September 2003

From Journal of Clinical Investigation

JCI Table of Contents

Analysis of the host response to anthrax lethal toxin suggests some current treatment strategies are inappropriate

Anthrax, a disease previously primarily relevant to the livestock-management community recently became a wordwide bioterrorism concern. However, human anthrax infection is primarily a result of direct or indirect contact with infected animals or exposure to contaminated animal products.

Bacillus anthracis, the causative agent of anthrax, is believed to induce disease and death in humans in an endotoxic shock�like manner.

A comprehensive study of the effects of anthrax lethal toxin in mice by Stephen Leppla and colleagues at the National Institutes of Health demonstrated that toxin-induced death does not result from septic shock mediated by cytokine release as previously thought, but via hypoxia-induced liver failure.

The study strongly suggests that the therapies developed for the treatment of cytokine-mediated septic shock will not be appropriate for the treatment of anthrax.

In an accompanying commentary, Alice Prince from Columbia University College of Physicians and Surgeons in New York states that "this analysis of the pathological effects of the B. anthracis lethal toxin should help focus future studies of optimal therapy for patients exposed to this organism.

These results make clear that anthrax patients exhibit a unique pathophysiology and should not be considered to have generic shock analogous to Gram-negative sepsis". Prince continues "exactly how the lethal factor produces such profound tissue hypoxia, what metabolic processes are affected in the liver and elsewhere, and how these effects may be blocked will require further studies".

TITLE: Bacillus anthracis lethal toxin induces TNF-alpha�independent hypoxia-mediated toxicity in mice

AUTHOR CONTACT:
Stephen Leppla
National Institutes of Health, Bethesda, Maryland, USA
Phone: 301-594-2865
Fax: 301-480-0326
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/17991.pdf

ACCOMPANYING COMMENTARY:
The host response to anthrax lethal toxin: unexpected observations

AUTHOR CONTACT:
Alice S. Prince
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: 212-305-4193
Fax: 212-305-2284
E-mail: [email protected]
View the PDF of this commentary at: https://www.the-jci.org/press/19581.pdf

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Safely achieving tolerance to stem cell transplantation

Dale Greiner and colleagues at the University of Massachusetts have developed a protocol for achieving stem cell transplantation that is not limited by significant patient side-effects and may not necessarily require that donor blood, bone marrow or whole organs are a "match" with the recipient �- characteristics that make these new procedures highly attractive for development and use in clinical human transplantation.

Hematopoietic stem cells (HSCs) are parent cells in the bone marrow that give rise to blood cells. Allogeneic stem cell transplantation has great potential in the treatment of malignancy, genetic disorders, and in solid organ transplantation.

However, the radiation or high doses of chemotherapy commonly used in the treatment of blood cancers to destroy abnormal HSCs--a process called myeloablation-- is very toxic.

Furthermore, even following this form of conditioning, many patients develop graft-versus-host disease (GVHD), where the host immune system launches an attack against the newly transplanted HSCs.

In order to avoid both lethal conditioning and GVHD, new HSC transplant strategies are in development. Greiner et al. have adapted a costimulatory blockade�based protocol developed for solid organ transplantation for use in stem cell transplantation. The authors combined donor-specific transfusion and anti-CD154 monoclonal antibody administration to achieve functional donor and recipient HSC populations within the donor without the need for myeloablation or stimulating the induction of GVHD.

TITLE: Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioning

AUTHOR CONTACT:
Dale L. Greiner
University of Massachusetts Medical School, Worcester, Massachusetts, USA
Phone: 508-856-3800
Fax: 508-856-4093
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/18599.pdf

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Scientists explain why Crohn disease is localized to specific regions of the gut

Markus Neurath and fellow researchers at the University of Mainz, Germany, have characterized the interaction between intestinal bacteria and dendritic cells (DCs) that may provide an explanation for the clinical symptoms of Crohn disease that only occur in specific regions of the gut.

The authors used transgenic mice to investigate the expression of the p40 subunit of IL-12 and IL-23. The authors demonstrate that p40 is expressed by a newly identified subset of DCs at greater levels in the lower part of the small intestine when compared to the proximal part of the small intestine or the colon. Neurath and colleagues demonstrate that p40 production is dependent on the intestinal bacteria as germ-free animals do not exhibit elevated p40 expression in the small intestine. The data reveal important functional differences between the mucosal immune systems of the small and large bowel in healthy mice and suggest that the high numbers of bacteria in the terminal ileum activate p40 expression. The authors suggest that this pattern of p40 expression may explain the predisposition of the terminal ileum to develop chronic inflammation responses via IL-23 and may therefore provide a molecular reason for the preferential clinical manifestation of Crohn disease in this region of the gut.

In an accompanying commentary, Holm Uhlig and Fiona Powrie from the University of Oxford discuss how intestinal DCs sense bacteria in the gut. They also comment that the IL-12 p40 promoter transgenic mice produced by Neurath and coworkers "will be an excellent tool to study the interaction between particular bacteria and the host immune system and how this influences the localization of the immune response".

TITLE: Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells

AUTHOR CONTACT:
Markus F. Neurath
University of Mainz, Mainz, Germany
Phone: 49-6131-172374
Fax: 49-6131-175508
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/17464.pdf

ACCOMPANYING COMMENTARY:
Dendritic cells and the intestinal bacterial flora: a role for localized mucosal immune responses

AUTHOR CONTACT:
Fiona Powrie
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
Phone: 44-1865-285494
Fax: 44-1865-275591
E-mail: In a second independent study in the same issue of the Journal of Clinical Investigation, Rajiv Kumar and colleagues at the Mayo Clinic in Rochester, Minnesota, report that secreted frizzled-related protein-4 (sFRP-4), a factor produced by tumors derived from subjects with tumor-induced osteomalacia (TIO, another syndrome associated with excessive renal phosphate excretion), also has phosphaturic activity.

In an accompanying commentary on both articles, L. Darryl Quarles from Duke University Medical Center in North Carolina discusses the interactions involved in the coordination of bone mineralization and phosphate handling by the kidney. It remains to be established whether FGF-23 and sFRP-4 represent two distinct phosphatonins or are somehow integrated in a novel phosphate-regulating bone-kidney axis. Quarles suggest that "a bone-kidney hormonal axis would provide a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracellular matrix with the renal handling of phosphate".

TITLE: FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting

AUTHOR CONTACT:
Paolo Bianco
Dipartmento di medicina Sperimentale e Patologia, Universit� "La Sapienza", Rome, Italy
Phone: 39-06-444-1049
Fax: 39-06-494-0896
E-mail:
[email protected]
View the PDF of this article at: https://www.the-jci.org/press/18399.pdf

ASSOCIATED ARTICLE: TITLE: Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent

AUTHOR CONTACT:
Rajiv Kumar
Mayo Clinic and Foundation, Rochester, Minnesota, USA
Phone: 507-284-0020
Fax: 507-266-4710
E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/18563.pdf

COMMENTARY ACCOMPANYING BOTH ARTICLES:
Evidence for a bone-kidney axis regulating phosphate homeostasis

AUTHOR CONTACT:
L. Darryl Quarles
Duke University Medical Center, Durham, North Carolina, USA
Phone: 919-660-6853
Fax: 919-684-4476
E-mail: [email protected]
View the PDF of this commentary at: https://www.the-jci.org/press/19687.pdf

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Lymphotoxin comes out of the LIGHT in multiple sclerosis

There is a long-standing conflict regarding the role of the lymphotoxin (LT) pathway in multiple sclerosis (MS). By using different animal models, Jen Gommerman and colleagues from Biogen Inc., in Cambridge, Massachusetts, demonstrate a clear role for this pathway in MS. The authors used a fusion protein decoy, which blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. Inhibition of the LT pathway prevented disease in two models of MS. Disease attenuation was due to inhibition of LT and not the related ligand LIGHT. These results suggest that the LT pathway and its ability to maintain lymphoid microenvironments are critical for sustaining late-phase T cell responses in MS. Inhibition of this pathway may be a promising strategy for the treatment of MS as well as other autoimmune diseases.

TITLE: A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT

AUTHOR CONTACT:
Jennifer Gommerman
University of Toronto, Toronto, Ontario, Canada
Phone: 416-978-6959
Fax: 416-978-1938
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/18648.pdf

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Steady your nerves, steady your bowels

A study by Matti Airaksinen and colleagues at the University of Helsinki in Finland has provided insight into intestinal obstruction associated with Hirschsprung disease, often suffered by individuals with Down Syndrome. The obstruction is caused by the absence of nerves in a section of intestine, which limits intestinal motility.

Formation of parasympathetic and enteric neurons requires glial cell line�derived neurotrophic factor (GDNF) signaling via GDNF family receptor alpha2 (GFRalpha2). The authors examined the factors that could contribute to growth retardation in GFRA2�/� mice. GFRA knockout mice had fewer intrapancreatic neurons, severely impaired cholinergic innervation of exocrine tissue, and little vagally-mediated stimulation of pancreatic secretion. Knockout mice had retarded growth that could be partially overcome with wet-mash feeding. These results suggest that the growth retardation of the Gfra2�/� mice is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility.

TITLE: Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha2

AUTHOR CONTACT:
Matti Airaksinen
Institute of Biotechnology, University of Helsinki, Helsinki, Finland
Phone: 3589-191-59397
Fax: 3589-191-59560
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/17995.pdf

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Troponin T controls energetic affairs of the heart

It has long been noted that while patients with familial hypertrophic cardiomyopathy due to cardiac troponin T (cTnT) mutations often suffer sudden cardiac death, they do not develop significant ventricular hypertrophy (ventricle enlargement), suggesting that a distinct cellular mechanism apart from alterations in myocardial contractility is responsible. A new study by Jil Tardiff and colleagues at the Albert Einstein College of Medicine in New York has revealed that a single missense mutation in cTnT causes a striking disruption to energy metabolism, and cardiomyopathy.

In an accompanying commentary, Ketty Schwartz and Jean-Jacques Mercadier from INSERM in Paris discuss how troponin T regulates cardiac contraction and the functional consequences of this mutation.

TITLE: Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T

AUTHOR CONTACT:
Jil C. Tardiff
Albert Einstein College of Medicine, Bronx, New York, USA
Phone: 718-430-8914
Fax: 718-430-8989
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/15967.pdf

ACCOMPANYING COMMENTARY:
Cardiac troponin T and familial hypertrophic cardiomyopathy: an energetic affair

AUTHOR CONTACT: Ketty Schwartz
INSERM U582, Institut F�d�ratif de Recherches 14, Paris, France
Phone: 33-1-42-16-57-05
Fax: 33-1-42-46-57-00
E-mail: [email protected]
View the PDF of this commentary at: https://www.the-jci.org/press/19632.pdf

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Follicular development in the ovary is driven by angiogenesis

Follicles in the ovary require new blood vessel growth in order to develop. The newly formed ovarian blood vessels secure an increasing supply of gonadotropins, growth factors, oxygen, and steroid precursors to the growing follicle. Blockage of angiogenesis can inhibit follicle development partly by blocking hormonal feedback loops between the ovary and the pituitary gland. Ralf Zimmermann and colleagues from Columbia University in New York studied the intraovarian role of VEGFR- 2 activity on follicular development by using a model in which the pituitary gland is absent, the prepuberally hypophysectomized mouse. Hypophysectomy prevents advanced follicle growth and maturation, but follicle development to the preovulatory stage could be stimulated with gonadotropins. The exogenous gonadotropins were unable to drive follicle development to the preovulatory stage in the presence of anti�VEGFR-2 antibodies. These results show that the intraovarian VEGF/VEGFR-2 pathway is critical for gonadotropin-dependent angiogenesis and follicular development.

TITLE: Vascular endothelial growth factor receptor 2�mediated angiogenesis is essential for gonadotropin-dependent follicle development

AUTHOR CONTACT:
Ralf C. Zimmerman
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: 212-305-8693
Fax: 212-305-3869
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/press/18740.pdf



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