JCI online early table of contents: Dec. 3, 2007

Parkinson disease (PD) is caused by the progressive degeneration of brain cells known as dopamine (DA) cells. Replacing these cells is considered a promising therapeutic strategy. Although DA cell–replacement therapy by transplantation of human fetal mesencephalic tissue has shown promise in clinical trials, limited tissue availability means that other sources of these cells are needed. Now, Ernest Arenas and colleagues at the Karolinska Institue, Sweden, have identified a new source for DA cells that provided marked benefit when transplanted into mice with a PD-like disease.

In the study, DA cells were derived from ventral midbrain (VM) neural stem cells/progenitors by culturing them in the presence of a number of factors — FGF2, sonic hedgehog, and FGF8 — and engineering them to express Wnt5a. This protocol generated 10-fold more DA cells than did conventional FGF2 treatment. Further analysis revealed that these cells initiated substantial cellular and functional recovery when transplanted into mice with PD-like disease. Importantly, the mice did not develop tumors, a potential risk that has precluded the clinical development of embryonic stem cells as a source of DA cells. These data led the authors to suggest that Wnt5a-treated neural stem cells might be an efficient and safe source of DA cells for the treatment of individuals with PD.

TITLE: Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice

AUTHOR CONTACT:
Ernest Arenas
Karolinska Institute, Stockholm, Sweden.
Phone: 468-524-87663; Fax: 468-34-19-60; E-mail: Ernest.Arenas@ki.se.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32273

Injury to peripheral nerves (the causes of which include shingles, HIV-AIDS, toxins, alcoholism, repetitive motion disorders, surgery, and cancer) causes neuropathic pain, which differs from ordinary pain and is usually perceived as a steady burning, pins and needles, electric shock sensations, and/or tickling. Normal pain relief therapies do not effectively provide relief from neuropathic pain. Further understanding of the molecular mechanisms underlying neuropathic pain is therefore essential to facilitate the development of new drugs. New research in rodents by Marie Campana and colleagues from the University of California at San Diego, has provided evidence that a fragment of the protein LRP1 (sLRP1-alpha) attenuates neuropathic pain.

In the study, it was first observed that injured peripheral nerves in both mice and rats released sLRP1-alpha into the surrounding tissue microenvironment. Administration of sLRP1-alpha into mouse sciatic nerves prior to injury decreased the levels of injury-induced inflammatory mediators in the local environment and inhibited neuropathic pain. In vitro analysis revealed that sLRP1-alpha modified cells known as glial cells so that they did not respond to the inflammatory mediator TNF-alpha. The authors therefore propose that sLRP1-alpha modifies the response of glial cells to mediators of neuropathic pain and that it might have therapeutic benefit for individuals suffering from neuropathic pain.

TITLE: A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

AUTHOR CONTACT:
W. Marie Campana
University of California at San Diego, La Jolla, California, USA.
Phone: (858) 822-3767; Fax: (858) 534-1445; E-mail: wcampana@ucsd.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32371

Sepsis is a potentially lethal condition that is characterized by a systemic (whole body) response to infection. It is the inflammatory phase of sepsis that has life-threatening effects if left unchecked. However, therapies aimed at limiting the inflammation have had little success in the clinic and, as this phase of sepsis is vital to the immune system’s efforts to clear the infection, have the potential to hamper the antimicrobial immune response. New data generated by Mark A. Perrella and colleagues at Brigham and Women’s Hospital and Harvard Medical School, Boston, using a mouse model of sepsis, has identified a role for the protein HO-1 as a mediator of defense against sepsis.

In the study, HO-1–deficient mice were more susceptible to the lethal effects of polymicrobial sepsis than normal mice. In addition, overexpressing HO-1 in certain cells in the walls of blood vessels and the intestine of HO-1–deficient mice prevented sepsis-induced death associated with Enterococcus faecalis, but not Escherichia coli, infection. Carbon monoxide (CO) is a generated by HO-1, and administration of a CO-releasing agent into both HO-1–deficient mice and normal mice reduced their susceptibility to the lethal effects of polymicrobial sepsis. The authors therefore concluded that HO-1–derived CO is an important component of host defense against sepsis and suggested that administration of CO might provide benefit to individuals with sepsis.

TITLE: Heme oxygenase-1–derived carbon monoxide enhances the host defense response to microbial sepsis in mice

AUTHOR CONTACT:
Mark A. Perrella
Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 732-6809; Fax: (617) 582-6148; E-mail: mperrella@rics.bwh.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32730

New approaches being developed for the treatment of cancer and infections include the infusion of large numbers of immune cells known as T cells that have been selected or engineered to specifically attack the cancer or infection and then expanded in number ex vivo. One problem faced by clinicians and researchers has been identifying T cell populations that persist in vivo after they have been expanded in vitro. However, Carolina Berger and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, have now shown that CD8+ T cells derived in vitro from a population of T cells known as central memory T cells persisted long-term in macaques.

In the study, macaque CD8+ T cells that recognized a specific protein were derived in large numbers in vitro from two sources, the central memory T cell population and the effector memory T cell population. When infused into macaques, CD8+ T cells derived from the effector memory T cell population survived in the blood for only a short period of time. By contrast, CD8+ T cells derived from the central memory T cell population persisted long term. Importantly, these cells were able to respond to antigen challenge, something that led the authors to suggest that human central memory T cells should provide a good source of T cells for ex vivo manipulation and expansion prior to infusion for the treatment of cancer and infections.

TITLE: Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates

AUTHOR CONTACT:
Carolina Berger
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Phone: (206) 667-4772; Fax: (206) 667-7983; E-mail: cberger@fhcrc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32103

Obesity and resistance to the hormone insulin, which can lead to type 2 diabetes, often contribute to the development of fatty liver — the buildup of fats called triglycerides in liver cells. On a cellular level, fatty liver results from the accumulation of misfolded proteins in the cells due to stress in an intracellular compartment called the endoplasmic reticulum (ER). Now, researchers from the laboratory of Henry Ginsberg at Columbia University College of Physicians and Surgeons, New York, have related ER stress to the ability of the liver to remove triglycerides from the body.

In the study, rat liver cells treated with either pure lipid (fat) or oleic acid (an unsaturated fatty acid found in olive oil) developed fat deposits and displayed signs of ER stress. Blood levels of the “bad” cholesterol–associated protein apoB100 directly correlate with triglyceride removal by the liver. Acute ER stress resulted in increased apoB100 levels in rat liver cells, but chronic exposure resulted in inhibition of apoB100 secretion. These results were verified in mice infused intravenously with oleic acid. From these results, the authors concluded that ER stress may be an intriguing therapeutic target in the treatment of fatty liver.

TITLE: Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in mice

AUTHOR CONTACT:
Henry N. Ginsberg
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-9562; Fax: (212) 305-3213; E-mail: hng1@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32752

CARDIOLOGY: Lipid homeostasis may be at the heart of it all

Special channels through the walls of cells in the heart control electrical impulses that regulate heart rate. Charged molecules called ions pass through these channels, generating the electrical potential needed to power the beating of the heart. A secondary positive effect of lowering “bad” cholesterol (a type of lipid) by statins is protection of the heart from life-threatening irregular heartbeat (ventricular arrhythmia), a condition resulting from imbalances in the parasympathetic branch of the nervous system. A new study by Jonas Gasper and his lab at Tufts-New England Medical Center, Boston, has explored the relationship between balanced lipid levels in the body and cardiac arrhythmia in chick and mouse heart cells (myocytes).

The GIRK1 ion channel is primarily responsible for electrical stimulation of myocytes during parasympathetic stimulation of the heart. Lipid-depleted chick myocytes had upregulated activity of GIRK1 and increased conductance through these ion channels. Levels of SREBPs, proteins responsible for lipid level maintenance, were not only increased in the lipid-depleted myocytes, but SREBP-1 was also responsible for regulation of GIRK1 expression by these cells. These results were verified in a SREBP-1–deficient mouse, where GIRK1 expression was decreased compared to normal mice. Furthermore, the SREBP-1–deficient mice had hearts that were less responsive to parasympathetic stimulation, with reduced ion passage through the myocyte ion channels. Most strikingly, following a heart attack SREBP-1–deficient mice were twice as likely to develop fast heart rates due to parasympathetic stimulation than normal mice. Taken together, these data provide a better understanding of the delicate relationship between fat metabolism and heart arrhythmia, and point the way towards new solutions for this life-threatening condition.

TITLE: Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP

AUTHOR CONTACT:
Jonas B. Galper
Tufts-New England Medical Center, Boston, Massachusetts, USA.
Phone: (617) 636-9004; Fax: (617) 636-4833; E-mail: jgalper@tufts-nemc.org.

Ho-Jin Park
Tufts-New England Medical Center, Boston, Massachusetts, USA.
Phone: (617) 636-9005; Fax: (617) 636-4833; E-mail: hpark@tufts-nemc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32011

One treatment approach in the management of cancer involves targeting the specific aberrant proteins responsible for the transformation of normal cells into cancerous cells. However, targeted therapy is limited in its success because treatment-resistant cancer cells survive and proliferate (i.e. the tumor escapes), and it therefore still must be accompanied by surgery and chemotherapy to be successful. Researchers from the lab of Edward Gunther at Pennsylvania State University College of Medicine, Hershey, have developed a mouse model of breast cancer treated by targeted therapy in order to explore the mechanisms of tumor escape.

Cancer cells are held in check through the activity of tumor suppressor proteins. Disruption of these proteins can lead to tumor escape in individuals who have previously undergone targeted therapy. Mice with breast cancer caused by Wnt1 protein–driven cell signaling were given targeted therapy that worked by preventing the expression of the Wnt1 gene driving the tumor growth. In mice with functional tumor suppressor proteins, tumor escape typically involved the cancer cells reactivating the Wnt signaling pathway. However, tumor escape occurred more rapidly and rarely involved the Wnt signaling pathway if the mice had expression of either of the tumor suppressors p53 or Arf disrupted. By contrast, tumor escape in mice that had another tumor suppressor, Ink4a, disrupted resembled that observed in normal mice. As Arf activates p53, the authors suggested that the success of targeted breast cancer therapy might be enhanced by reactivating the p53 tumor suppressor pathway to suppress tumor escape caused by disruption of upstream regulatory factors such as Arf.

TITLE: Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16Ink4a loss

AUTHOR CONTACT:
Edward J. Gunther
Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Phone: (717) 531-7022; Fax: (717) 531-5634; E-mail: ejg12@psu.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33320

T cells are powerful immune cells that play a vital role in clearing infections and that can also attack tumors. These immune cells require activation by two separate signals: one provided by an antigen, which is a molecule specific to the infectious microorganism or tumor; and the second by a nonspecific costimulatory molecule. One costimulatory molecule expressed primarily on the subset of T cells that can mediate antitumor immunity is 4-1BB. To manipulate the potential antitumoral properties of 4-BB1, antibodies have been previously manufactured to stimulate 4-BB1 in mice. However, the process of developing antibodies as costimulatory agents is expensive, time consuming, and technically challenging. Now, Eli Gilboa and colleagues at the University of Miami Miller School of Medicine have potentially overcome many of these obstacles by generating molecules known as aptamers that are capable of activating 4-BB1 in mice.

Aptamers are very small compounds capable of strongly binding to a specific target. In the study, the researchers developed aptamers that specifically bound to and activated 4-1BB on mouse T cells. In addition, multivalent forms of these aptamers caused immune-mediated tumor regression when injected directly into tumors in mice. The authors therefore suggested that aptamers might serve as a viable alternative to antibodies in the development of antitumor costimulatory molecules.

TITLE: Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice

AUTHOR CONTACT:
Eli Gilboa
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: (305) 243-1767; Fax: (305) 243-4409; E-mail: egilboa@med.miami.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33365

New data generated by Shahla Abdollahi-Roodsaz and colleagues at Radboud University Nijmegen Medical Centre, The Netherlands, has provided insight into the development of disease in a mouse model of rheumatoid arthritis.

Mice lacking a protein known as IL-1Ra spontaneously develop arthritis mediated by immune cells known as T cells. In the study, IL-1Ra–deficient mice housed in a germfree environment did not develop arthritis; infecting these animals with a single species of bacteria caused the rapid onset of arthritis. Consistent with this, mice lacking IL-1Ra and TLR4, a protein that can sense bacterial products such as LPS (as well as some host-derived products), were protected against severe arthritis. Protection was associated with decreased numbers of pathogenic Th17 cells. By contrast, mice lacking IL-1Ra and TLR2, a protein that can sense bacterial products such as peptidoglycan, developed more severe disease than IL-1Ra–deficient mice. Increased disease severity was associated with decreased regulatory T cell function and increased IFN-gamma production. No role for TLR9, a protein that can sense bacterial and viral DNA, in the development of arthritis in IL-1Ra–deficient mice was observed. The clinical relevance of these observations was indicated by the demonstration that TLR4 ligands were present in synovial fluid isolated from individuals with rheumatoid arthritis.

TITLE: Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis

AUTHOR CONTACT:
Shahla Abdollahi-Roodsaz
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Phone: 31-24-3616451; Fax: 31-24-3540403; E-mail: s.abdollahi-roodsaz@reuma.umcn.nl.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32639