JCI table of contents, 2 August, 2004

07/26/04

Stroking Up Cellular Therapy

Stroke is the second largest cause of death worldwide and the leading cause of long-term neurological disability. Therapies for stroke victims are improving, but remain hampered by the limited repair capacity of nerves in the brain and the unique properties of brain vasculature. Akihiko Taguchi and colleagues, of the National Cardiovascular Center in Japan, make great strides in providing new means to aid stroke victims with their current work showing that intravenous injection of specific immune cells called CD34+ cells after stroke greatly enhances nerve restoration in the region of damage in mice. The authors isolated CD34+ cells from human cord blood and injected them into mice within 48 hours of a stroke. These mice experienced increase new blood vessel growth in stoke-damaged region. The CD34+ cells also produced growth factors to aid in neural regeneration. There was also evidence of migration of nerve progenitors into the region of stroke damage. The mice that were treated with CD34+ cells showed improved behavioral characteristics. Of note, if blockers to blood vessel growth were given in addition to the CD34+ cells, all of the benefits of CD34+ treatment were lost. These data provide direct evidence that new blood vessel growth is essential for repairing stroke damage, and provide important information for investigating therapies for this deadly and debilitating affliction.

An accompanying commentary by Daniel Peterson, of the Rosalind Franklin University of Medicine and Science, places these data into the context of the difficulties of treating stroke victims, and what additional information beyond this study is required to best understand how these data will be useful for understanding and treating stroke patients.

TITLE: Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model

AUTHOR CONTACT:
Akihiko Taguchi National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan
Phone: 81-6-6833-5012; Fax: 81-6-6872-7485; E-mail: ataguchi@res.ncvc.go.jp

View the PDF of this article at: https://www.the-jci.org/press/20622.pdf

ACCOMPANYING COMMENTARY: Umbilical cord blood cells and brain stroke injury: bringing in fresh blood to address an old problem

AUTHOR CONTACT:
Daniel A. Peterson The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL 60064, USA
Phone: 847-578-3411; Fax: 847-578-8545; E-mail: daniel.peterson@rosalindfranklin.edu

View the PDF of this article at: https://www.the-jci.org/press/22540.pdf

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Leptin Has Layers of Control

Leptin is a neurotransmitter that is produced in fat cells and is involved in appetite. Leptin works through the action of several small proteins called neuropeptides, such as thyrotopin-releasing hormone. Many of these neuropeptides are first made in a longer inactive form (called a prohormone) and are subsequently cut into a smaller active form; this is called prohormone processing. While leptin is known to regulate energy balance by controlling whether these neuropeptides are produced in any form, Eduardo Nillni and colleagues, from Brown Medical School and Rhode Island Hospital, theorized that leptin might have an additional layer of control, by regulating the production of the enzymes that are used to convert the inactive prohormones to the smaller active hormones. They tested their hypothesis by examining leptin's effect on two enzymes prohormone convertase 1 and 2, these enzymes cut the prohormone form of thyrotopin-releasing hormone into its active form. In cell culture of neuronal cells from the hippocampus (the area of the brain where leptin acts), leptin treatment led to a significant increase in the expression of these two enzymes at both the genetic and protein level. Rats that were starved, and thus had low levels of leptin in their blood serum levels also had lower levels of these two enzymes. Consistent with the lower levels of the enzymes, these fasted rats likewise did not have a significant amount of the active (cleaved form) of thyrotopin-releasing hormone. Giving leptin directly to these rats, increased enzyme levels and, inevitably, the amount of active thyrotopin-releasing hormone. These data provide evidence for an additional key regulatory point in the control of energy balance through leptin and may suggest novel therapeutic strategies for treatment of obesity and thyroid axis–related diseases.

TITLE: Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

AUTHOR CONTACT:
Eduardo A. Nillni Brown Medical School/Rhode Island Hospital, 55 Claverick St. Providence, RI 02903, USA.
Phone: 401-444-5733; Fax: 401-444-6964; E-mail: Eduardo_Nillni@Brown.edu

View the PDF of this article at: https://www.the-jci.org/press/21620.pdf

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Wasting Away in Muscle-ville

Loss of skeletal muscle tissue, termed cachexia, occurs in over half of cancer patients and, rather than tumor burden, is the direct cause of nearly one-third of cancer deaths. There are several regulatory proteins that are released from immune cells are known to be involved in the development of cachexia. These proteins are called cytokines and include TNF-alpha and IFN-gamma. The proteins in the muscles that are affected by these cytokines, however, remain largely unknown. Using both cell culture and animal models of cachexia, Denis Guttridge and colleagues, from the Ohio State University College of Medicine, investigated which the proteins in muscle that are altered the presence of cytokines, and discovered their target was surprisingly specific. The authors examined several model protein targets of muscle wasting, including myosin heavy chain, actin, troponin, and tropomyosin. They found a striking specificity for the loss of myosin heavy chain only. Intriguingly, TNF-alpha/IFN-gamma–dependent loss of myosin heavy chain occurred through different mechanisms depending on whether they were examining it in cell culture or in a mouse model. In culture, loss of myosin heavy chain occurred through an RNA-dependent mechanism, while in tumor-bearing mice loss occurred through a protein breakdown process. The authors suggest that the choice of which mechanism reduces the amount of myosin heavy chain in cachexia may be related to the specific factor that is mediating muscle wasting. The identification that myosin heavy chain is such a selective target in cachexia may be useful in the design of future therapies for this major contributor to cancer patient death.

TITLE: Cancer cachexia is regulated by selective targeting of skeletal muscle gene products

AUTHOR CONTACT:
Denis C. Guttridge The Ohio State University College of Medicine, 420 W. Twelfth Ave. Columbus, OH 43210, USA
Phone: 614-688-3137; Fax: 614-688-4006; E-mail: guttridge-1@medctr.osu.edu

View the PDF of this article at: https://www.the-jci.org/press/20174.pdf

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Linking Defenses to Combat Atherosclerosis

The immune system is capable of providing some protection against the development of atherosclerosis. When a lipid-containing protein called low-density lipoprotein, which is involved in the development of atherosclerosis, is broken down, it creates small peptides that are recognized by the two components of the immune system: the natural immune system, which every individual is born with and that responds to a fixed set of conserved pathogenic markers; and the adaptive immune system, which responds to previously unknown pathogenic markers and changes its complement of antibodies over an individual's lifetime in a manner dependent on the types of pathogens it encounters. Christoph Binder, Joseph Witztum, and colleagues, from the University of California, San Diego, present intriguing data that show that the adaptive immune system, when activated to produce an anti-atherosclerosis response, enhances the natural immune anti-athersclerosis response, creating increased protection against atherosclerosis. By injecting a breakdown product of low-density lipoprotein into mouse models for atherosclerosis, the authors found that an adaptive immune response against this peptide was initiated, and that this was followed by an increase in the production of a natural antibody, called T15/EO6, which also recognizes the lipoprotein breakdown product. Mice treated in such a manner showed reduced atherosclerotic lesion size. The increase in the natural antibody production required the presence of a cytokine called IL-5, which was produced by cells in the adaptive immune system. This work identifies a molecular mechanism that can link the adaptive and natural immune responses against atherosclerosis and thus provides potential new means to enhance anti-atherosclerotic immune responses for therapeutic purposes.

An accompanying commentary by Alan Daugherty and colleagues, from the University of Kentucky, present these data in the context of what is currently understood about the interaction of the natural and adaptive immune response and the immune system's ability to protect against atherosclerosis.

TITLE: IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

AUTHOR CONTACTS:
Christoph J. Binder or Joseph L. Witztum University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
Phone: 858-534-4402; Fax: 858-534-2005;
E-mail: cbinder@ucsd.edu (C.J.B.), jwitztum@ucsd.edu (J.L.W.)

View the PDF of this article at: https://www.the-jci.org/press/20479.pdf

ACCOMPANYING COMMENTARY: IL-5 links adaptive and natural immunity in reducing atherosclerotic disease

AUTHOR CONTACT:
Alan Daugherty University of Kentucky, 900 S. Limestone Rd, Lexington, KY 40536, USA
Phone: 859-323-4933 ext. 81389; Fax: 859-257-3646; E-mail: Alan.Daugherty@uky.edu

View the PDF of this article at: https://www.the-jci.org/press/22561.pdf

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The Straight and Marrow in Vascular Disease

Blood vessel health and survival require appropriate and constant repair of vascular damage. Bone marrow-derived cells are known to be one of the predominant areas that provide cells that target these damaged regions and promote healing. Both cells from the immune system and blood progenitor cells are mobilized to the wound, but little is understood about the molecular mechanisms that regulate the activation and targeting of these bone-marrow cells and what roles they play in promoting or inhibiting repair. Elizabeth Nabel and colleagues from the National Heart, Lung and Blood Institute at the NIH, theorized that factors important for cell cycle might be involved in this mechanism as they are important for stimulating or inhibiting the growth of a variety of cell types, and likely affect the growth and repair of tissue damage. To test their hypothesis, they used mice that are defective in the production of a cell cycle molecule called p27kip1 and show that these mice, after experiencing mechanical damage to an artery, had increased lesion formation with increased infiltration by immune and inflammatory cells. When the researchers transplanted bone-marrow cells from p27kip1 defective mice into normal mice, these transplant mice had higher a higher prevalence of arterial blockage. To assess the importance of immune cells in the repair of vascular tissues, the authors looked at the vascular repair in mice that were transplanted with bone marrow from mice that are unable to make immune cells, these are called RAG deficient mice. Mice transplanted with normal bone marrow cells showed greatly exacerbated the vascular injury compared to mice transplanted with bone marrow cells from RAG deficient mice. The data here show a direct link vascular inflammation and proliferation, and indicate that treatment for cardiovascular disease should target factors involved in immunity and inflammation.

TITLE: Bone marrow-derived immune cells regulate vascular disease through a p27Kip1-dependent mechanism

AUTHOR CONTACT:
Elizabeth G. Nabel National Heart, Lung, and Blood Institute, NIH, 50 Center Dr, Bethesda, MD 20892, USA
Phone: 301-496-1518; Fax: 301-402-7560; E-mail: nabele@nhlbi.nih.gov

View the PDF of this article at: https://www.the-jci.org/press/20176.pdf

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Interferon Interference Obstructs Ducts

Biliary atresia is a disease in which bile flow is increasingly impeded due to a progressive obstruction of the bile ducts that are found outside the liver. Biliary atresia occurs within the first few weeks of life and is the primary cause of chronic liver disease in children. Liver transplant is ultimately the only treatment, as little is known about the underlying pathogenic mechanisms. Individuals with biliary atresia do not all show the same symptoms, but all cases do have inflammatory injury to the bile ducts. Jorge Bezerra and colleagues, from Cincinnati Children's Hospital Medical Center, used a mouse model biliary atresia and investigated the whether a protein known to be involved in the immune response that mediates inflammation, a protein called interferon-gamma, is involved in the development of this disease. Infecting mice with a specific virus within the first 24 hours of life generates a pathology similar to that seen in humans with biliary atresia. The authors found that in infected mice, in contrast to uninfected mice, immune cells that produced interferon-gamma invaded the portal tracts of the bile ducts. They also found that the amount of interferon-gamma that was produced was markedly increased in several types of immune cells. They also found that when they infected mice that had been genetically altered so that they lacked functional interferon- gamma, the invasion of cells into the bile ducts was blocked. However, giving the mice interferon-gamma following infection resulted in bile duct blockage. These data identify interferon-gamma as a key player underlying this deadly condition in children and suggest potential new investigative and therapeutic directions for the study of bile duct obstruction.

TITLE: Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia

AUTHOR CONTACT:
Jorge A. Bezerra Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave. Cincinnati, Ohio 45229, USA
Phone: 513-636-3008; Fax: 513-636-5581. E-mail: jorge.bezerra@cchmc.org

View the PDF of this article at: https://www.the-jci.org/press/21153.pdf

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Putting the B Cell in Bowel Disease

Inflammatory bowel disease, which includes Crohn disease and ulcerative colitis, afflicts approximately 1.4 million people in the United States and 2.2 million people in Europe Research into the basic underlying causes of these disorders has focused primarily on a the improper functioning of a specific subset of immune cell called CD4+ T cells. Investigation of the role other immune cells might play in the pathogenicity of these diseases has just begun. Now, Klaus Ley and colleagues, from the University of Virginia Health Science Center, investigate what role another type of immune cell, the B cells, may play in the development inflammatory bowel disease. For their study, the authors used a mouse model of human Crohn disease and found that the B cell population had expanded in the mesenteric lymph nodes (lymph nodes associated with folds in the peritoneum of the intestines) of these mice. The severity of inflammatory bowel disease in these mice was highly correlative with the number of B cells found in the mesenteric lymph nodes. Of interest, there was also a higher number of immune cells that can normally regulate increased inflammation (a special subset of CD4+ T cells), but even though the number of these regulatory cells were higher, they were unable to prevent inflammatory bowel disease development when transferred into mice that were immune suppressed. Additionally, if B cells were also transferred into these mice, the severity of inflammatory bowel disease in these mice increased. The work here provides evidence for important interactions between T and B cells as well as for B cell function in the development of a Crohn-like mouse model, and open new avenues for exploration for treating these disorders.

TITLE: Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease

AUTHOR CONTACT:
Klaus Ley University of Virginia Health Science Center, Charlottesville, VA 22908, USA
Phone: 434-243-9966; Fax: 434-924-2828; E-mail: klausley@virginia.edu

View the PDF of this article at: https://www.the-jci.org/press/20855.pdf

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OTHER PAPERS IN THIS ISSUE

Sugar Baby Lacks Control

TITLE: Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM

AUTHOR CONTACT:
Gavin Kelsey The Babraham Institute, Cambridge CB2 4AT, UK
Phone: 44-1223-496332; Fax: 44-1223-496022; E-mail: gavin.kelsey@bbsrc.ac.uk

View the PDF of this article at: https://www.the-jci.org/press/19876.pdf

ACCOMPANYING COMMENTARY: Unlocking the secrets of the pancreatic beta cell: man and mouse provide the key

AUTHOR CONTACT:
Andrew T. Hattersley Peninsula Medical School, Barrack Rd, Exeter, EX2 5AX, UK
Phone: 44-1392-403089; Fax: 44-1392-403027; E-mail: A.T.Hattersley@ex.ac.uk

View the PDF of this article at: https://www.the-jci.org/press/22506.pdf

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Circulating Fibrocyte Traffic Make Lungs Suffer

TITLE: Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis

AUTHOR CONTACT:
Robert M. Strieter University of California, Los Angeles, School of Medicine, 900 Veteran Ave, Los Angeles, CA 90095, USA
Phone: 310-794-1999; Fax: 310-794-1998; E-mail: rstrieter@mednet.ucla.edu

View the PDF of this article at: https://www.the-jci.org/press/20997.pdf

ACCOMPANYING COMMENTARY: Pulmonary fibrosis: thinking outside of the lung

AUTHOR CONTACT:
David A. Schwartz Duke University Medical Center, Durham, NC 27710, USA
Phone: 919-668-0380; Fax: 919-668-0494; E-mail: david.schwartz@duke.edu

View the PDF of this article at: https://www.the-jci.org/press/22497.pdf

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Kinase Has New Antitumor Tricks

TITLE: Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects

AUTHOR CONTACT:
Laurence Zitvogel INSERM, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France
Phone: 33-1-42-11-50-41; Fax: 33-1-42-11-60-94; E-mail: zitvogel@igr.fr

View the PDF of this article at: https://www.the-jci.org/press/21102.pdf

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The Ins and Outs of Somatostatin Action

TITLE: Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis

AUTHOR CONTACT:
Shlomo Melmed Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA Phone: 310-423-4691; Fax: 310-423-0119; E-mail: melmed@csmc.edu

View the PDF of this article at: https://www.the-jci.org/press/19933.pdf

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C3a Puts the Kibosh on Skin Allergy

TITLE: The anaphylatoxin C3a downregulates the Th2 response to epicutaneously introduced antigen

AUTHOR CONTACT:
Raif S. Geha Children's Hospital, One Blackfan Circle, Boston, MA 02115, USA
Phone: 617-919-2482; Fax: 617-730-0528; E-mail: raif.geha@tch.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/19082.pdf

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Engaging Differentiation

TITLE: Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1

AUTHOR CONTACT:
Daniel I. Simon Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA
Phone: 617-525-4371; Fax: 617-525-4377; E-mail: dsimon@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/21100.pdf

Source: Eurekalert & others

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