Claiborn|
Journal of Clinical Investigation