JCI online early table of contents: Oct. 24, 2011

Fetal and neonatal immune thrombocytopenia (FNIT; aka FNAIT) is a condition in which fetuses and newborns have reduced numbers of blood cells known as platelets. Platelets have a key role in blood clotting; if the reduction in platelet number in a fetus or newborn is dramatic, it can lead to bleeding within the skull, which can result in brain damage or even death. A team of researchers led by Heyu Ni, at the University of Toronto, Toronto, has now identified in mice a non-classical form of FNIT that does not cause uncontrolled bleeding within the skull of the fetus/newborn. Rather, the condition is characterized by excessive platelet activation and blood clot formation in the placenta, resulting in miscarriage. Importantly, the team identified two treatments that prevented this nonclassical form of FNIT. Ni and colleagues therefore suggest that the nonclassical FNIT that they observed in mice should be considered as an underlying cause of miscarriage and habitual abortion in women. Alvin Schmaier, at Case Western Reserve University, Cleveland, concurs with this suggestion in his accompany commentary and discusses potential ways to treat those women determined to have the condition.

TITLE: The maternal immune response to fetal platelet GPIb-alpha causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies

AUTHOR CONTACT:
Heyu Ni
University of Toronto, Toronto, Ontario, Canada.
Phone: 416.847.1738; Fax: 416.864.5826; E-mail: nih@smh.ca.

View this article at: http://www.jci.org/articles/view/57850?key=39fd0dc4f3e3dc6e4f76

ACCOMPANYING COMMENTARY
TITLE: Are maternal antiplatelet antibodies a prothrombotic condition leading to miscarriage?

AUTHOR CONTACT:
Alvin H. Schmaier
Case Western Reserve University, Cleveland, Ohio, USA.
Phone: 216.368.1172; Fax: 216.368.3014; E-mail: schmaier@case.edu.

View this article at: http://www.jci.org/articles/view/60749?key=acca5014a81a66688ea4

It is estimated that 15% of older adults in the United States have wounds that fail to heal (which are known as chronic wounds). Among the most common causes of chronic wounds is diabetes; it is estimated that every 30 seconds, someone in the world loses a lower limb as result of infection of a diabetic wound that has failed to heal. As there are no effective treatments for chronic wounds, researchers are seeking to identify molecules that drive wound healing that can be harnessed therapeutically. In this context, a team of researchers led by Wei Li, at The University of Southern California Keck School of Medicine, Los Angeles, has shown that topical application of a fragment of the secreted form of the protein Hsp90-alpha promotes the healing of diabetic wounds in mice. The authors hope that these data can be replicated in humans because they believe that the treatment would improve patient life and help reduce the cost of treating patients with a diabetic wound.

TITLE: A fragment of secreted Hsp90-alpha carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice

AUTHOR CONTACT:
Wei Li
The University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Phone: 323.865.0618; Fax: 323.865.0105; E-mail: wli@usc.edu.

View this article at: http://www.jci.org/articles/view/46475?key=a8293ad8be0653c9c19e

There are many types of non-Hodgkin lymphoma (NHL); together they account for approximately 4% of all cancer diagnoses. The majority of NHLs arise from B cells and express the B cell marker CD20. Treatment therefore often includes a drug known as rituximab, which targets CD20, causing the death of cells that express it. Although effective in many patients, for a substantial number, rituximab does not lead to a durable response. Thomas Tedder and colleagues, at Duke University, Durham, have now studied this problem in a mouse model of NHL and identified a possible reason for the inability of rituximab to be effective in all NHL patients. Specifically, they found that if treatment with a drug like rituximab failed to eliminate all the noncancerous B cells in the mice, in particular B cells producing the immune mediator IL-10, then the NHL was not cleared. Of potential therapeutic interest, treating the mice with a molecule that stimulated the protein TLR3 overcame the effects of the IL-10–producing B cells. Tedder and colleagues therefore suggest that either eliminating IL-10–producing B cells or co-administrating TLR3 triggers could provide ways to improve the efficacy of rituximab and related drugs in individuals with NHL.

TITLE: Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice

AUTHOR CONTACT:
Thomas F. Tedder
Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919.684.3578; Fax: 919.684.8982; E-mail thomas.tedder@duke.edu.

View this article at: http://www.jci.org/articles/view/59266?key=f889d7484b3580ab1ce6

Type 1 diabetes is a lifelong disease characterized by high levels of sugar (glucose) in the blood. New insight into the mechanisms underlying type 1 diabetes, gained by a team of researchers led by Vijay Kuchroo, at Harvard Medical School, Boston, who studied a mouse model of the condition, reveals a potential new therapeutic approach.

Type 1 diabetes is caused by the patient's immune system attacking and destroying the cells in their pancreas that produce the hormone insulin, which regulates blood glucose levels. There is a genetic component to susceptibility to type 1 diabetes, since it can run in families, and several genetic regions (loci) in humans and mice have been shown to modulate disease susceptibility. Kuchroo and colleagues analyzed a mouse type 1 diabetes susceptibility locus known as Idd3, which has a homologous genetic interval in humans, and found that the protective form of the locus was associated with the development of fewer Th17 cells, immune cells thought to have a role in causing type 1 diabetes. Further mechanistic analysis revealed a role for altered signaling in immune cells known as APCs, leading Kuchroo and colleagues to suggest that APCs provide a new candidate target for therapeutic intervention in individuals with type 1 diabetes.

TITLE: Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice

AUTHOR CONTACT:
Vijay K. Kuchroo
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.525.5350; Fax: 617.525.5566; Email: vkuchroo@rics.bwh.harvard.edu.

View this article at: http://www.jci.org/articles/view/46187?key=da2e9a9e9671b1a2992c