Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact

Issue published April 1, 2004

  • Volume 113, Issue 7 , Pages 933-1070
  • Previous Issue | Next Issue
Go to section:
  • In this issue (1)
  • Book Review (1)
  • News (1)
  • Review Series (2)
  • Commentaries (4)
  • Research Articles (12)
  • Errata (3)
In this issue
In This Issue
/articles/view/119996
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):933-933. https://doi.org/10.1172/JCI119996.
View: Text | PDF

In This Issue

  • Text
  • PDF
Abstract

Authors

×
Book Review
Black death: AIDS in Africa
Roger J. Pomerantz
Roger J. Pomerantz
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):935-935. https://doi.org/10.1172/JCI21490.
View: Text | PDF

Black death: AIDS in Africa

  • Text
  • PDF
Abstract

Authors

Roger J. Pomerantz

×
News
Persistence—luck—Avastin
Laurie Goodman
Laurie Goodman
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):934-934. https://doi.org/10.1172/JCI21507.
View: Text | PDF

Persistence—luck—Avastin

  • Text
  • PDF
Abstract

Authors

Laurie Goodman

×
Review Series
Acute HIV revisited: new opportunities for treatment and prevention
Christopher D. Pilcher, … , Cynthia Gay, Myron S. Cohen
Christopher D. Pilcher, … , Cynthia Gay, Myron S. Cohen
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):937-945. https://doi.org/10.1172/JCI21540.
View: Text | PDF | Corrigendum

Acute HIV revisited: new opportunities for treatment and prevention

  • Text
  • PDF
Abstract

Inability to recognize incident infection has traditionally limited both scientific and public health approaches to HIV disease. Recently, some laboratories have begun adding HIV nucleic acid amplification testing to HIV diagnostic testing algorithms so that acute (antibody-negative) HIV infections can be routinely detected within the first 1–3 weeks of exposure. In this review article, we will highlight critical opportunities for HIV treatment and prevention that are presented by these diagnostic strategies.

Authors

Christopher D. Pilcher, Joseph J. Eron Jr., Shannon Galvin, Cynthia Gay, Myron S. Cohen

×

Dengue: defining protective versus pathologic immunity
Alan L. Rothman
Alan L. Rothman
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):946-951. https://doi.org/10.1172/JCI21512.
View: Text | PDF

Dengue: defining protective versus pathologic immunity

  • Text
  • PDF
Abstract

Dengue is an expanding public health problem, and an effective vaccine remains elusive. This review discusses how the significant influence of sequential infection with different dengue virus serotypes on the severity of disease can be viewed in terms of beneficial and detrimental effects of heterologous immunity. A more complete understanding of these effects is likely to be critical for predicting optimal vaccine-induced immune responses.

Authors

Alan L. Rothman

×
Commentaries
Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin
Grant R. Kolar, J. Donald Capra
Grant R. Kolar, J. Donald Capra
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):952-954. https://doi.org/10.1172/JCI21412.
View: Text | PDF

Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin

  • Text
  • PDF
Abstract

The factors that contribute to the development of B cell chronic lymphocytic leukemia (B-CLL) are unknown, and the groups of individuals at the greatest risk for developing this common leukemia are not well defined. Molecular features are important for classifying cases of B-CLL, and it is now apparent that similarities among Ig rearrangements between patients may give important clues to the origin of this disease.

Authors

Grant R. Kolar, J. Donald Capra

×

The β1 subunit of the Ca2+-sensitive K+ channel protects against hypertension
Mark T. Nelson, Adrian D. Bonev
Mark T. Nelson, Adrian D. Bonev
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):955-957. https://doi.org/10.1172/JCI21388.
View: Text | PDF

The β1 subunit of the Ca2+-sensitive K+ channel protects against hypertension

  • Text
  • PDF
Abstract

Previous animal studies have demonstrated that the loss of the β1 subunit of the large-conductance Ca2+-activated K+ (BK) channel leads to hypertension. A new study demonstrates that a gain in β1 subunit function is associated with protection against diastolic hypertension in humans, underscoring the importance of the β1 subunit and the BK channel in the regulation of vascular resistance.

Authors

Mark T. Nelson, Adrian D. Bonev

×

Functional obstruction: the renal pelvis rules
Cathy Mendelsohn
Cathy Mendelsohn
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):957-959. https://doi.org/10.1172/JCI21402.
View: Text | PDF

Functional obstruction: the renal pelvis rules

  • Text
  • PDF
Abstract

Failure in the peristaltic mechanism that conducts urine from the kidney to the bladder can lead to hydronephrosis, a common birth defect associated with obstructive nephropathy. New animal models reveal molecular pathways important for peristalsis and point to the central role of the renal pelvis in urine transport.

Authors

Cathy Mendelsohn

×

Bim, Bad, and Bax: a deadly combination in epileptic seizures
Jerome Niquet, Claude G. Wasterlain
Jerome Niquet, Claude G. Wasterlain
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):960-962. https://doi.org/10.1172/JCI21478.
View: Text | PDF

Bim, Bad, and Bax: a deadly combination in epileptic seizures

  • Text
  • PDF
Abstract

Several Bcl-2 family members, including Bim, may contribute to programmed cell death by inducing mitochondrial cytochrome c release, which activates caspase-9 and then caspase-3, the “executioner” of the cell. In this issue of the JCI, Shinoda and collaborators show the key role of Bim in epileptic seizure–induced neuronal injury and identify the contribution of transcription factors responsible for seizure-induced Bim upregulation .

Authors

Jerome Niquet, Claude G. Wasterlain

×
Research Articles
Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection
Daniele Accapezzato, … , Mario U. Mondelli, Vincenzo Barnaba
Daniele Accapezzato, … , Mario U. Mondelli, Vincenzo Barnaba
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):963-972. https://doi.org/10.1172/JCI20515.
View: Text | PDF | Corrigendum

Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection

  • Text
  • PDF
Abstract

Regulatory T (TR) cells consist of phenotypically and functionally distinct CD4+ and CD8+ T cell subsets engaged both in maintaining self-tolerance and in preventing anti–non-self effector responses (microbial, tumor, transplant, and so on) that may be harmful to the host. Here we propose that the proinflammatory function of virus-specific memory effector CCR7–CD8+ T cells, which are massively recruited in the liver, are inefficient (in terms of IFN-γ production) in patients with chronic hepatitis C virus (HCV) infection because of the concomitant presence of virus-specific CCR7–CD8+ TR cells producing considerable amounts of IL-10. These CD8+ TR cells are antigen specific, as they can be stimulated by HCV epitopes and suppress T cell responses that are in turn restored by the addition of neutralizing anti–IL-10. This study provides for the first time to our knowledge direct evidence of the existence of virus-specific CD8+ TR cells that infiltrate the livers of patients with chronic HCV infection, identifies IL-10 as a soluble inhibitory factor mediating suppression, and suggests that these cells play a pivotal role in controlling hepatic effector CD8+ T cell responses.

Authors

Daniele Accapezzato, Vittorio Francavilla, Marino Paroli, Marco Casciaro, Lucia Valeria Chircu, Agostino Cividini, Sergio Abrignani, Mario U. Mondelli, Vincenzo Barnaba

×

Complement-independent Ab-induced peroxide lysis of platelets requires 12-lipoxygenase and a platelet NADPH oxidase pathway
Michael Nardi, … , Zongdong Li, Simon Karpatkin
Michael Nardi, … , Zongdong Li, Simon Karpatkin
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):973-980. https://doi.org/10.1172/JCI20726.
View: Text | PDF

Complement-independent Ab-induced peroxide lysis of platelets requires 12-lipoxygenase and a platelet NADPH oxidase pathway

  • Text
  • PDF
Abstract

Antiplatelet GPIIIa49–66 Ab of HIV-related thrombocytopenic patients induces thrombocytopenia and platelet fragmentation by the generation of peroxide and other reactive oxygen species (ROS). Here we report the presence of a functional platelet NADPH oxidase pathway that requires activation by the platelet 12-lipoxygenase (12-LO) pathway to fragment platelets. A new Ab-mediated mechanism is described in which the platelet 12-LO product, 12(S)-HETE activates the NADPH oxidase pathway to generate ROS.

Authors

Michael Nardi, Steven J. Feinmark, Liang Hu, Zongdong Li, Simon Karpatkin

×

PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS
Sriram Venneti, … , Stephen R. Wisniewski, Clayton A. Wiley
Sriram Venneti, … , Stephen R. Wisniewski, Clayton A. Wiley
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):981-989. https://doi.org/10.1172/JCI20227.
View: Text | PDF

PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS

  • Text
  • PDF
Abstract

HIV infection in humans and simian immunodeficiency virus (SIV) infection in macaques result in encephalitis in approximately one-quarter of infected individuals and is characterized by infiltration of the brain with infected and activated macrophages. 1-(2-chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (PK11195) is a ligand specific for the peripheral benzodiazepine receptor abundant on macrophages and is expressed in low levels in the noninfected brain. We hypothesized that positron-emission tomography (PET) with the carbon-11–labeled, R-enantiomer form of PK11195 ([11C](R)-PK11195) could image brain macrophages and hence the development of encephalitis in vivo. [11C](R)-PK11195 binding was assessed in the brain using PET in 11 SIV infected macaques, six of which showed increased binding in vivo. Postmortem examination of the brain in these six macaques demonstrated encephalitis, while macaques that did not show an increase in [11C](R)-PK11195 binding did not develop SIV encephalitis. Brain tissue from SIV encephalitic macaques also showed increased [3H](R)-PK11195 binding compared with binding in nonencephalitic macaques. Increased PK11195 binding in vivo and in postmortem brain tissue correlated with abundance of macrophages but not astrocytes. Our results suggest that PET [11C](R)-PK11195 imaging can detect the presence of macrophages in SIV encephalitis in vivo and may be useful to predict the development of HIV encephalitis and in studies of the pathogenesis and treatment of HIV dementia.

Authors

Sriram Venneti, Brian J. Lopresti, Guoji Wang, Stephanie J. Bissel, Chester A. Mathis, Carolyn C. Meltzer, Fernando Boada, Saverio Capuano III, Geraldine J. Kress, Denise K. Davis, James Ruszkiewicz, Ian J. Reynolds, Michael Murphey-Corb, Anita M. Trichel, Stephen R. Wisniewski, Clayton A. Wiley

×

Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease
Hanspeter Waldner, … , Mary Collins, Vijay K. Kuchroo
Hanspeter Waldner, … , Mary Collins, Vijay K. Kuchroo
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):990-997. https://doi.org/10.1172/JCI19388.
View: Text | PDF

Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease

  • Text
  • PDF
Abstract

We describe the generation of mice that express a transgenic T cell receptor (TCR) (5B6) specific for the encephalitogenic myelin proteolipid protein (PLP) peptide 139–151, on the experimental autoimmune encephalomyelitis–resistant (EAE-resistant) B10.S background. Despite harboring a high frequency of self-reactive T cells, 5B6 transgenic mice on the B10.S background rarely develop spontaneous EAE, which is in striking contrast to 5B6 transgenic mice on the EAE-susceptible SJL background. The relative resistance to spontaneous EAE in transgenic B10.S mice is not due to deletion or anergy of T cells, but appears to be controlled by APCs. Analysis of APCs revealed a lower activation state and a lower T cell–activating capacity for APCs from B10.S mice than for those from EAE-susceptible SJL mice. When APCs in 5B6 transgenic B10.S mice were activated, for example, via TLR9 or TLR4, T cell tolerance was broken, resulting in EAE. Our findings demonstrate that activation of APCs via innate immune receptors can break self tolerance and trigger the development of autoimmunity even in a genetically resistant strain. These findings suggest that the development of autoimmune diseases such as multiple sclerosis is determined at least partly by the endogenous activation state of APCs.

Authors

Hanspeter Waldner, Mary Collins, Vijay K. Kuchroo

×

Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells
Igor M. Belyakov, … , Gregory M. Glenn, Jay A. Berzofsky
Igor M. Belyakov, … , Gregory M. Glenn, Jay A. Berzofsky
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):998-1007. https://doi.org/10.1172/JCI20261.
View: Text | PDF

Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells

  • Text
  • PDF
Abstract

Transcutaneous immunization (TCI), the application of vaccines on the skin, induces robust systemic and mucosal antibodies in animal models and in humans. The means by which mucosal immune responses to vaccine antigens are elicited by TCI has not been well characterized. We examined the effect of TCI with an HIV peptide vaccine on the induction of mucosal and systemic CTL responses and protective immunity against mucosal challenge with live virus in mice. Robust HIV-specific CTL responses in the spleen and in the gut mucosa were detected after TCI. The responses were dependent upon the addition of an adjuvant and resulted in protection against mucosal challenge with recombinant vaccinia virus encoding HIV gp160. Although it is clear that adjuvant-activated DCs migrated mainly to draining lymph nodes, coculture with specific T cells and flow cytometry studies with DCs isolated from Peyer’s patches after TCI suggested that activated DCs carrying skin-derived antigen also migrated from the skin to immune-inductive sites in gut mucosa and presented antigen directly to resident lymphocytes. These results and previous clinical trial results support the observation that TCI is a safe and effective strategy for inducing strong mucosal antibody and CTL responses.

Authors

Igor M. Belyakov, Scott A. Hammond, Jeffrey D. Ahlers, Gregory M. Glenn, Jay A. Berzofsky

×

Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia
Fabio Ghiotto, … , Manlio Ferrarini, Nicholas Chiorazzi
Fabio Ghiotto, … , Manlio Ferrarini, Nicholas Chiorazzi
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1008-1016. https://doi.org/10.1172/JCI19399.
View: Text | PDF

Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia

  • Text
  • PDF
Abstract

Studies of B cell antigen receptors (BCRs) expressed by leukemic lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that B lymphocytes with some level of BCR structural restriction become transformed. While analyzing rearranged VHDJH and VLJL genes of 25 non–IgM-producing B-CLL cases, we found five IgG+ cases that display strikingly similar BCRs (use of the same H- and L-chain V gene segments with unique, shared heavy chain third complementarity-determining region [HCDR3] and light chain third complementarity-determining region [LCDR3] motifs). These H- and L-chain characteristics were not identified in other B-CLL cases or in normal B lymphocytes whose sequences are available in the public databases. Three-dimensional modeling studies suggest that these BCRs could bind the same antigenic epitope. The structural features of the B-CLL BCRs resemble those of mAb’s reactive with carbohydrate determinants of bacterial capsules or viral coats and with certain autoantigens. These findings suggest that the B lymphocytes that gave rise to these IgG+ B-CLL cells were selected for this unique BCR structure. This selection could have occurred because the precursors of the B-CLL cells were chosen for their antigen-binding capabilities by antigen(s) of restricted nature and structure, or because the precursors derived from a B cell subpopulation with limited BCR heterogeneity, or both.

Authors

Fabio Ghiotto, Franco Fais, Angelo Valetto, Emilia Albesiano, Shiori Hashimoto, Mariella Dono, Hideyuki Ikematsu, Steven L. Allen, Jonathan Kolitz, Kanti R. Rai, Marco Nardini, Anna Tramontano, Manlio Ferrarini, Nicholas Chiorazzi

×

Transcription-controlled gene therapy against tumor angiogenesis
Shoshana Greenberger, … , David Wallach, Dror Harats
Shoshana Greenberger, … , David Wallach, Dror Harats
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1017-1024. https://doi.org/10.1172/JCI20007.
View: Text | PDF

Transcription-controlled gene therapy against tumor angiogenesis

  • Text
  • PDF
Abstract

A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell–specific apoptosis, using adenoviral vector–mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-α. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1–based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.

Authors

Shoshana Greenberger, Aviv Shaish, Nira Varda-Bloom, Keren Levanon, Eyal Breitbart, Iris Goldberg, Iris Barshack, Israel Hodish, Niva Yaacov, Livnat Bangio, Tanya Goncharov, David Wallach, Dror Harats

×

Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII
Paris Margaritis, … , Alexander Schlachterman, Katherine A. High
Paris Margaritis, … , Alexander Schlachterman, Katherine A. High
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1025-1031. https://doi.org/10.1172/JCI20106.
View: Text | PDF

Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII

  • Text
  • PDF
Abstract

Hemophilia is a bleeding disorder caused by mutations in the genes encoding coagulation Factor VIII (FVIII) or FIX. Current treatment is through intravenous infusion of the missing protein. The major complication of treatment is the development of neutralizing Ab’s to the clotting factor. Infusion of recombinant activated human Factor VII (rhFVIIa), driving procoagulant reactions independently of human FVIII (hFVIII) or hFIX, has been successful in such patients and could in theory provide hemostasis in all hemophilia patients. However, its high cost and short half-life have limited its use. Here, we report a novel treatment strategy with a recombinant adeno-associated virus vector delivering a modified FVII transgene that can be intracellularly processed and secreted as activated FVII (FVIIa). We show long-term expression, as well as phenotypic correction of hemophilia B mice following gene transfer of the murine FVIIa homolog, with no evidence of thrombotic complications at these doses. These data hold promise for a potential treatment for hemophilia and other bleeding disorders.

Authors

Paris Margaritis, Valder R. Arruda, Majed Aljamali, Rodney M. Camire, Alexander Schlachterman, Katherine A. High

×

Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension
José M. Fernández-Fernández, … , Jaume Marrugat, Miguel A. Valverde
José M. Fernández-Fernández, … , Jaume Marrugat, Miguel A. Valverde
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1032-1039. https://doi.org/10.1172/JCI20347.
View: Text | PDF

Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension

  • Text
  • PDF
Abstract

Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca2+-dependent K+ (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting α subunit and a regulatory β1 subunit, which couples local increases in intracellular Ca2+ to augmented channel activity and vascular relaxation. Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the β1 gene (KCNMB1), corresponding to an E65K mutation in the protein. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-β1E65K channels showed increased Ca2+ sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-β1E65K channel might offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension.

Authors

José M. Fernández-Fernández, Marta Tomás, Esther Vázquez, Patricio Orio, Ramón Latorre, Mariano Sentí, Jaume Marrugat, Miguel A. Valverde

×

VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment
Claus Cursiefen, … , Stanley J. Wiegand, J. Wayne Streilein
Claus Cursiefen, … , Stanley J. Wiegand, J. Wayne Streilein
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1040-1050. https://doi.org/10.1172/JCI20465.
View: Text | PDF

VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment

  • Text
  • PDF
Abstract

Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1+ lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A164/164 or VEGF-A188/188 (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A–mediated lymphangiogenesis. Either systemic depletion of all bone marrow–derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis.

Authors

Claus Cursiefen, Lu Chen, Leonardo P. Borges, David Jackson, Jingtai Cao, Czeslaw Radziejewski, Patricia A. D’Amore, M. Reza Dana, Stanley J. Wiegand, J. Wayne Streilein

×

Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery
Ching-Pin Chang, … , Gerald R. Crabtree, Feng Chen
Ching-Pin Chang, … , Gerald R. Crabtree, Feng Chen
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1051-1058. https://doi.org/10.1172/JCI20049.
View: Text | PDF

Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

  • Text
  • PDF
Abstract

Congenital obstructive nephropathy is the principal cause of renal failure in infants and children. The underlying molecular and cellular mechanisms of this disease, however, remain largely undetermined. We generated a mouse model of congenital obstructive nephropathy that resembles ureteropelvic junction obstruction in humans. In these mice, calcineurin function is removed by the selective deletion of Cnb1 in the mesenchyme of the developing urinary tract using the Cre/lox system. This deletion results in reduced proliferation in the smooth muscle cells and other mesenchymal cells in the developing urinary tract. Compromised cell proliferation causes abnormal development of the renal pelvis and ureter, leading to defective pyeloureteral peristalsis, progressive renal obstruction, and, eventually, fatal renal failure. Our study demonstrates that calcineurin is an essential signaling molecule in urinary tract development and is required for normal proliferation of the urinary tract mesenchymal cells in a cell-autonomous manner. These studies also emphasize the importance of functional obstruction, resulting from developmental abnormality, in causing congenital obstructive nephropathy.

Authors

Ching-Pin Chang, Bradley W. McDill, Joel R. Neilson, Heidi E. Joist, Jonathan A. Epstein, Gerald R. Crabtree, Feng Chen

×

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy
Sachiko Shinoda, … , Roger P. Simon, David C. Henshall
Sachiko Shinoda, … , Roger P. Simon, David C. Henshall
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1059-1068. https://doi.org/10.1172/JCI19971.
View: Text | PDF

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

  • Text
  • PDF
Abstract

Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2–interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.

Authors

Sachiko Shinoda, Clara K. Schindler, Robert Meller, Norman K. So, Tomohiro Araki, Akitaka Yamamoto, Jing-Quan Lan, Waro Taki, Roger P. Simon, David C. Henshall

×
Errata
BAFF selectively enhances the survival of plasmablasts generated from human memory B cells
Danielle T. Avery, … , Philip D. Hodgkin, Stuart G. Tangye
Danielle T. Avery, … , Philip D. Hodgkin, Stuart G. Tangye
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1069-1069. https://doi.org/10.1172/JCI18025E1.
View: Text | PDF | Amended Article

BAFF selectively enhances the survival of plasmablasts generated from human memory B cells

  • Text
  • PDF
Abstract

Authors

Danielle T. Avery, Susan L. Kalled, Julia I. Ellyard, Christine Ambrose, Sarah A. Bixler, Marilyn Thien, Robert Brink, Fabienne Mackay, Philip D. Hodgkin, Stuart G. Tangye

×

New insights into atopic dermatitis
Donald Y.M. Leung, … , Ichiro Nomura, Qutayba A. Hamid
Donald Y.M. Leung, … , Ichiro Nomura, Qutayba A. Hamid
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1070-1070. https://doi.org/10.1172/JCI21060E1.
View: Text | PDF | Amended Article

New insights into atopic dermatitis

  • Text
  • PDF
Abstract

Authors

Donald Y.M. Leung, Mark Boguniewicz, Michael D. Howell, Ichiro Nomura, Qutayba A. Hamid

×

Multiple sclerosis
David A. Hafler
David A. Hafler
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1070-1070. https://doi.org/10.1172/JCI21357E1.
View: Text | PDF | Amended Article

Multiple sclerosis

  • Text
  • PDF
Abstract

Authors

David A. Hafler

×
Advertisement
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts