ONLINE FIRST ARTICLE
Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors
CONTACT:
Gabriele Bergers
UCSF San Francisco
Dep. of Neurosurgery
Preuss Laboratory HSE722
513 Parnassus Ave
San Francisco, CA 94143-0520
USA
Phone 1: 415-476-6786
Fax 1: 415-476-0388
E-mail: bergers@cgl.ucsf.edu
View the PDF of this article at: https://www.the-jci.org/press/17929.pdf
TABLE OF CONTENTS
The risks and benefits of accelerating suicide.
Failure to undergo activation-induced cell death is a major cause of autoimmune diseases, suggesting that enhancing a T cell's sensitivity to apoptosis might have therapeutic potential for the treatment of autoimmunity. Based on the fact that the PKC inhibitor Bis VIII can sensitize CD4+ T cells for death receptor–induced apoptosis, Thomas Brunner and colleagues analyzed the ability of Bis VIII to sensitize CD8+ T cells for accelerated suicide and the consequences of a CD8+ T cell–mediated response. Their findings (pages 1191–1199) – that Bis VIII is able to sensitize CD8+ cells but decreases the normal protective immune response – suggest that resistance to death receptor–mediated apoptosis is necessary for mounting an efficient immune response against life-threatening infections. Bis VIII–based therapies for autoimmune diseases, therefore, must be applied under well-controlled conditions to avoid immune deficiency against opportunistic viral or bacterial infections.
CONTACT:
Thomas Brunner
University of Bern, Institute of Pathology
Division of Immunopathology
PO Box 62
Murtenstrasse 31
Bern, NULL 3010
SWEDEN
Phone 1: 41-31-632-4971
Fax 1: 41-31-381-8764
E-mail: tbrunner@pathology.unibe.ch
View the PDF of this article at: https://www.the-jci.org/press/16344.pdf
Alterations in PDX1 levels affect islet survival.
PDX1 belongs to a family of homeobox genes that regulate initial pancreatic development and the lifelong maintenance of insulin-producing b cells. Human heterozygote carriers develop MODY4, a form of maturity-onset diabetes of the young, a monogenic form of type 2 diabetes characterized by early disease onset, autosomal-dominant inheritance, and defective insulin secretion. In studying Pdx1+/– mice, Kenneth Polonsky and colleagues found that Pdx1+/– islets and b cells were more susceptible to apoptosis at basal glucose concentrations when compared to controls (pages 1147–1160). They also observed early abnormalities in islet architecture in the Pdx1+/– mutants. The data suggest that increased apoptosis and abnormal regulation of islet number and b cell mass are key mechanisms by which partial PDX1 deficiency leads to defective insulin secretion and diabetes.
CONTACT:
Kenneth S. Polonsky
Department of Medicine,
Washington University School of Medicine, Box 8066,
St. Louis, Missouri 63110
USA.
Phone: 314-362-8061
Fax: 314-362-8015
E-mail: Polonsky@im.wustl.edu.
View the PDF of this article at: https://www.the-jci.org/press/16537.pdf
Modeling uveitis.
Intraocular inflammatory disease, or uveitis, appears to be due in large part to noninfectious, cell-mediated mechanisms. Experimental autoimmune uveitis (EAU) in animals has been a valuable tool for better understanding underlying mechanisms of this disorder and also has provided the possibility of evaluating new approaches to therapy. Both human uveitis and EAU are genetically controlled. Human autoimmune uveitis, in which patients exhibit immunological responses to retinal antigens, has been associated with HLA genes. As they report (pages 1171–1180), Rachel Caspi and colleagues have now succeeded in generating a "humanized" transgenic mouse model of EAU in which disease-relevant epitopes appear to be largely restricted by the human class II molecules. These mice offer a more relevant approximation of human uveitis and should facilitate the characterization of uveitogenic epitopes presented by different HLA class II types.
CONTACT:
Rachel Caspi
National Institute of Health
Laboratory of Immunology, NEI
10 Center Drive, 10/10N222
Bethesda, Maryland 20892-1857
USA
Phone 1: 301-435-4555
Fax 1: 301-480-6668
E-mail: rcaspi@helix.nih.gov
View the PDF of this article at: https://www.the-jci.org/press/15155.pdf
Factor H: protector of tissue integrity.
Factor H is a potent suppressor of the alternative complement pathway. As a complement regulator, Factor H maintains tissue integrity and possesses anti-inflammatory properties. Mutations in the gene encoding factor H have been found in individuals with hemolytic uremic syndrome. These patients have widespread microthrombi and reactive endothelial proliferation. As a consequence, they suffer from hemolytic anemia, thrombocytopenia, and acute renal failure. On pages 1181–1190, Peter Zipfel and colleagues describe the functional consequences of three-point mutations in the factor H gene associated with hemolytic uremic syndrome. The features of the defective protein help to explain progression of vascular damage in patients and underline a role for factor H in tissue integrity during thrombus formation.
CONTACT:
Peter Zipfel
Hans Knoell Institute for Natural Products Research
Department of Infection Biology
Beutenbergstrasse 11a
D-07745 Jena,
GERMANY
Phone 1: 49-3641-656900
Fax 1: 49-3641-656902
E-mail: zipfel@pmail.hki-jena.de
View the PDF of this article at: https://www.the-jci.org/press/16651.pdf
Cannabinoids and multiple sclerosis.
Previous in vitro studies have demonstrated the immunomodulatory effects of cannabinoids; however, little is known about their immunosuppressive properties in autoimmune diseases such as multiple sclerosis (MS). Using a mouse model of virus-induced chronic–progressive MS, Stephen Miller and J. Ludovic Croxford investigated the immunosuppressive potential of the cannabinoid receptor agonist R(+)WIN55,212 (pages 1231–1240). The authors demonstrated that R(+)WIN55,212, when given at the time of initial infection, can suppress the development of MS-like disease. When administered at the onset of symptoms or during established disease, R(+)WIN55,212 significantly inhibited levels of IL-1b, IL-6, TNF-a, and IFN-g, important inflammatory mediators in the induction and progression of autoimmune disease in a number of MS-like mouse models of disease and presumably in MS. The data suggest that the potent immunosuppressive properties of R(+)WIN55,212 or other cannabinoids may have therapeutic potential in halting disease progression in individuals with MS in addition to providing symptomatic relief of limb spasticity, tremor, and pain.
CONTACT:
Stephen D. Miller
Northwestern University Medical School
Department of Microbiology-Immunology
303 E. Chicago Ave.
Chicago, IL 60611
USA
Phone 1: 312-503-7674
Fax 1: 312-503-1154
E-mail: s-d-miller@northwestern.edu
View the PDF of this article at: https://www.the-jci.org/press/17652.pdf
CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes
CONTACT:
Markus F. Neurath
University of Mainz
Laboratory of Immunology
I. Medical Clinic
Langenbeckstrasse 1
55101 Mainz,
GERMANY
Phone 1: 49-613-117-2489
Fax 1: 49-613-117-5508
E-mail: neurath@1-med.klinik.uni-mainz.de
View the PDF of this article at: https://www.the-jci.org/press/16432.pdf
ACCOMPANYING COMMENTARY:
Azathioprine:Old drug, new actions
CONTACT:
Gary A. Koretzky
Abramson Family Cancer Research Institute
University of Pennsylvania School of Medicine, 415 BRB II/III
421 Curie Boulevard
Philadelphia, Pennsylvania 19104
USA.
Phone: 215-746-5522
Fax: 215-746-5525
Email: Koretzky@mail.med.upenn.edu.
View the PDF of this commentary at: https://www.the-jci.org/press/18384.pdf
Genetic Disruption of gamma-Melanocyte Stimulating Hormone Signaling Leads to Salt-Sensitive Hypertension in the Mouse
CONTACT:
Michael H. Humphreys
University of California, San Francisco
Box 1341
San Francisco, CA 94143
USA
Phone 1: 415-476-4104
Phone 2: 415-476-4638
Fax 1: 415-282-8182
E-mail: mhhsfgh@itsa.ucsf.edu
View the PDF of this article at: https://www.the-jci.org/press/16993.pdf
ACCOMPANYING COMMENTARY:
Salt-sensitive hypertension: If only it were as simple as rocket science
CONTACT:
Timothy L. Reudelhuber
Clinical Research Institute
110 Pine Avenue West
Montreal, Quebec H2W 1R7,
CANADA
Phone 1: 514-987-5716
Fax 1: 514-987-5717
E-mail: reudelt@ircm.qc.ca
View the PDF of this commentary at: https://www.the-jci.org/press/18397.pdf
Nonreduntant roles of antibody, cytokines and perforin for the immune eradication of established Her-2/neu carcinomas
CONTACT:
G. Forni
University of Turin
Dip. Sci. Clin. Biologiche
Ospedale San Luigi Gonzaga
Orbassano, 10043
ITALY
Phone 1: 39-011-670-8119
Fax 1: 39-011-903-8639
E-mail: guido.forni@unito.it
View the PDF of this article at: https://www.the-jci.org/press/17426.pdf
ACCOMPANYING COMMENTARY:
Coordinated tumor immunity
CONTACT:
Glenn Dranoff
Dana Farber Cancer Institute
44 Binney St. Dana 510E
Division of Hematologic Malignancies
Boston, MA 02115
USA
Phone 1: 617-632-5051
Fax 1: 617-632-5167
E-mail: glenn_dranoff@dfci.harvard.edu
View the PDF of this commentary at: https://www.the-jci.org/press/18359.pdf
Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in man
CONTACT:
Philip M. Murphy
NIH/NIAID
Laboratory of Host Defenses
Bldg. 10, Room 11N113
Bethesda, MD 20892
USA
Phone 1: 301-496-8616
Fax 1: 301-402-4369
E-mail: pmm@nih.gov
View the PDF of this article at: https://www.the-jci.org/press/16790.pdf
ACCOMPANYING COMMENTARY:
The fractalkine receptor CX3CR1 is a key mediator of atherogenesis
CONTACT:
Myron I. Cybulsky
Toronto General Research Institute
200 Elizabeth St., CCRW 1-855
Toronto, ON M5G 2C4
CANADA
Phone 1: 416-340-3578
Fax 1: 416-340-3578
E-mail: myron.cybulsky@utoronto.ca
View the PDF of this commentary at: https://www.the-jci.org/press/18237.pdf
Role of RANK Ligand in Mediating the Increased Bone Resorption in Early Postmenopausal Women
CONTACT:
Lawrence B. Riggs
Mayo Clinic
Osteoporosis Research
200 1st St. SW
North 6 Plummer
Rochester, MN 55905
USA
Phone 1: 507-284-3961
Phone 2: 507-284-2511
Fax 1: 507-284-8271
E-mail: riggs.lawrence@mayo.edu
View the PDF of this article at: https://www.the-jci.org/press/17215.pdf
ACCOMPANYING COMMENTARY:
RANKL and the regulation of skeletal modeling
CONTACT:
Norman H. Bell
Bone & Mineral Metabolism
Medical University of South Carolina
114 Doughty Street, PO Box 250775
Charleston, SC 29425
USA
Phone 1: 843-876-5162
Fax 1: 843-876-5163
E-mail: belln@musc.edu
View the PDF of this commentary at: https://www.the-jci.org/press/18358.pdf
Epidermal growth factor amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia
CONTACT:
Michael Moskowitz
Dept. Neurology
Mass. General Hospital
149 13th Street, Rm 6403
Charlestown, MA 02129
USA
Phone 1: 617-726-8440
Fax 1: 617-726-2547
E-mail: moskowitz@helix.mgh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/17170.pdf
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension: Role of the NADPH-oxidase
CONTACT:
David G. Harrison
Emory University School Of Medicine
Division of Cardiology
1639 Pierce Drive
319 WMB
Atlanta, GA 30322
USA
Phone 1: 404-727-8147
Fax 1: 404-727-3585
E-mail: dharr02@emory.edu
View the PDF of this article at: https://www.the-jci.org/press/14172.pdf
A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of fgf with its receptor
CONTACT:
David Naor
The Lautenberg Center for General and Tumor Immunology
The Hebrew University-Hadassah Medical School
Jerusalem 91120
ISRAEL
Phone: 972-2-675-8722
Fax: 972-2-642-4653
E-mail: naord@md2.huji.ac.il
View the PDF of this article at: https://www.the-jci.org/press/17100.pdf
Journal
Journal of Clinical Investigation