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JCI Table of Contents, November 14, 2003

JCI Journals

Stem cell gene therapy: selecting only the best

Curing human diseases using gene transfer into human hematopoietic stem cells (HSCs) remains a promising avenue for development. In the November 14 issue of the Journal of Clinical Investigation, two independent studies - the first by Stanton Gerson and colleagues at Case Western University and the second by Hans-Peter Kiem and colleagues at the Fred Hutchinson Cancer Research Center - have accomplished, for the first time, the selection and expansion of gene-corrected HSCs from large animals (dogs and humans), using a novel drug-resistance gene, MGMT.

Highly efficient transfer and expression of MGMT into relatively few HSCs using a lentivirus vector led to repopulation of the hematopoietic compartment with gene-corrected cells following suitable drug treatment. This selection system may be useful in human clinical trials of gene therapy in bone marrow transplantation settings.

In an accompanying commentary, Arthur Bank from Columbia University College of Physicians and Surgeons discusses the potential of these results in significantly advancing our knowledge and ability to perform human HSC gene therapy.

TITLE: In vivo selection of MGMT(P140K) lentivirus-transduced human NOD/SCID repopulating cells without pretransplant irradiation conditioning

AUTHOR CONTACT:
Stanton L. Gerson
Case Western Reserve University, Cleveland, Ohio, USA.
Phone: 216-368-1177
Fax: 216-368-1166
E-mail: slg5@po.cwru.edu

View the PDF of this article at: https://www.the-jci.org/press/17922.pdf

RELATED ARTICLE:

TITLE: Methylguanine methyltransferase-mediated in vivo selection and chemoprotection of allogeneic stem cells in a large-animal model

AUTHOR CONTACT:
Hans-Peter Kiem
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Phone: 206-667-4425
Fax: 206-667-6124
E-mail: hkiem@fhcrc.org

View the PDF of this article at: https://www.the-jci.org/press/18782.pdf

ACCOMPANYING COMMENTARY:
Hematopoietic stem cell gene therapy: selecting only the best

AUTHOR CONTACT:
Arthur Bank
Columbia University, New York, New York, USA.
Phone: 212-305-4186
Fax: 212-923-2090
E-mail: ab13@columbia.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20336.pdf

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Upregulation of Irs2 prevents diabetes

Insulin action and secretion are closely linked at the molecular level through the insulin receptor substrate-2 (Irs2) branch of the insulin/IGF signaling cascade. Mice lacking the Irs2 gene display similarities to humans with type 2 diabetes. Morris White and colleagues from the Joslin Diabetes Center evaluated the actions of beta cell-specific overexpression of the Irs2 gene on diabetes development and pancreatic beta cell function in murine models of autoimmune diabetes and islet transplantation in the November 14 issue of the Journal of Clinical Investigation.

The authors show that upregulation of Irs2 in pancreatic beta cells promotes beta cell growth, survival, and insulin secretion. Further, they demonstrate that increased expression of Irs2 in beta cells improves islet transplantation, as significantly fewer islets were required to normalize serum glucose levels. The data support a potential pharmacological role for Irs2 or downstream factors in the treatment of beta cell failure and human diabetes.

TITLE: Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes

AUTHOR CONTACT:
Morris White
Howard Hughes Medical Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.
Phone: 617-732-2578
Fax: 617-732-2593
E-mail: morris.white@joslin.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/18581.pdf

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IL-15 antibodies to the rescue in psoriasis

Psoriasis is a chronic inflammatory disease of the skin characterized by overgrowth of epidermal cells, angiogenesis, infiltration of immune cells, and increased production of cytokines. Interleukin-15 (IL-15) can trigger inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines. In the November 14 issue of the Journal of Clinical Investigation, Janine Schuurman and colleagues from Genmab in The Netherlands generated novel monoclonal antibodies to IL-15 using human immunoglobulin-transgenic mice and demonstrated that one specific monoclonal antibody, 146B7, was able to block IL-15-induced inflammation and resolve psoriasis.

The newly created antibody (146B7) did not compete with IL-15 for binding to its receptor, but interfered with the assembly of the IL-15 receptor alpha beta gamma complex. 146B7 effectively blocked IL-15-induced T cell proliferation, and monocyte TNF-alpha release. In a human psoriasis xenograft model, 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, numbers of inflammatory cells, parakeratosis and cycling keratinocytes. These results support an important role for IL-15 in the pathogenesis of psoriasis and identify a new target for therapeutic intervention.

TITLE: Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model

AUTHOR CONTACT:
Janine Schuurman
Genmab, Utrecht, The Netherlands.
Phone: 31-30-212-3126
Fax: 31-30-212-3111
E-mail: j.schuurman@nl.genmab.com

View the PDF of this article at: https://www.the-jci.org/press/18986.pdf

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Therapeutic CD154 antibody shows utility in the treatment of lupus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of pathogenic antibodies. A report in the November 14 issue of the Journal of Clinical Investigation by Peter Lipsky and colleagues at the National Institutes of Health demonstrates that passive antibody specific for CD154 ameliorates disease by reducing levels of self-reactive antibody in the serum. The report suggests a substantial potential for CD154 antibody in the treatment of humoral autoimmune diseases such as lupus.

In an accompanying commentary, Garnett Kelsoe from Duke University Medical Center discusses the potential cell targets for anti-CD154 and how CD154 acts to reduce SLE disease.

TITLE: Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions

AUTHOR CONTACT:
Peter E. Lipsky
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301-496-2612
Fax: 301-402-0012
E-mail: lipskyp@mail.nih.gov

View the PDF of this article at: https://www.the-jci.org/press/19301.pdf

ACCOMPANYING COMMENTARY:
Therapeutic CD154 antibody for lupus: promise for the future?

AUTHOR CONTACT:
Garnett Kelsoe
Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919-613-7815
Fax: 919-613-7878
E-mail: ghkelsoe@duke.edu

View the PDF of this article at: https://www.the-jci.org/press/20371.pdf

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Building better barriers with hyperosmolar sucrose

During lung injury, the normally air-filled alveoli fill with fluid from the surrounding vasculature (edema). Jahar Bhattacharya and colleagues from Columbia University have now described a therapeutic scheme to treat lung edema through the use of hyperosmolar sucrose in the November 14 issue of the Journal of Clinical Investigation.

The authors gave 15-minute infusions of hyperosmolar sucrose in lung venular capillaries. The barrier enhancement was sufficient to block the injurious effects of various injurious agents in the lung. Hyperosmolar infusion of sucrose augmented the structure of the cell cytoskeleton component, actin. An actin depolymerizing agent abrogated both the barrier enhancement as well the actin filament formation, suggesting a role for actin in the barrier response. Further, hyperosmolar infusion blocked TNF-alpha-induced P-selectin expression in an actin-dependent manner. These results suggest that hyperosmolar therapy may be beneficial in lung inflammatory disease.

TITLE: Hyperosmolarity enhances the lung capillary barrier

AUTHOR CONTACT:
Jahar Bhattacharya
St. Luke's Roosevelt Hospital Center, New York, New York, USA.
Phone: 212-523-7310
Fax: 212-523-8005
E-mail: jb39@columbia.edu

View the PDF of this article at: https://www.the-jci.org/press/18370.pdf

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A bright beacon at the blood-brain barrier

The LDL receptor gene family is most often associated with the removal of the cholesterol carrier LDL. In the November 14 issue of the Journal of Clinical Investigation, Daniel A. Lawrence and colleagues from the American Red Cross report a novel role of the LDL receptor-related protein (LRP), and one of its ligands, tissue-type plasminogen activator (tPA): the regulation of vascular tone and the permeability of the blood-brain barrier (BBB).

The authors demonstrate that an increase in perivascular tPA, as a consequence of cerebral ischemia, results in an opening of the BBB. Blockade of LRP, with anti-LRP antibodies or by other mechanisms, abolished the vasoactive effect of tPA.

In an accompanying commentary, Joachim Herz from University of Texas Southwestern Medical Center discusses the potential mechanisms of signaling by tPA and LRP at the BBB and how these elements impact upon post-ischemic infarct size following stroke.

TITLE: Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein

AUTHOR CONTACT:
Daniel A. Lawrence
Red Cross, Rockville, Maryland, USA.
Phone: 301-517-0356
Fax: 301-738-0794
E-mail: lawrenced@usa.redcross.org

View the PDF of this article at: https://www.the-jci.org/press/19212.pdf

ACCOMPANYING COMMENTARY:
LRP: a bright beacon at the blood-brain barrier

AUTHOR CONTACT:
Joachim Herz
University of Texas South West Medical Center, Dallas, Texas, USA.
Phone: 214-648-5633
Fax: 214-648-8804
Email: jherz@mednet.swmed.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20337.pdf

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CCL21 shows T cells the way to nonlymphoid tissues

The critical function of the chemo-kine CCL21 in directing lymphocytes from primary to secondary lymphoid tissues is well established; however, little is known about the molecular cues responsible for lymphocyte trafficking to nonlymphoid tissues. Yang-Xin Fu and colleagues from the University of Chicago investigated the role of CCL21 in recruiting lymphocytes to a nonlymphoid organ -- the lung -- in a murine model of airway inflammation in the November 14 issue of the Journal of Clinical Investigation.

The authors found that CCL21 in lymphoid and nonlymphoid tissues is differentially regulated by lymphotoxin-dependent (LT-dependent) and -independent mechanisms, respectively. This is due to the selective regulation of the Ccl21-Ser but not the Ccl21-Leu gene by the LT and noncanonical NF-kappaB pathways. These findings establish an essential role for CCL21 in the recruitment of effector T cells to peripheral tissues and suggest that LT-dependent and -independent regulation of CCL21 plays a role in balancing the central and peripheral immune responses between lymphoid and nonlymphoid tissues.

TITLE: Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues

AUTHOR CONTACT:
Yang-Xin Fu
The University of Chicago, Chicago, Illinois, USA.
Phone 1: 773-702-0929
Fax 1: 773-834-8940
E-mail: yfu@midway.uchicago.edu

View the PDF of this article at: https://www.the-jci.org/press/19188.pdf

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Curious antithrombotic effects of TNF-a_

It is commonly believed that TNF-alpha, a proinflammatory cytokine, also has strong prothrombotic effects. Denisa Wagner and colleagues at Harvard Medical School have now addressed this question experimentally using intravital microscopy of thrombus formation in mice arterioles in the November 14 issue of the Journal of Clinical Investigation.

Treatment with doses of TNF-alpha, such as would occur in patients with septic conditions or related infectious disorders, actually inhibited platelet aggregation and thrombus formation in vivo. Platelets from TNF-alpha-treated mice had decreased fibrinogen binding and P-selectin expression and reduced platelet aggregation in response to agonists. In contrast, in vitro treatment of platelets with TNF-alpha_did not affect their function. The antithrombotic effect of TNF-alpha was mediated through rapid production of NO by inducible nitric oxide synthase from cells of the vessel wall. This study points to a new inflammatory function of TNF-alpha in transiently inhibiting thrombosis to allow the immune response to be optimally executed.

TITLE: Antithrombotic activity of TNF-alpha

AUTHOR CONTACT:
Denisa Wagner
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617-278-3344
Fax: 617-278-3368
E-mail: wagner@cbr.med.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/19284.pdf

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Second case of rare human enzyme deficiency identified

Proprotein convertase 1 (PC1) cleaves large inactive secreted protein precursors in order to release their bioactive fragments. In an earlier study, Stephen O'Rahilly and colleagues from the University of Cambridge described the only reported case of human PC1 deficiency. In the November 14 issue of the Journal of Clinical Investigation this same group reports a second case of human PC1 deficiency. While both subjects suffered from obesity, hypoadrenalism, reactive hypoglycemia, and elevated levels of certain prohormones, the clinical presentation of subject B was dominated by small intestine dysfunction manifest as severe refractory neonatal diarrhea. Subsequent examination of subject A also revealed such dysfunction. The authors propose that PC1 is essential for the normal absorptive function of the human small intestine. Interestingly, mice lacking PC1 do not manifest the degree of obesity or growth retardation observed in human subjects, suggesting that the precise physiological repertoire of this enzyme may vary between mammalian species.

TITLE: Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency

AUTHOR CONTACT:
Stephen O'Rahilly
Addenbrooke's Hospital, Cambridge, United Kingdom.
Phone: 44-122-333-6855
Fax: 44-122-333-0598
E-mail: sorahill@hgmp.mrc.ac.uk

View the PDF of this article at: https://www.the-jci.org/press/18784.pdf

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Disruption of Smad3 signaling prevents fibrosis

Renal interstitial fibrosis is a progressive and potentially lethal disease caused by urinary tract obstruction, chronic inflammation, and diabetes. A critical step in the development of this condition is the transition of renal tubular epithelial cells to myofibroblasts, which deposit excess extracellular matrix causing irreversible renal failure. In the November 14 issue of the Journal of Clinical Investigation, Akira Ooshima and colleagues from Wakayama Medical University, Japan, demonstrate that in mice lacking Smad3, unilateral ureteral obstruction does not cause epithelial-mesenchymal transition, and there is no fibrosis. The data indicate that Smad3 signaling is central for the transdifferentiation of epithelial cells to myofibroblastic cells and represents a possible target for disruption in order to control fibrosis at multiple organ sites.

TITLE: Targeted disruption of TGF-b1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction

AUTHOR CONTACT:
Akira Ooshima
Wakayama Medical University, Wakayama, Japan.
Phone: 073-441-0634
Fax: 073-446-3781
E-mail: aooshima@wakayama-med.ac.jp

View the PDF of this article at: https://www.the-jci.org/press/19270.pdf

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