IMMUNOLOGY: Context, context, context: all important for the immune function of NKT cells

A therapeutic approach to harnessing immune cells known as NKT cells, which have potent immunomodulatory properties, is currently being tested in cancer patients in phase I clinical trials. However, initial results suggest that the approach will need to be modified if clinical outcomes are to be maximized. Rational modification of the approach requires increased understanding of the molecules that regulate NKT cell activation in vivo. In this regard, Luc Teyton and colleagues, at The Scripps Research Institute, La Jolla, have identified the protein FAAH as a protein that modulates NKT cell responses in mice. Specifically they found that FAAH bound to the molecules that activate NKT cells and modulated the way in which they were presented to the NKT cells. Importantly, NKT cells responses in mice lacking FAAH differed from those in normal mice and were better at generating protective immunity in models of bacteria infection and tumor spread. These data suggest that modulating the context in which the molecules that activate NKT cells are found in the body could provide a way to enhance the effectiveness of vaccines.

Title: Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice

GASTROENTEROLOGY: Maintaining the barrier integrity of the gut

New research in mice, performed by Albert Reynolds and colleagues, at Vanderbilt University, Nashville, now suggests a role for the protein p120 in maintaining the integrity of the lining of the gut. These data are likely to have clinical relevance, as some studies have indicated that p120 is locally downregulated in many patients with inflammatory bowel disease (IBD).

IBD is a chronic, remitting inflammatory condition whose overall cause is poorly understood and multifactorial. Recent studies have indicated that adhesion molecules known as cadherins have a role in IBD. Consistent with the previous observation that the function of E-cadherin is regulated in part by p120, Reynolds and colleagues found that mice lacking p120 in the small intestine and colon died soon after birth as a result of massive intestinal bleeding caused by defects in adhesion between the cells lining the gut in both the small intestine and colon. An increase in inflammatory cells known as neutrophila in the tissue layer beneath the lining of the colon was also observed. These and other data presented in the study indicate that p120 deficiency in the mouse small intestine and colon leads to a loss of barrier integrity of the lining of the gut and increased neutrophil accumulation. The data also suggest a role for p120 in IBD.

Title: p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

HEMATOLOGY: The protein MCL1: a new therapeutic target in acute myeloid leukemia?

The approach to treating acute myeloid leukemia (AML) has not changed much over the past 30 years. Recent data suggest that targeting a group of proteins that inhibit cell death, the so called 'antiapoptotic BCL2 family members', might be a new approach to treating many forms of cancer. However, the functional significance and relative role of individual antiapoptotic BCL2 family members has not been determined. Through their analysis of leukemic cells from patients with AML and a mouse model of AML, a team of researchers, led by Michael Tomasson, at Washington University School of Medicine, St. Louis, has now determined that the antiapoptotic BCL2 family member MCL1 might make a good therapeutic target for the treatment of AML.

Title: Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia

HEMATOLOGY: Tracking the spread of lymphomas with the protein p73

The protein p53 is well known to function as a suppressor of tumor development and progression. But whether its close relative p73 also does has not been unequivocally determined. Now, a team of researchers, led by Ute M. Moll, at Stony Brook University, Stony Brook, has found in a mouse model of B cell lymphoma that p73 does not suppress tumor formation but does repress widespread dissemination of the tumor. Consistent with the data generated in the mouse model of B cell lymphomas, p73 expression was observed to be frequently downregulated in human mature aggressive B cell lymphomas. Furthermore, both the incidence and degree of p73 downregulation in these tumors correlated with their dissemination status. The authors therefore suggest that assessing whether or not p73 has been downregulated in a B cell lymphoma could provide a way to identify those patients whose tumors are likely to have spread to distant sites.

Title: Loss of p73 promotes dissemination of Myc-induced B cell lymphomas in mice Title

CARDIOLOGY: Heart protection via sonic hedgehog

Erythropoietin (EPO) is a hormone that controls the production of red blood cells. In the clinic, administration of EPO provides tremendous benefit to individuals with congestive heart failure. The mechanisms underlying these effects of EPO have not been clearly determined. However, Issei Komuro and colleagues, at Chiba University Graduate School of Medicine, Japan, have now established that EPO prevents mouse heart muscle cells from dying and increases the number blood vessels in the hearts of mice after a heart attack. The beneficial effects of EPO were mediated via the signaling protein sonic hedgehog, providing a clear molecular explanation for the protection afforded to the heart by EPO administration. Title: Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice

PULMONARY: Stopping the lung from scarring

Pulmonary fibrosis, a medical condition often described as scarring of the lungs, develops as a progressive, dysregulated response to lung injury. Disease progression results in dramatically impaired lung function and there are currently no good treatment options. However, a team of researchers, led by Paul Noble and Dianhua Jiang, at Duke University School of Medicine, Durham, has identified a potential new therapeutic approach to treating pulmonary fibrosis by studying a mouse model of the condition.

The team found that expression of the protein syndecan-4 increased in their mouse model and that pulmonary fibrosis was exacerbated in mice lacking syndecan-4. Further analysis indicated that syndecan-4 provided natural protection against pulmonary fibrosis by interacting with the protein CXCL10, a cellular attractant known to have anti-fibrotic properties. Importantly, a mutant CXCL10 protein incapable of mediating cellular attraction still protected mice in the model of pulmonary fibrosis in a syndecan-4-dependent manner. As the mutant CXCL10 protein incapable of mediating cellular attraction should have few side effects, unlike the normal protein, the authors suggest that it might provide a new therapy for the treatment of pulmonary fibrosis.

Title: Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4

ENDOCRINOLOGY: Getting down to the specifics of GATA3 function in the parathyroid

Individuals with hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome suffer from mild to profound hearing loss, some form of kidney disease, and hypoparathyroidism, a condition in which the function of the parathyroid gland is impaired, leading to low levels of calcium in the blood, a potentially life-threatening state. Although it is know that HDR is caused by mutations in the GATA3 gene, the function of GATA3 in parathyroid formation and function is not well known. However, a team of researchers, at the University of Oxford, United Kingdom, has now determined that GATA3 is critical for the generation and survival of parathyroid progenitor cells in mice. Further analysis indicated that the effects of GATA3 on parathyroid development and function are largely mediated via the protein Gcm2 (the equivalent of the human GCMB protein). The authors therefore suggest that hypoparathyroidism in individuals with HDR is caused by dysregulation of the GATA3/GCMB pathway.

Title: Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2

NEPHROLOGY: The protein NHE4 takes care handling acid in the kidney

A team of researchers, led by Pascal Houillier, at Hôpital Européen Georges Pompidou, France, has provided new insight into the regulation of acid levels in the body by studying in rodents the molecular mechanisms controlling the handling of ammonia by the kidney and its excretion in the urine.

Ammonia is the main acid component of urine. Transport of ammonia out of cells in the kidney known as MTALH cells and the subsequent excretion of ammonia in the urine is critical for regulating acid levels in the body. In the study, analysis of mice lacking the transport protein NHE4 and of NHE4 activity in the rat kidney indicated that NHE4 is important for ammonia transport by MTALH cells and maintenance of normal acid-base balance in the body. The authors therefore conclude that NHE4 could be at fault in individuals with adult renal tubular acidosis, a medical condition characterized by the accumulation of acid in the body due to a failure of the kidneys to remove acid from the body in the urine.

Title: NHE4 is critical for the renal handling of ammonia in rodents

Source:
Karen Honey
Journal of Clinical Investigation