JCI table of contents, March 16, 2006EDITOR'S PICK
Combining multiple treatments improves multiple sclerosis therapy
Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) in which white blood cells known as lymphocytes attack the myelin insulation on nerves in the spinal cord and brain. Glatiramer acetate (GA) is a drug currently approved for MS treatment, but new therapies are needed to improve effectiveness and reduce side effects. Now, in a study appearing online on March 16 in advance of print publication in the April issue of the Journal of Clinical Investigation, Scott S. Zamvil and colleagues at the University of California, San Francisco, show that treating MS with combinations of immune modulating drugs can greatly reduce MS disease. The researchers treated the "EAE mouse" model of MS with GA in combination with atorvastatin (Lipitor), a cholesterol-lowering drug shown to improve MS symptoms in clinical trials. Compared to EAE animals treated with either drug alone (which had no effect on established MS), EAE mice receiving the combination therapy demonstrated a significant prevention and reversal of clinical MS severity, with less myelin loss, CNS inflammation, and MS disease incidence. The authors then treated isolated inflammatory cells called macrophages with these drugs and found that the combination therapy mediated its effects by promoting the secretion of the anti-inflammatory molecule IL-10 and suppressed production of the proinflammatory molecules IL-12 and TNF-alpha. Importantly, the combined drug therapy utilized doses of each drug that were lower than the doses used in the single-drug treatment method. These data suggest that combined delivery of drugs that act through different mechanisms may enhance their therapeutic efficacy in the treatment of MS and reduce the adverse side effects that result from treatment strategies that use the single-drug delivery approach.
TITLE: Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity
Scott S. Zamvil
University of California, San Francisco, California, USA
Phone: (415) 502-7395; Fax: (415) 502-8512; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25805
The role of the intestine in HDL cholesterol production and heart disease risk
Low levels of the "good" cholesterol known as HDL (high-density lipoprotein) cholesterol in the blood are a risk factor for heart disease. Now, in a study appearing online on March 16 in advance of print publication in the April issue of the Journal of Clinical Investigation, Michael R. Hayden and colleagues at the Centre for Molecular Medicine and Therapeutics in Vancouver report that not only is the liver important in the production of HDL, but the intestine is too. The researchers created genetically modified mice in which a molecule involved in HDL formation, called ABCA1, was specifically deleted from the intestine. These intestine-specific ABCA1 "knockout mice" had a 30% reduction in HDL levels in blood, compared to normal mice, demonstrating that the intestine is a critical site of HDL synthesis. The researchers then studied the metabolic effects of loss of intestinal ABCA1 by feeding the mice radioactive cholesterol and measuring the distribution of cholesterol metabolites two hours later. Intestine-specific ABCA1 knockout mice demonstrated reduced levels of radioactive cholesterol in blood and liver, with increased retention of cholesterol in the intestine. These tracer studies suggest that uptake of cholesterol from the intestine is not affected in ABCA1 knockout mice, but that transport of absorbed cholesterol into the blood is dramatically impaired. Together these data demonstrate that intestinal ABCA1 is a major player in the production of HDL, as was previously shown for the liver, and suggest that therapies targeting intestinal ABCA1 production may increase HDL levels in individuals at risk for heart disease.
TITLE: Intestinal ABCA1 directly contributes to HDL biogenesis in vivo
Michael R. Hayden
Centre for Molecular Medicine and Therapeutics, Vancouver, Canada
Phone: (604) 875-3535; Fax: (604) 875-3819; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=27352
The fungus among us: the surprising anti-inflammatory effects of yeast
Exposure to a pathogen such as a virus, fungus, or bacterium normally activates immune cells called dendritic cells (DCs) and macrophages which recognize, kill, and digest the pathogen using molecules called TLR2 and dectin-1. Now, in a study appearing online on March 16 in advance of print publication in the April issue of the Journal of Clinical Investigation, researcher Bali Pulendran and colleagues at Emory University in Atlanta show that zymosan, a component of the cell wall of yeast, actually acts to suppress the immune response. The researchers stimulated human and mouse DCs with either a bacterial sugar called lipopolysaccharide (LPS) or with yeast zymosan for 24 hours, and found that zymosan mediated the expression of anti-inflammatory molecules called TGF-beta and IL-10, and caused immune cells called T cells to become unresponsive. The induction of IL-10 required dectin-1. The researchers next found that inhibiting a cell signaling pathway called ERK MAPK using a drug called UO126 blocked IL-10 induction by zymosan. Most importantly, the researchers injected mice with zymosan, which increased IL-10 production, impaired T cell proliferation, and elevated production by macrophages of TGF-beta. These results suggest that strategies targeting TLR2 and dectin-1 in a manner similar to zymosan may be used to dampen the immune response in conditions such as allergy and organ transplantation, which are characterized by an overactive immune response.
TITLE: Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen presenting cells and immunological tolerance
Emory University, Atlanta, Georgia, USA
Phone: (404) 727-8945; Fax: (404) 727-8199; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=27203
A hairy solution to the problem of inflammation and allergy
During the immune response T cells attack foreign antigens directly. However, a specialized subset of T cells, known as regulatory T cells (Tregs) helps to ensure that the T cell response doesn't get out of control and lead to autoimmune disorders. Just how Tregs mediate this control has not been fully elucidated. Experimental research shows that repeated exposure of mice to a single allergen induces a biological state called "antigen-induced tolerance", in which mice become resistant to inflammation or allergy from that allergen. Now, in a study appearing online on March 16 in advance of print publication in the April issue of the Journal of Clinical Investigation, Anuradha Ray and colleagues at the University of Pittsburgh School of Medicine show that a protein known as TGF-beta on the surface of Treg cells stimulates a pathway called Notch-HES1 (hairy and enhancer of split 1) in target T cells. The researchers collected T cells from mice that had inhaled egg albumin protein, and found that the cells from mice that developed tolerance expressed high levels of the Notch protein on their surfaces, and that Notch induction occurred in T cells having a cell-surface TGF-beta receptor. Importantly, the soluble form of TGF-beta could not induce this response, suggesting a specific function for the membrane-bound TGF-beta molecule and for direct cell-cell interactions. Next the researchers treated T cells with an antibody that blocks the action of Notch and its target HES1, which resulted in an impaired ability of TGF-beta to activate Notch and suppress the immune response. These studies demonstrate that coordination of membrane-bound TGF-beta expression on Treg cells, and activation of Notch-HES1 on target T cells can regulate the development of tolerance following repeated allergen exposures.
TITLE: Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Phone: (412) 802-3191; Fax: (412) 692-2260; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=26490
It's not stress, it's bacteria: another source of stomach ulcers
Helicobacter pylori is a bacterium that infects over 50% of the human population, and is associated with various gastric diseases, including ulcers. H. pylori infection leads to recruitment of diverse immune cells such as leukocytes, monocytes, macrophages, and lymphocytes to the gastric mucosa, but the precise mechanisms driving this recruitment are unclear. One H. pylori protein that may mediate the inflammation is the H. pylori neutrophil-activating protein (HP-NAP). In a study appearing online on March 16 in advance of print publication in the April issue of the Journal of Clinical Investigation, Marina de Bernard and colleagues at the Venetian Institute of Molecular Medicine in Italy grew mouse monocytes and neutrophils in the presence of HP-NAP and found that HP-NAP induced a dose-dependent expression of proinflammatory proteins called interleukin-12 (IL-12) and IL-23. Treatment of cells with mutant H. pylori bacteria that did not have HP-NAP failed to induce the interleukins, demonstrating the specific role of HP-NAP in inflammation. The authors then treated T cells from human donors sensitive to allergen with HP-NAP and found a significant increase in production of a "Th1" molecule called TNF-gamma and reduced numbers of cells producing the "Th2" molecule called IL-4, suggesting that HP-NAP induces a shift in the development of allergen-specific T cells toward Th1. These studies suggest that HP-NAP is a potent immune modulator that not only alters expression of interleukins, but also mediates a transition in the development of immune T cell types.
TITLE: The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses
Marina de Bernard
Venetian Institute of Molecular Medicine, Padua, Italy
Phone: 39049-7923-223; Fax: 39049-7923-250; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=27177
Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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