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JCI table of contents: May 24, 2010

EDITOR'S PICK: Signatures of kidney transplant rejection and acceptance

Three new reports describe biomarkers that identify either kidney transplant recipients likely to maintain excellent and stable allograft function in the absence of immunosuppressive drugs or those at risk of losing their transplants. Peter Heeger and Bernd Schrppel, at Mount Sinai School of Medicine, New York, describe in an accompanying commentary, the importance of these studies and how they might impact the management of patients in the clinic to provide a more personalized treatment regimen.

The most common solid organ transplant procedure performed in the US is kidney transplantation for the treatment of end-stage kidney disease. Transplant recipients must take immunosuppressive drugs for the rest of their lives to prevent rejection of their transplanted kidney, and this has serious negative health consequences. Furthermore, these drugs do not prevent either late-stage rejection of the transplant or transplant failure. To improve long-term outcomes it would be helpful if physicians could determine whether a patient was at risk of losing their transplanted kidney or whether a patient's immune system was sufficiently tolerant of the transplanted kidney that they could stop taking their immunosuppressive drugs.

Two teams of researchers one led by Maria Hernandez-Fuentes, at King's College London, United Kingdom, and the other led by Kenneth Newell, at Emory University, Atlanta, Laurence Turka, at Beth Israel Deaconess Medical Center, Boston, and Vicki Seyfert-Margolis, at Immune Tolerance Network, Bethesda, independently identified and studied rare kidney transplant recipients who have excellent and stable graft function despite no longer taking their immunosuppressive drugs. Both groups identified a signature that was associated with this outcome and both signatures were indicative of immune cells known as B cells having a beneficial role. In contrast, in the third study, researchers led by Philip Halloran, at the University of Alberta, Edmonton, identified in patients who had received their kidney transplant more than a year prior to the analysis a molecular signature indicative of future organ failure. All three groups hope that if validated in further studies their signatures might help physicians design more personalized treatment regimens for kidney transplant recipients, for example identifying those that might be candidates for drug-weaning protocols.

TITLE: Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans

Maria Hernandez-Fuentes
King's College London, Guy's Hospital, London, United Kingdom.
Phone: 44.20718.85435; Fax: 44.20718.83638; E-mail:

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TITLE: Identification of a B cell signature associated with renal transplant tolerance in humans

Kenneth A. Newell
Emory University, Atlanta, Georgia, USA.
Phone: 404.727.2489; Fax: 404.727.3660; E-mail:

Laurence A. Turka
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: 617.735.2919; Fax: 617.735.2902; E-mail:

Vicki L. Seyfert-Margolis
Food and Drug Administration, Silver Spring, Maryland, USA.
Phone: 301.796.5307; Fax: 301.847.3533; E-mail:

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TITLE: A molecular classifier for predicting future graft loss in late kidney transplant biopsies

Philip F. Halloran
Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Alberta, Canada.
Phone: 780.407.8880; Fax: 780.407.3417; E-mail:

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TITLE: Gazing into a crystal ball to predict kidney transplant outcome

Peter S. Heeger
Mount Sinai School of Medicine, New York, New York, USA.
Phone: 212.241.6324; Fax: 212.987.0389; E-mail:

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EDITOR'S PICK: What is the protein modification hypusine? A therapeutic target in diabetes

Underlying all forms of diabetes is dysfunction of cells in the pancreas known as beta cells. The dysfunction is, in part, a result of inflammation mediated by soluble immune molecules known as cytokines. Greater understanding is needed of the molecular mechanisms by which beta cells respond to cytokines if protective therapeutics are to be developed. Insight into this issue has now been generated in mice by researchers, led by Raghavendra G. Mirmira, at Indiana University School of Medicine, Indianapolis, who have identified a crucial role in this response for the protein eIF5A. Importantly, both depleting eIF5A and preventing it from becoming active, by blocking its modification to contain the molecule hypusine, protected mice in a model of diabetes. The authors therefore suggest that developing therapeutics that prevent the hypusine modification of eIF5A might be a good way to preserve pancreatic beta cell function.

In an accompanying commentary, Joachim Hauber, at Heinrich-Pette-Institute for Experimental Virology and Immunology, Germany, agrees that targeting eIF5A hypusine modification might make a good therapeutic approach and discusses how these data provide new understanding of the function of eIF5A, information that has thus far been elusive to uncover.

TITLE: The unique hypusine modification of eIF5A promotes islet beta cell inflammation and dysfunction in mice

Raghavendra G. Mirmira
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Phone: 317.274.4145; Fax: 317.274.4107; E-mail:

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TITLE: Revisiting an old acquaintance: role for eIF5A in diabetes

Joachim Hauber
Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany.
Phone: 49.40.48051.241; Fax: 49.40.48051.184; E-mail:

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ONCOLOGY: Tumor cell spread: an early event kept in check by the immune system

The major cause of death in patients with cancer is the formation of tumors at sites distant to the initial tumor. Understanding more about the processes involved in the spread and development of tumors at distant sites is therefore of great importance for developing new anticancer therapeutics. A team of researchers, led by Jean-Pierre Abastado, at the Singapore Immunology Network, Singapore, has now provided insight into the issue by studying tumor cell dissemination in a mouse model of spontaneous melanoma (the most dangerous form of skin cancer). Martin Rcken, at Eberhard Karls University, Germany, discusses the importance of these data in an accompanying commentary.

The classical model of tumor cell dissemination is that it occurs late in tumor development, after the original tumor has grown. However, recent evidence suggests that single tumor cells spread to distant sites very early in the development of the original tumor. In the study, Abastado and colleagues found that tumor cells did spread to distant sites early during the development of the original tumor, even before it became clinically detectable. Interestingly, the disseminated tumor cells remained dormant for varying periods of time depending on the tissue to which they had spread. The reason the disseminated tumor cells remained dormant was that they were prevented from proliferating by immune cells known as CD8+ T cells. The authors therefore suggest that therapeutic approaches designed to bolster these immune responses should help prevent the outgrowth of tumor cells at distant sites and improve outcomes for individuals with early-stage cancer.

TITLE: Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma

Jean-Pierre Abastado
Singapore Immunology Network, BMSI, A-STAR, Singapore.
Phone: 65.6407.0003; Fax: 65.6464.2057; E-mail:

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TITLE: Early tumor dissemination, but late metastasis: insights into tumor dormancy

Martin Rcken
Eberhard Karls University, Tbingen, Germany.
Phone: 49.7071.2984556; Fax: 49.7071.295450; E-mail:

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INFLAMMATION: Uric acid: an in vivo trigger of sterile inflammation

Inflammation occurs not only upon microbial infection but also in response to tissue damage under sterile conditions, an event that contributes to many diseases including acetaminophen-induced liver toxicity, the most common cause of acute liver failure in the Western world. Exactly what triggers the inflammatory response under sterile conditions in vivo has not been determined, although in vitro studies have suggested several molecular candidate triggers. Now, a team of researchers, led by Kenneth Rock, at the University of Massachusetts Medical School, Worcester, has determined that one of these candidate molecules, uric acid, is a proinflammatory molecule released from dying cells and that it acts as an important trigger of cell deathinduced inflammatory responses, such as those that model acetaminophen-induced liver toxicity, in mice. In an accompanying commentary, Yan Shi, at the University of Calgary, Edmonton, outlines the novelty of this observation and suggests that uric acid might be a good therapeutic target for the treatment of inflammation induced under sterile conditions associated with substantial cell death.

TITLE: Uric acid promotes an acute inflammatory response to sterile cell death in mice

Kenneth L. Rock
University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Phone: 508.856.2521; Fax: 508.856.1094; E-mail:

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TITLE: Caught red handed: uric acid is an agent of inflammation

Yan Shi
University of Calgary, Calgary, Alberta, Canada.
Phone: 403.220.2536; Fax: 403.220.2772; E-mail:

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PULMONARY: Natural protection from scarring of the lungs

Pulmonary fibrosis, a medical condition often described as scarring of the lungs, develops as a progressive, dysregulated response to lung injury. One natural process that protects the lung from fibrosis is activation of the protein plasminogen, but how this provides protection has not been determined. Now, a team of researchers, led by Bethany Moore and Marc Peters-Golden, at the University of Michigan, Ann Arbor, has provided insight into this issue by studying the mechanism by which mice lacking an inhibitor of plasminogen activation known as PAI-1 are protected in a model of pulmonary fibrosis. The key finding of the study was that a known antifibrotic mediator, PGE2, was expressed at high levels in the lungs of mice lacking PAI-1 during fibrosis. Further analysis clearly defined the molecular pathway by which increased plasminogen led to PGE2 production. The clinical relevance of these data was highlighted by the observation that cells in the lungs of patients with a form of pulmonary fibrosis known as idiopathic pulmonary fibrosis were unable to increase PGE2 production in response to the production of plasminogen activation.

TITLE: The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice

Bethany B. Moore
University of Michigan, Ann Arbor, Michigan, USA.
Phone: 734.647.8378; Fax: 734.612.2331; E-mail:

Marc Peters-Golden
University of Michigan, Ann Arbor, Michigan, USA.
Phone: 734.763.9077; Fax: 734.764.4556; E-mail:

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BONE BIOLOGY: A key role in breaking bone down for the protein Cdc42

A team of researchers, led by Patrick Ross and Haibo Zhao, at Washington University School of Medicine, St. Louis, has determined that the protein Cdc42 has an important role in regulating the formation and function of cells that destroy bone in mice. Their data lead them to suggest that Cdc42 might be a good target for developing therapies for the treatment of conditions associated with bone loss such as osteoporosis.

Bone destruction is mediated by cells known as osteoclasts. Osteoporosis occurs when osteoclast numbers or function are greater than normal. In the study, mice lacking functional Cdc42 in their osteoclasts were resistant to bone loss in a model of postmenopausal osteoporosis. Conversely, mice in which Cdc42 activity was increased showed enhanced bone accumulation. Further analysis provided insight into the molecular mechanisms underlying the effects of Cdc42 and indicated that it had a key role in several signaling pathways that regulate osteoclast formation and function.

TITLE: Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization

F. Patrick Ross
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314.454.8463; Fax: 314.454.5505; E-mail:

Haibo Zhao
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314.454.8463; Fax: 314.454.5505; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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