Public Release: 

JCI Table of Contents, November 3, 2003

JCI Journals

Gene therapy establishes a TRAIL to arthritis treatment

In the November 3 issue of the Journal of Clinical Investigation, John Mountz and colleagues from the University of Alabama at Birmingham describe a gene-modified cell therapy utilizing the TRAIL molecule that successfully limits the incidence and severity of arthritis in a mouse model of collagen-induced arthritis and joint inflammation. The regime represents a therapeutic option for systemic rheumatic diseases.

Mountz and colleagues isolated dendritic cells prepared from either peripheral blood or bone marrow, which were then pulsed with collagen. The DNA of an adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was then introduced into these cells. The design of the adenovirus vector allowed the researchers to "switch on" the expression of TRAIL by these gene-modified dendritic cells at their discretion, by the addition of doxycycline (DOX).

A cascade of immunological events including lymphocyte activation, lymphokine production, and proliferation of synovial cells (which comprise the loose connective tissue lining the joint cavity) is associated with collagen-induced arthritis in mice. Mountz and colleagues found that infusion of collagen-pulsed DOX-inducible TRAIL-expressing dendritic cells into these mice induced the apoptosis of collagen-specific T cells, a reduction in lymphokine production, and suppression of collagen-induced arthritis. The data suggest that this gene therapy regime is a safe and effective method for inhibiting the development of collagen-induced arthritis

In an accompanying commentary in the same issue, George and Maria Tsokos from the Walter Reed Army Institute of Research, Maryland, discuss how the results of Mountz and colleagues propose new possibilities for gene-modified cell-based treatment of rheumatoid arthritis.

TITLE: CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis

AUTHOR CONTACT:
John D. Mountz
University of Alabama at Birmingham, Birmingham, Alabama, USA.
Phone: 205-934-8909
Fax: 205-975-6648
E-mail: john.mountz@ccc.uab.edu

View the PDF of this article at: https://www.the-jci.org/press/19209.pdf

ACCOMPANYING COMMENTARY: The TRAIL to arthritis

AUTHOR CONTACT:
George C. Tsokos
Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Phone: 301-319-9911
Fax: 301-319-9133
E-mail: gtsokos@usa.net

View the PDF of this commentary at: https://www.the-jci.org/press/20297.pdf

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Stem cell factor: secret to liver's fountain of youth

Following surgical liver resection, a technique known as partial hepatectomy, which is often employed in the removal of benign or malignant tumors, a large reservoir of stem cell factor (SCF) in the liver drives increased hepatocyte proliferation in order to restore liver mass to normal. Lisa Colletti and colleagues from the University of Michigan report their findings in the November 3 issue of the Journal of Clinical Investigation.

Following most cases of partial hepatectomy the remnant liver regenerates until normal hepatic mass is reestablished. However the specific factors involved in this complex regulatory phenomenon remain to be completely defined.

Colletti and colleagues demonstrate that hepatic SCF levels change dramatically following partial hepatectomy in mice, and that SCF blockade, either by administration of anti-SCF antibodies or by using genetically altered, SCF-deficient mice, inhibits hepatocyte proliferation. Furthermore, SCF administration in SCF-deficient mice was shown to restore hepatocyte proliferation to normal and this effect occurs via an IL-6-mediated pathway.

Colletti and colleagues suggest that while hepatic homeostasis and regeneration likely involves multiple complex mechanisms and pathways, their current report indicates that SCF plays a significant role in maintaining and reestablishing the health of the liver.

TITLE: Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy

AUTHOR CONTACT:
Lisa Colletti
University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Phone: 734-936-7944
Fax: 734-936-5930
E-mail: colletti@umich.edu

View the PDF of this article at: https://www.the-jci.org/press/17391.pdf

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VLA-1 expression is critical for T cell memory of previously encountered antigens

In the November 3 issue of the Journal of Clinical investigation Leonard Chess and colleagues from Columbia University College of Physicians and Surgeons in New York report that following T cell activation the collagen receptor very late antigen-1 (VLA-1) is stably expressed on a subset of human CD4+ memory T cells and can be used as a marker to identify this cellular population. VLA-1 is also important in the ability of CD4+ memory T cells to recognize and mount a response to previously encountered antigens.

Approximately 1-4% of CD4+ T cells were shown to express VLA-1 and following T cell receptor activation the percentage of VLA-1+ cells increased. The authors found that CD4+ memory T cells that divide rapidly following stimulation with a previously encountered antigen were highly enriched for VLA-1+ cells. Furthermore, depletion of the small fraction of VLA-1+ cells present in the CD4+ peripheral blood lymphocyte population significantly reduced the immune response to previously encountered antigens. Therefore VLA-1 appears to be of unique value in the identification and physiology of peripheral CD4+ T cell memory.

TITLE: Expression of the alpha1beta1 integrin, VLA-1, marks a distinct subset of human CD4+ memory T cells.

AUTHOR CONTACT:
Leonard Chess
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-9984
Fax: 212-305-4943
E-mail: lc19@columbia.edu

View a PDF of this article at: https://www.the-jci.org/press/19607.pdf

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Decreased elastin in blood vessel walls is linked to hypertension

Mutations in the elastin gene cause mechanical changes in the walls of blood vessels that increase arterial blood pressure suggesting that alterations in elastin may contribute to the development of hypertension in humans. Robert Mecham and colleagues from Washington University, Missouri, and Université Joseph Fourier, in Grenoble, France, report their findings in the November 3 issue of the Journal of Clinical Investigation.

Elastin constitutes approximately 50% of the dry weight of the human aorta and during vessel development elastin synthesized by smooth muscle cells forms elastic fibers arranged in concentric rings of elastic lamellae around blood vessel lumen. The elastic lamellae allow the vessel to expand and contract with the stress of blood flow and maintain sufficient blood pressure during diastole (filling) and systole (contraction) phases of the heart beat.

To directly investigate the consequence of elastin mutations on vessel formation, Mecham and colleagues generated a mouse haploinsufficient for elastin (Eln+/-). The arteries of Eln+/- mice had thinner elastic lamellae and an increased number of smooth muscle cell layers. The animals demonstrated blood pressure 30-40% higher than control animals.

The association of hypertension with elastin haploinsufficiency strongly suggests that genes encoding vessel wall proteins, particularly elastin, should be considered as causal genes for hypertension.

In an accompanying commentary in the same issue of the Journal of Clinical Investigation, Jeanine D'Armiento, from Columbia University College of Physicians and Surgeons in New York discusses possible mechanisms by which a change in elastin content leads to alterations in cell signaling and subsequent changes in vessel wall structure.

TITLE: Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency

AUTHOR CONTACT:
Robert P. Mecham
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314-362-2254
Fax: 314-362-2252
E-mail: bmecham@cellbiology.wustl.edu

View the PDF of this article at: https://www.the-jci.org/press/19028.pdf

ACCOMANYING COMMENTARY: Decreased elastin in vessel walls puts the pressure on

AUTHOR CONTACT:
Jeanine D'Armiento
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-3745
Fax: 212-305-5052
Email: jmd12@columbia.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20226.pdf

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High rates of mitochondrial DNA mutations found in human colonic crypt stem cells

High rates of mitochondrial DNA (mtDNA) mutation occur in human colonic crypt stem cells. This finding, reported by Douglass Turnbull and colleagues from the University of Newcastle upon Tyne in the November 3 issue of the Journal of Clinical Investigation, could have profound implications for our understanding of the potential importance of these mutations in aging and cancer.

In addition to their role in tissue and organ formation during embryonic development, stem cells are also called upon to repopulate cells that undergo continual turnover. It stands to reason that if mtDNA is always replicating in cells, then somatic mtDNA mutations could also arise in stem cells. However, evidence to indicate that these mutations do indeed happen, and if so, at what rate, has been lacking.

Turnbull and colleagues provide evidence that at least one population of stem cells -- those giving rise to intestinal colonic crypts - do indeed harbor somatic mtDNA mutations, which, even more surprisingly, arise at a relatively high frequency. The colonic crypt provides an ideal system for study as crypt cells are all derived from one or two single cells - stem cells - located at the base of each crypt. Therefore any mtDNA mutation found in the crypt must have been amplified from that very mutation in the stem cell itself. Turnbull and colleagues used molecular, histological, and biochemical means to identify the mutation-carrying cells throughout the crypt. The authors determined that the rate of mtDNA mutation - 5 x 10-5 per genome per day - far exceeded that of nuclear DNA.

In an accompanying commentary in the same issue, Eric Schon from Columbia University in New York discusses how the use of colonic crypts as a stem cell model system should allow investigators to better study the dynamics underlying the shift from heteroplasmy (the coexistence, within the same cell, of both wild-type and mutated mtDNA) to homoplasmy (the presence of completely normal or completely mutant mtDNA) - the latter of which has been shown to occur in tumors.

TITLE: Mitochondrial DNA mutations in human colonic crypt stem cells

AUTHOR CONTACT:
Douglass Turnbull
University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
Phone: 44-191-222-8334
Fax: 44-191-222-8553
E-mail: d.m.turnbull@ncl.ac.uk

View the PDF of this article at: https://www.the-jci.org/press/19435.pdf

ACCOMPANYING COMMENTARY:
Tales from the crypt

AUTHOR CONTACT:
Eric A. Schon
Columbia University, New York, New York, USA.
Phone: 212-305-1665
Fax: 212-305-3986
E-mail: eas3@columbia.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20249.pdf

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The anti-oxidant thioredoxin helps prevent cardiac hypertrophy

In the November 3 issue of the Journal of Clinical Investigation Junichi Sadoshima and colleagues from the University of Medicine and Dentistry of New Jersey report that thioredoxin acts as an anti-oxidant in the heart and plays an essential role in regulating oxidative stress and preventing cardiac hypertrophy.

Although it has been suggested that thioredoxin acts as an anti-oxidant in cells, the extent of thioredoxin contribution to overall cellular anti-oxidant mechanisms has not been clearly demonstrated in any organs in vivo. Sadoshima and colleagues now demonstrate that the heart-specific overexpression of a dominant-negative form of thioredoxin in mice causes increased oxidative stress and stimulates cardiac hypertrophy via redox-sensitive mechanisms when the animal is at rest and also when subjected to pressure overload.

Therefore, both thioredoxin and its downstream target proteins may be an important therapeutic focus for the treatment of cardiac hypertrophy.

TITLE: Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy

AUTHOR CONTACT:
Junichi Sadoshima
University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
Phone: 973-972-8619
Fax: 973-972-8919
E-mail: Sadoshju@umdnj.edu

View the PDF of this article at: https://www.the-jci.org/press/17700.pdf

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Diversity is the spice of autoimmune life

In the November 3 issue of the Journal of Clinical Investigation, Terri Laufer and colleagues from the University of Pennsylvania report that a diverse CD4+ T cell repertoire is required to activate autoreactive B cells to attack host tissues in autoimmune diseases such as systemic lupus erythematosus.

Whether help for autoantibody production comes from a finite number of T cells or a more diverse repertoire has remained, until now, an unanswered question. Laufer and colleagues used a chronic graft-versus-host disease model of systemic autoimmunity to examine the diversity of the T cell repertoire required for antinuclear antibody formation. The authors found that loss of B cell tolerance can be divided into two distinct components with different CD4+ cell requirements. CD4+ cell diversity is specifically required for the trafficking of CD4+ cells into the B cell follicle and the production of isotype-switched IgG autoantibodies. This work provides new insight into the pathogenesis of lupus and suggests therapeutic targets.

TITLE: Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance

AUTHOR CONTACT:
Terri M. Laufer
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215-573-2955
Fax: 215-573-7599
E-mail: tlaufer@mail.med.upenn.edu

View the PDF of this article at: https://www.the-jci.org/press/18310.pdf

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ARNT mice controlling skin function?

Junji Takeda and colleagues from Osaka University and the National Cancer Institute reveal that the aryl hydrocarbon receptor nuclear translocator (ARNT) affects the structure of ceramides in the skin and disrupts the function of the epidermal barrier, which protects against foreign environmental stimuli and injury. These findings are reported in the November 3 issue of the Journal of Clinical Investigation.

ARNT, a transcription factor of the Per/AHR/ARNT/Sim family, regulates gene expression in response to environmental stimuli such as xenobiotics and hypoxia. To examine its role in the epidermis, Takeda and colleagues disrupted Arnt in keratinocytes. While the architecture of the stratum corneum in Arnt-/- mice was found to be similar to that in control mice, the permeability barrier function and the composition of ceramides were significantly different. In particular, 4-desaturated and 4-hydroxylated ceramide species were diminished in the Arnt-/- mice, whereas 4-saturated ceramides were elevated.

These data suggest that ARNT regulates ceramide biosynthesis through 4-desaturation and that maintenance of ceramide composition is important in epithelial barrier function.

TITLE: Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function

AUTHOR CONTACT:
Junji Takeda
Osaka University Graduate School of Medicine, Osaka, Japan.
Phone: 81-6-6879-3262
Fax: 81-6-6879-3266
E-mail: takeda@mr-envi.med.osaka-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/press/18513.pdf

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TGF-beta keeps T cells in check in atherosclerosis

TGF-beta inhibits atherosclerosis by dampening T cell activation, which suggests that inhibition of T cell activation may represent a strategy for anti-atherosclerotic therapy. These findings, by Göran Hansson and colleagues from the Karolinska Institute, Stockholm, are reported in the November 3 issue of the Journal of Clinical Investigation.

Increasing evidence suggests that atherosclerosis is an inflammatory disease promoted by hypercholesterolemia. However, the role of immune cells has been controversial. Hansson and colleagues crossed atherosclerosis-prone ApoE-/- mice with transgenic mice carrying dominant-negative TGF-b receptor II in T cells. In the absence of functional TGF-beta signaling in T cells, the authors observed a dramatic increase in atherosclerosis concomitant with increased T cell activation. These results show that abrogation of TGF-beta signaling in T cells increases atherosclerosis and suggest that TGF-beta reduces atherosclerosis by dampening T cell activation. Inhibition of T cell activation may therefore represent a strategy for anti-atherosclerotic therapy.

TITLE: Disruption of TGF-beta signaling in T cells accelerates atherosclerosis

AUTHOR CONTACT:
Göran K. Hansson
Karolinska Hospital, Stockholm, Sweden.
Phone: 46-8-51776222
Fax: 46-8-313147
E-mail: Goran.Hansson@cmm.ki.se

View the PDF of this article at: https://www.the-jci.org/press/18607.pdf

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Foxp3 controls regulatory T cell function

In the November 3 issue of the Journal of Clinical Investigation, Steven Ziegler and colleagues from the Benaroya Research Institute in Seattle report that CD25-CD4+ T cells produced in the thymus can differentiate to Foxp3-expressing CD25+CD4+ T regulatory cells in the periphery and are capable of suppressing the activation and expansion of self-reactive T cells that may cause autoimmune disease. The report suggests an active role for Foxp3 in suppressing self-directed immune responses and a therapeutic role for Foxp3 in the treatment of autoimmune diseases.

In an accompanying commentary in the same issue, Shimon Sakaguchi from Kyoto University, Japan, discusses the developmental pathway of Foxp3-expressing T regulatory cells and their role in controlling self-tolerance and autoimmunity.

TITLE: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+Cd25- T cells.

AUTHOR CONTACT:
Steven F. Ziegler
Benaroya Research Institute, Seattle, Washington, USA.
Phone: 206-344-7950
Fax: 206-223-7543
E-mail: sziegler@benaroyaresearch.org

View the PDF of this article at: https://www.the-jci.org/press/19441.pdf

ACCOMPANYING COMMENTARY:
The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery

AUTHOR CONTACT:
Shimon Sakaguchi
Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Phone: 81-75-751-3888
Fax: 81-75-751-3820
E-mail: shimon@frontier.kyoto-u.ac.jp

View the PDF of this commentary at: https://www.the-jci.org/press/20274.pdf

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Stopping bone loss during lactation

Parathyroid hormone-related protein (PTHrP) is secreted in mammary epithelial cells during lactation and promotes maternal bone loss by increasing the rates of bone resorption. John Wysolmerski and colleagues from Yale University report these findings in the November 3 issue of the Journal of Clinical Investigation.

Lactating mothers transfer large amounts of calcium to offspring via milk. This demand is associated with rapid bone loss in the mother; however, the mechanisms of bone loss during lactation are not completely understood. PTHrP is secreted by the lactating mammary gland to regulate bone turnover during lactation. Wysolmerski and colleagues designed mice in which PTHrP was specifically deleted in mammary epithelial cells during late pregnancy and lactation. The authors found that mammary gland PTHrP mRNA and milk PTHrP protein were almost completely absent in these mice. Removal of PTHrP from the lactating mammary glands resulted in reductions in bone turnover and attenuated bone loss during lactation. This study suggests that during lactation, mammary epithelial cells are a source of circulating PTHrP, which promotes bone loss by increasing rates of bone resorption.

TITLE: Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation

AUTHOR CONTACT:
John J. Wysolmerski
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-7447
Fax: 203-785-6015
E-mail: john.wysolmerski@yale.edu

View the PDF of this article at: https://www.the-jci.org/press/19504.pdf

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A role for osteopontin in atherosclerosis and abdominal aneurysms

In the November 3 issue of the Journal of Clinical investigation Willa Hsueh and colleagues from the University of California, Los Angeles, report that osteopontin is a key participant in the development of atherosclerosis and abdominal aortic aneurysms.

Hsueh and colleagues studied mice in which the genes encoding osteopontin (OPN) and apolipoprotein E (ApoE) had been deleted. ApoE-/- OPN-/- mice were infused with Angiotensin II (Ang II), which induces vascular OPN expression and accelerates atherosclerosis. Mice lacking OPN and ApoE demonstrated a significant reduction in atherosclerotic lesion size and macrophage content in the vessel wall in the absence of significant differences in their levels of insulin, plasma lipids, glucose, or blood pressure. These data demonstrate that partial or complete lack of OPN is sufficient to abrogate the extensive inflammatory response associated with Ang II-accelerated atherosclerosis. OPN deficiency does not however appear to affect slower-progressing atherosclerosis in non-Ang II-infused ApoE-/- mice where hypocholesterolemia is the man trigger of the atherosclerotic process.

Atherosclerosis-associated inflammation of the arterial wall also appears to play a fundamental role in the development of Ang II--induced abdominal aortic aneurysms (AAAs). Hsueh and colleagues found that in ApoE-/- OPN-/- mice, the incidence and severity of Ang II-accelerated AAA formation was significantly reduced, suggesting that the proinflammatory effects of OPN are not only involved in the development of atherosclerosis but also in AAA formation.

The data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation. OPN may therefore be an important therapeutic target for the prevention and treatment of atherosclerosis and abdominal aneurysms.

TITLE: Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice

AUTHOR CONTACT:
Willa A. Hsueh
David Geffen School of Medicine, University of California, Los Angeles, USA.
Phone: 310-794-7555
Fax: 310-794-7654
E-mail: whsueh@mednet.ucla.edu

View the PDF of this article at: https://www.the-jci.org/press/18141.pdf

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Revealed: a role for angiotensin II in liver fibrosis

NADPH oxidase mediates the effects of angiotensin II, which causes fibrosis following liver injury. David Brenner and colleagues from the University of North Carolina report these findings in the November 3 issue of the Journal of Clinical Investigation.

While there is increasing evidence that the renin-angiotensin system plays an important role during liver fibrosis and that anti-angiotensin II (anti-Ang II) therapy is useful in chronic liver injury, the mechanisms by which Ang II facilitates these effects is unclear.

In their study, Brenner and colleagues provide evidence that the enzyme NADPH oxidase mediates the effects of Ang II on hepatic stellate cells, major fibrogenic cells in the injured liver. Ang II phosphorylated p47phox, a key regulatory subunit of NADPH oxidase, and induced toxic reactive oxygen species formation via NADPH oxidase activity. Ang II stimulated collagen deposition and the secretion of inflammatory cytokines, leading to fibrosis. These effects were attenuated by an NADPH inhibitor and in NADPH knockout cells. Furthermore, microarray analysis revealed that Ang II induces upregulation of genes involved in liver fibrogenesis. This study suggests that NADPH oxidase may be a potential pharmacologic target for the treatment of liver fibrosis.

TITLE: NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis

AUTHOR CONTACT:
David A. Brenner
Columbia University of College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-5838
Fax: 212-305-9822
E-mail: dab2106@columbia.edu

View the PDF of this article at: https://www.the-jci.org/press/18212.pdf

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