A new step towards an AIDS vaccine
Progressive disease after HIV infection is inversely correlated with the presence of plasmacytoid dendritic cells (pDCs), a subset of the dendritic cell family and the major producers of type 1 interferon in the body. High numbers of pDCs is related to successful control of HIV. In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation, Nina Bhardwaj and colleagues from New York University report the mechanisms by which HIV-1 activates human pDCs.
The authors show that pDC activation by HIV-1 requires at least two interactions between the cell and virus. Initially, envelope-CD4 interactions mediate the endocytosis of HIV-1. Next, viral nucleic acids, particularly RNA, stimulate pDCs through Toll-like receptors.
A decrease of blood pDC frequency is typically observed in chronic infections due to HIV-1 and correlates with high viral load, reduced CD4 counts and susceptibility to opportunistic infections, and is only partially reverted by anti-retroviral therapy. By identifying the active component of HIV-1 which stimulates pDC function, and consequently other antigen presenting cell function, the authors have recognized an important pathway whereby DC function can be targeted in the design of efficient vaccines or immunotherapies for HIV.
TITLE: Endocytosis of HIV-1 Activates Plasmacytoid Dendritic Cells via Toll-Like Receptor -viral RNA interactions
AUTHOR CONTACT:
Nina Bhardwaj
New York University School of Medicine, New York, NY USA
Phone: 1 212 263 5814; Fax: 1 212 263 6729; E-mail: bhardn02@popmail.med.nyu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=26032
EDITOR'S PICK
Good news for the medical marijuana movement: pot proliferates brain cells and boosts mood
Most drugs of abuse decrease the generation of new neurons in the brain, but the effects of marijuana on this process, called neurogenesis, had not been clear. In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation, Xia Zhang and colleagues from University of Saskatchewan show that a potent and synthetic cannabinoid promotes neurogenesis. This drug also exerts anti-anxiety and antidepressant-like effects.
The researchers suggest that there is a positive correlation between increased adult neurogenesis and modified behavior following chronic cannabinoid treatment. These data expand the existing knowledge about the positive roles cannabinoids and their receptors play in brain processing and medicine. Moreover, cannabinoids are perhaps the only illicit drug that can enhance adult neurogenesis and subsequently modify behavior.
TITLE: Cannabinoid promotes embryonic and adult hippocampus neurogenesis and produces anxiolytic- and antidepression-like effects
AUTHOR CONTACT:
Xia Zhang
University of Saskatchewan, Saskatoon, Canada
Phone: 306-966-2288; Fax: 306-966-8830; E-mail: zhangxia@duke.usask.ca
View the PDF of this article at: https://www.the-jci.org/article.php?id=25509
IMMUNOLOGY
In vitro generation of human T cells not naïve anymore
T cells are the front line of the human immune system, and their depletion can lead to life-threatening infections. Because the unique requirements for T cell development are so complicated, it has not been possible to generate these cells in vitro from bone marrow progenitor cells. The ability to do so would lead to significant advancements in the treatment of immune diseases.
In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation, Thomas Kupper and colleagues from Harvard develop an in vitro system for the production of diverse, functional, and self-tolerant human T cells from hematopoietic precursors.
Because the cells of human skin share many similarities with cells of the thymus – an organ required for T-cell production, the authors use normal human skin keratinocytes and fibroblasts on a three-dimensional matrix to support the complete process of T cell development from bone marrow-derived precursor cells.
This work provides evidence that skin and bone marrow biopsies can provide the starting material for generation of a new, patient specific T-cell repertoire. Naïve, newly-generated T cells could have broad clinical applications for a variety of diseases including malignancies, autoimmune diseases, immunodeficiencies, and even transplant rejection.
TITLE: Human skin cells support thymus-independent T cell development
In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation,
AUTHOR CONTACT:
Thomas Kupper
Harvard Skin Disease Research Center, Boston, MA USA
Phone: (617) 525-5550; Fax: (617) 525-5571; E-mail: tkupper@partners.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24731
ONCOLOGY
A 5-gene cancer specific signature signs on in neoplasia
Unbiased screening for cancer-specific transcriptional signatures can help in patient management, but can also assume homogeneity within populations that can, in turn, decrease reliability of predictors when applied on a larger scale.
In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation, Pier Paolo Di Fiore and colleagues undertook an approach based on a biased, rather than unbiased, screening of transformation-specific transcriptomes.
The researchers uncovered "shadow' oncogenic pathways contributing to the development of human malignancies and, perhaps working in parallel with well-documented p53- and Rb-driven oncogenic pathways in human tumors.
Using E1A, an early gene product of tumorigenic adenovirus, which transforms cells in culture and forces terminally differentiated cells to re-enter the cell cycle, the authors identified a transcriptional signature in myotubes, then dissected the mechanisms responsible for activating the individual genes in the signature. Finally, they screened for alterations of the E1A-induced genes in naturally occurring cancers. This led to the identification of a cancer-specific signature composed of 5 genes induced by E1A that are overexpressed in a large fraction of cancers, correlating with tumor progression and unfavorable prognosis. One gene called SKIN, was found to be a novel oncogene that represents the prototype of a bona fide cancer signature, causally involved in human cancer.
TITLE:A cancer-specific transcriptional signature in human neoplasia
AUTHOR CONTACT:
Pier Paolo Di Fiore
IFOM, Istituto FIRC di Oncologia Molecolare, Milan, Italy
Phone: 39-02-574303247; Fax: 39-02-574303231; E-mail: pierpaolo.difiore@ifom-ieo-campus.it
View the PDF of this article at: https://www.the-jci.org/article.php?id=24862
IMMUNOLOGY
New research aims for a novel lupus target
Patients with the autoimmune disease systemic lupus erythematosus (SLE) have decreased production of a protein called IL-2, which is needed for proper immune system function. Loss of IL-2 leads to improper cell-killing responses and the persistence of autoreactive immune T cells. An enzyme that suppresses IL-2 production is called PP2A.
In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation, George Tsokos and colleagues from Walter Reed Army Institute report that the message, protein and catalytic activity of PP2A are increased in patients with SLE regardless of disease activity and treatment and in a disease-specific manner.
The authors show that downregulation of PP2A activity in SLE T cells using a PP2A-small interefering RNA (siRNA) resulted in normalization of IL-2 production. PP2A limits IL-2 production by limiting the binding of pCREB to the IL-2 promoter and by decreasing pCREB binding to the c-fos promoter which results in decreased formation of AP-1 and decreased binding to the IL-2 promoter. Thus, correction of IL-2 production in SLE T cells treated with PP2A-siRNA, as demonstrated in this study, may be useful in treating SLE patients.
TITLE: Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus
AUTHOR CONTACT:
George Tsokos
Walter Reed Army Institute, Silver Spring, MD USA
Phone: 301 319 9911; Fax: 301 319 9133; E-mail: gtsokos@usuhs.mil
View the PDF of this article at: https://www.the-jci.org/article.php?id=24895
ONCOLOGY
Ridding the pesky problem of leukemia after stem cell transplant
In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation, Edward Morris and colleagues from Queensland Institute of Medical Research we have examined the cellular and molecular mechanisms of graft-versus-leukemia after allogeneic stem cell transplantation (SCT).
The authors use novel new analogs of the stem cell mobilization factor G-CSF to mobilize stem cells. They show that natural killer cells play a critical role in eradicating leukemia after allogeneic SCT and that this pathway is enhanced by the use of new potent G-CSF analogs. This data have implications on the stem cell transplant field and introduce a new therapeutic approach for the treatment of hematological malignancy.
TITLE: NKT cell-dependent leukaemia eradication following stem cell mobilization with potent G-CSF analogues
AUTHOR CONTACT:
Edward Morris
Queensland Institute of Medical Research, Brisbane, Australia
Phone: 61 7 3845 3773; Fax: 61 7 3845 3509; E-mail: edwardM@qimr.edu.au
View the PDF of this article at: https://www.the-jci.org/article.php?id=25249
PHYSIOLOGY
Paring down occlusive cardiac disease with PPARs
Proliferation of smooth muscle cells (SMC) is a key event in the development of occlusive cardiovascular diseases, like atherosclerosis. PPAR alpha is a nuclear receptor that plays roles in metabolism, but its involvement in SMC proliferation was not clear.
In a paper appearing online on October 13 in advance of print publication of the November issue of the Journal of Clinical Investigation, Bart Staels and colleague from the Pasteur Institute show that PPAR alpha controls vascular SMC proliferation. The authors show that PPAR alpha inhibits the transition of the SMCs through a specific step in the cell cycle. PPAR alpha activation inhibits the growth of the cells in vivo.
Based on these data, the PPAR alpha pathway outlined may be a potential target for pharmacotherapies directed at preventing atherosclerosis and other cardiac occlusive diseases.
TITLE: PARa inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a
AUTHOR CONTACT:
Florence Gizard
Pasteur Institute, Lille, France
Phone: 00320877387; E-mail: florence.gizard@pasteur-lille.fr
View the PDF of this article at: https://www.the-jci.org/article.php?id=22756
Journal
Journal of Clinical Investigation