JCI online early table of contents: June 14, 2010

Prion diseases are lethal neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE; commonly known as mad cow disease) in cows. A team of researchers, led by Adriano Aguzzi and Christina Sigurdson, at UniversitätsSpital Zürich, Switzerland, has generated data in mice that provides greater understanding of the factors that determine how easy it is for prion diseases to be transmitted to a new host species. This information provides new insight into a highly important food safety issue; dietary exposure to beef contaminated with the BSE agent is believed to have caused nearly 200 cases of variant CJD in humans.

The key infectious agent in prion diseases is PrPSc, a highly aggregated form of the cellular prion protein (PrPC). The ease with which prions from different species can be transmitted to a new host species varies dramatically. The team found that transmission between species with the same protein building block at position 170 in PrPC was relatively easy while it was relatively difficult between those species with different building blocks at that position. As this protein building block influences the structure of the PrPC protein, the authors suggest that local structure of PrPC affected by the protein building block at position 170 might have a triggering role in prion transmissibility between different species.

TITLE: A molecular switch controls interspecies prion disease transmission in mice

AUTHOR CONTACT:
Adriano Aguzzi
UniversitätsSpital Zürich, Zürich, Switzerland.
Phone: 41.44.255.2107; Fax: 41.44.255.4402;E-mail: adriano.aguzzi@usz.ch.

Christina Sigurdson
University of California at San Diego, La Jolla, California, USA.
Phone: 858.534.0978; Fax: 858.246.0523; E-mail: csigurdson@ucsd.edu.

View this article at: http://www.jci.org/articles/view/42051?key=456180f4a34aad821c6f

One therapy that is being developed for the treatment of various genetic diseases, cancer, and HIV, is transplantation with the patient's own bone marrow after it has been genetically modified. However, current methods of gene transfer to bone marrow cells are not sufficiently efficient for the treatment of many of the conditions for which this is a potential therapy. A team of researchers, led by Hans-Peter Kiem, at the Fred Hutchinson Cancer Research Center, Seattle, has now provided proof of principle in nonhuman primates for a method to overcome low gene transfer efficiency to bone marrow cells.

The mutant protein MGMTP140K provides cells with protection from the drug combination of O6BG and BCNU. It has therefore been suggested that genetically modifying bone marrow cells to express both the mutant protein MGMTP140K and the therapeutic gene might allow for the selection of the modified cells by treating patients with O6BG and BCNU. This approach had been shown to work in mice and dogs but not to be efficient in primates. However, Kiem and colleagues, have now shown that this approach leads to the efficient selection of genetically modified cells in both macaque and baboon nonhuman primates. Importantly, treatment with O6BG and BCNU was well tolerated. The authors note that their model is as close to the clinical setting as you can get and suggest that it could be tried in humans.

TITLE: Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates

AUTHOR CONTACT:
Hans-Peter Kiem
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Phone: 206.667.4425; Fax: 206.667.6124; E-mail: hkiem@fhcrc.org.

View this article at: http://www.jci.org/articles/view/40767?key=411297dfeae28ca04b9b

Valvular heart disease (VHD) is any disease process involving one or more of the heart valves. There are many causes of VHD, including hardening of the arteries (atherosclerosis) and rheumatic fever, but no therapies to prevent progressive valvular degeneration. A team of researchers, led by Keiichi Fukuda, at Keio University School of Medicine, Japan, has now provided new insight into the molecular mechanisms underlying VHD by analyzing degenerated human heart valves from patients with either atherosclerotic or rheumatic VHD. Specifically, they found that the protein periostin, a protein that plays critical roles in cardiac valve development, was expressed aberrantly in the degenerated heart valves. As mice lacking periostin developed fewer heart valve defects after consuming a high-fat diet than did normal mice, the authors suggest that periostin might be a good therapeutic target to prevent progressive valvular degeneration in atherosclerotic VHD.

TITLE: Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents

AUTHOR CONTACT:
Keiichi Fukuda
Keio University School of Medicine, Tokyo, Japan.
Phone: 81.3.5363.3874; Fax: 81.3.5363.3875; E-mail: kfukuda@sc.itc.keio.ac.jp.

View this article at: http://www.jci.org/articles/view/40973?key=bfbb4a7ca78212888e7a

The Holy Grail for clinicians treating individuals who have received a solid organ transplant, for example a heart or a kidney, is a treatment strategy that establishes indefinite graft survival in the absence of long-term treatment with immunosuppressive drugs and chronic rejection. Understanding more about the cells that can naturally induce this state, which is known as a state of tolerance, is considered an important step in reaching this Holy Grail. A team of researchers, led by Jordi Ochando, at Instituto de Salud Carlos III, Spain, has now identified in mice a population of cells important for inducing tolerance to transplanted hearts. Specifically, migration of a population of immune cells known as CD11b+CD115+Gr1+ monocytes from the bone marrow into the transplanted heart mediated the induction of indefinite graft survival. The authors therefore suggest that manipulating precursors of the equivalent cell population in the bone marrow of humans could be a useful clinical therapeutic approach for inducing transplantation tolerance.

TITLE: Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice

AUTHOR CONTACT:
Jordi C. Ochando
Instituto de Salud Carlos III, Madrid, Spain.
Phone: 34.918223274; Fax: 34.918223269; E-mail: jochando@isciii.es.

View this article at: http://www.jci.org/articles/view/41628?key=cffa22aa9b772fb73921

Crucial to developing new drugs for the treatment of bone loss, which is associated with conditions such as osteoporosis and aging, is greater understanding of the molecules that regulate the maintenance of bone. MAPK signaling pathways are triggered by many of the extracellular ligands that regulate bone maintenance. Despite this, the relative contribution of specific MAPKs has not been clearly determined. However, a team of researchers, led by Laurie Glimcher, at Harvard School of Public Health, Boston, has now determined that the p38 MAPK pathway is important for normal skeletogenesis in mice. Among the four p38 MAPK isoforms, p38-alpha and p38-beta were both found to contribute to in vivo bone formation, and the authors suggest that selective p38-beta agonists may prevent the bone loss associated with osteoporosis and aging.

TITLE: The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

AUTHOR CONTACT:
Laurie H. Glimcher
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: 617.432.0622; Fax: 617.432.0084; E-mail: lglimche@hsph.harvard.edu.

View this article at: http://www.jci.org/articles/view/42285?key=e199df11012523cb816b

Essential to maintaining blood pressure and flow is blood vessel tone, i.e., the degree of constriction experienced by a blood vessel relative to its maximally dilated state. Aberrant regulation of vascular tone plays an important role in several common conditions, including high blood pressure and heart attack. The capacity of cells in the wall of blood vessels known as vascular smooth muscle cells (VSMCs) to contract is a key determinant of vascular tone. A team of researchers, led by Marina Schorpp-Kistner, at the German Cancer Research Center, Germany, has now provided new insight into the molecular control of VSMC contractility and the maintenance of vascular tone in mice. Specifically, the gene regulatory protein Junb was found to be required for optimal VSMC and arterial blood vessel contractility and to mediate this function by increasing expression of the Myl9 gene. These data have clinical significance because drugs being developed for several health conditions, including cancer and some heart conditions, have an effect on levels of Junb activity.

TITLE: Junb regulates arterial contraction capacity, cellular contractility, and motility via its target Myl9 in mice

AUTHOR CONTACT:
Marina Schorpp-Kistner
German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
Phone: 49.6221.42.4575; Fax: 49.6221.42.4554; E-mail: marina.schorpp@dkfz.de.

View this article at: http://www.jci.org/articles/view/41749?key=1cce7391987a827a2e27

A team of researchers, led by Rafi Ahmed and Scott Mueller, at Emory University School of Medicine, Atlanta, has now determined the exact roles of the protein PD-L1 on different cell populations in regulating immune responses by CD8+ T cells and immune clearance of viruses.

In individuals who are persistently infected with some types of virus, the subset of their CD8+ T cells that target the virus becomes functionally exhausted. This occurs because virus-targeting CD8+ T cells upregulate expression of the protein PD-1 and signaling to CD8+ T cell PD-1 from PD-L1 causes them to become exhausted. PD-L1 is expressed on different cell populations and how PD-L1 on these discrete populations modulates the immune response to viral infection has not been determined. The team found that in mice infected with lymphocytic choriomeningitis virus, PD-L1 on blood cells inhibited CD8+ T cell numbers and function while PD-L1 on tissues cells limited viral clearance in the infected tissues. Importantly, PD-L1 on tissues cells also limited immune-mediated damage to the tissues. These data should help design therapeutics that target this inhibitory pathway but do not cause uncontrolled immune-mediated damage to infected tissues.

TITLE: PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice

AUTHOR CONTACT:
Rafi Ahmed
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: 404.727.3571; Fax: 404.727.3722; E-mail: rahmed@emory.edu.

Scott Mueller
The University of Melbourne, Parkville, Victoria, Australia.
Phone: 61.3.8344.6132; Fax: 61.3.9347.1540; E-mail: smue@unimelb.edu.

View this article at: http://www.jci.org/articles/view/40040?key=45e1d58fece897a2b7d0