Treating type 1 diabetes by eliminating B cells
Autoimmune diseases such as type 1 diabetes and rheumatoid arthritis (RA) are caused when immune cells known as lymphocytes attack our own body tissues. Depletion of the B cell subset of lymphocytes using an antibody specific for the protein CD20 has been shown to be effective for the treatment of RA. The effectiveness of such an approach for the treatment of type I diabetes is not known, largely because the reagents to address this question in preclinical models have been lacking. This problem has now been overcome by Li Wen and colleagues from Yale School of Medicine, New Haven, who have developed the necessary tools and shown that depletion of B cells can both prevent diabetes and reverse established disease in mice. In the accompanying commentary, Hélène Bour-Jordan and Jeffrey Bluestone from the University of California, San Francisco, highlight the importance of these advances for developing and optimizing the potential of CD20-specific antibodies for the treatment of type 1 diabetes.
In the study, autoimmune diabetes-susceptible mice were engineered such that their B cells expressed human CD20. Depletion of B cells in these mice before they showed signs of diabetes, using a single dose of a CD20-specific antibody, delayed and/or reduced the onset of disease. Similarly, in mice already showing signs of diabetes, a single dose of the CD20-specific antibody reversed disease in a substantial proportion of the mice. Furthermore, the mechanism behind the protection afforded by CD20-specific antibody treatment was shown to be associated with increased numbers of regulatory T cells and B cells.
Title: Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice
Author Contact:
Li Wen
Yale School of Medicine, New Haven, Connecticut, USA.
Title: B cell depletion: a novel therapy for autoimmune diabetes?
Author Contact:
Jeffrey A. Bluestone
University of California at San Francisco, San Francisco, California, USA.
Get an extended warranty on your new lung: Artery reattachment may be the key to long-term transplant survival
Small-airway fibrosis, the chronic scarring and subsequent occlusion of the lung airways, is a major contributor to death following lung transplantation. Once the diagnosis of fibrosis is made, a patient's chances of survival are very poor. The functionality of small vessels feeding the transplanted organ is likely to play a key role in preventing fibrosis and improving long-term patient survival, according to new research in a mouse model of airway (trachea) transplantation from Mark Nicolls and colleagues at the VA Palo Alto Health Care System.
Lung transplantation is the only same-species transplant surgery not followed by reconnection of the arteries, a process known as revascularization. Because a loss of blood flow (ischemia) and subsequent loss of oxygen (hypoxia) are almost always harmful to organ tissues, researchers examined the functionality of mouse blood vessels following tracheal transplants where surgical revascularization was not performed. In rejected organs, prior to fibrosis of the trachea being observed, researchers found deposition of immune proteins on the blood vessel walls, as well as an absence of blood flow through the vessels. This inflammation-induced ischemia resulted in tissue hypoxia, as the oxygen content of the tracheal tissue decreased with blood flow loss. The hypoxia and ischemia preceded fibrosis of the trachea. The authors therefore suggested that revascularization following lung transplantation might be the key to preventing organ rejection and fibrosis. In an accompanying commentary, Alan Contreras and David Briscoe, from Children's Hospital Boston, delve further into the problem, suggesting that inflammatory revascularization following ischemia is actually what leads to fibrosis and chronic rejection of the organ.
Title: Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis
Author Contact:
Mark R. Nicolls
Medical Service (111P), Palo Alto, California, USA.
Title: : Every allograft needs a silver lining
Author Contact:
David M. Briscoe
Children's Hospital Boston, Boston, Massachusetts, USA
On the origin of the fat cell
A recent study in the Journal of Clinical Investigation indicated that in mice, under certain circumstances (either a high-fat diet or treatment with the antidiabetic drug rosiglitazone), cells derived from the bone marrow known as BMDCPCs can act as precursors of fat cells (adipocytes). However, a new study in mice by Gou Young Koh and colleagues at the Korea Advanced Institute of Science and Technology, Republic of Korea, suggests that this is not the case. The potential reasons for these distinct observations, as well as the impact of the observation that BMDCPCs cannot become adipocytes in vivo, are discussed in an accompanying commentary by David Scadden from Massachusetts General Hospital Center for Regenerative Medicine, Boston.
In the study, mouse bone marrow cells expressing a fluorescent marker were transplanted into normal mice and the fat tissue of the recipient mice was analyzed for the presence or absence of marked cells 2 months later. No marked adipocytes were detected, even in mice fed a high-fat diet and in mice treated with rosiglitazone. Although marked cells that looked similar to adipocytes were observed in the fat tissues, further analysis indicated that these cells expressed no proteins characteristic of adipocytes. Instead, the marked cells expressed proteins characteristic of cells known as macrophages. The authors therefore concluded that BMDCPCs do not become adipocytes in vivo.
Title: Bone marrow-derived circulating progenitor cells fail to transdifferentiate into adipocytes in adult adipose tissues in mice
Author Contact:
Gou Young Koh
Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Title: : The weight of cell identity
Author Contact:
David T. Scadden
Massachusetts General Hospital Center for Regenerative Medicine, Boston, Massachusetts, USA.
You snooze, you don't lose: Cellular repercussions of sleep deprivation
Sleep loss can be both beneficial (as an antidepressive) and detrimental (as it can cause cognitive impairment). Hypocretin/orexin neurons are brain cells that support wakefulness, but how they might contribute to the prolonged wakefulness that occurs upon sleep deprivation is not clear. However, in a new study, Xiao-Bing Gao and colleagues at Yale University School of Medicine, New Haven, have identified changes involving these neurons that occur in the brain of mice during prolonged sleep loss.
Communication between neurons occurs across synapses, the junctions between these cells. When the communication across a synapse is enhanced for a long time, it is called long-term potentiation. Following an imposed sleep deprivation (induced either by a drug or continual gentle handling) of 2-4 hours in mice, long-term potentiation of the synapses between hypocretin/orexin neurons was detected. The authors therefore suggested that these changes might be responsible for the effects of sleep deprivation. Indeed, in an accompanying commentary, Chiara Cirelli and Giulio Tononi from the University of Wisconsin, Madison, suggest that "This increase in [long-term potentiation of the synapses between hypocretin/orexin neurons] may be one of the mechanisms that help us to stay awake when we are sleep deprived, but it may also represent one of the signals telling the brain that it is time to sleep".
Title: Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons
Author Contact:
Xiao-Bing Gao
Yale University School of Medicine, New Haven, Connecticut, USA.
Title: : Staying awake puts pressure on brain arousal systems
Author Contact:
Chiara Cirelli
University of Wisconsin-Madison, Madison, Wisconsin, USA
Giulio Tononi
University of Wisconsin-Madison, Madison, Wisconsin, USA
Role for the immune factor IL-6 in cancer development
Individuals with several different types of cancer, including breast cancer and lung cancer, have elevated levels of the pro-inflammatory soluble factor IL-6 in their serum. However, the role of IL-6 in cancer is unclear, as both pro- and anti-tumor effects have been reported. Some insight into this has been provided by two new studies in the December issue of the Journal of Clinical Investigation that have indicated that IL-6 has a role in the development of both breast and lung tumors. As discussed in the accompanying commentary by Zachary Schafer and Joan Brugge from Harvard Medical School, Boston, these data raise the possibility that IL-6-targeted chemotherapeutics might be effective for the treatment of patients with certain forms of breast and lung cancer.
Massimiliano Bonafè and colleagues from the University of Bologna, Italy, showed that primary human mammospheres (MS), multicellular structures enriched in stem/progenitor cells of the mammary gland, from tumor tissue expressed higher levels of IL-6 than MS from normal breast tissue. Further in vitro analysis revealed that IL-6 induced MS self-renewal and promoted MS to adopt invasive characteristics. These effects of IL-6 were dependent on the protein Notch-3 and led the authors to conclude that, "IL-6 is a potent promoter of malignant features in Notch-3-expressing normal and tumor stem/progenitor cells of the mammary gland."
Similarly, a pro-tumor role for IL-6 in certain types of lung cancer is suggested by the work of Jacqueline Bromberg and colleagues at the Memorial Sloan-Kettering Cancer Center, New York. A protein known as STAT3 is persistently activated in 50% of lung cancers known as adenocarcinomas, including those that are associated with genetic mutations that result in chronic signaling through the cell surface receptor EGFR. In the study, which was performed using both mice and human lung adenocarcinoma cell lines, activated EGFR was shown to induce the expression of IL-6, which led to activation of STAT3. The clinical significance of this was suggested by the observed correlation between activated STAT3 and IL-6 expression in primary lung adenocarcinomas.
Title: IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland
Author Contact:
Massimiliano Bonafè
University of Bologna, Bologna, Italy.
Related Manuscript:
Title: : Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas
Author Contact:
Jacqueline F. Bromberg
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Title: : IL-6 involvement in epithelial cancers
Author Contact:
Joan S. Brugge
Harvard Medical School, Boston, Massachusetts, USA.
G1ME more platelets: An inflammatory mediator drives maturation of platelet precursor cells
Infection and inflammation are sometimes accompanied by an excess of circulating platelet cells, a condition called thrombocytosis. In a new study, John Crispino and his colleagues at Northwestern University Feinberg School of Medicine, Chicago, have explored this relationship between inflammatory disease and platelet formation in mice.
Cellular differentiation is the process by which cells specialize. For example, megakaryocytic precursor cells differentiate into megakaryocytes, the parent cells of platelets. G1ME cells are mouse megakaryocytic precursors that lack the protein Gata-1, rendering them incapable of further differentiation. When G1ME cells were engineered to produce STAT1, a protein that is expressed in response to inflammatory markers, they displayed distinguishing characteristics of megakaryocytic differentiation, including the expression of genes found in platelets and chromosomal duplication. Similarly, megakaryocytes from mice deficient in STAT1 lacked the chromosomal duplication inherent to this cell type. The authors concluded from these results that inflammatory stimulation of STAT1 can lead to thrombocytosis through enhanced differentiation of platelet precursor cells.
Title: STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice
Author Contact:
John D. Crispino
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
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Source: Karen Honey
Journal of Clinical Investigation