BiTEs Snap at Brain Cancer

Researchers at Duke University and the National Institutes of Health have intravenously administered bispecific T-cell engager antibodies, or BiTEs, to improve the survival of mice with brain tumors. BiTEs are antibodies with two binding sites that simultaneously bind tumor cells and tumor-fighting T cells. The most famous BiTE, Amgen Inc.'s blinatumomab, is in clinical development for several types of cancer. In their work, the authors directed BiTEs to a form of the epidermal growth factor receptor found specifically on tumor cells. Such BiTEs were able to cross the blood-brain barrier and cured six of eight mice with established brain tumors. The authors noted that whether the same approach works in humans, where radiation for brain tumors often produces a lack of T cells, remains to be seen, but concluded overall that "BiTEs can be used to elicit functional antitumor immunity in the CNS," and that their work "represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity." The work appeared in the Dec. 17, 2012, online edition of the Proceedings of the National Academy of Sciences.

Activating Immunity Helps Against Sepsis

Sepsis is a hyperinflammatory reaction that simultaneously has some aspects of too little and too much immune system activation. A team from the Chinese Ningbo University discovered that the chemokine LECT2 can improve protective immunity in sepsis, through its effects on macrophages. Macrophages are a bridge between innate and adaptive immunity, because they eat dying cells and present antigens to the T and B cells of the adaptive immune system. They also secrete cytokines. The authors showed that when they administered recombinant LECT2 to mice after inducing sepsis, the animals' macrophages were better at killing bacteria, and the animals were less likely to die from sepsis. The authors also identified CD209 as the receptor through which LECT2 exerted its effects on macrophages. They concluded that "the modulation of [macrophage] functions by LECT2 may serve as a novel potential treatment for sepsis." Their work appeared in the Dec. 17, 2012, issue of the Journal of Experimental Medicine.

Inflammasome Contributes to Alzheimer's

Researchers from the German University of Bonn and the University of Massachusetts Medical School discovered that the inflammasome is necessary for mice to develop most symptoms of the disease. The inflammasome, a group of proteins activated by innate immune system sensors, can be activated by amyloid-beta, but whether that contributed to disease progression in Alzheimer's disease had not been clear. The authors engineered mice that overproduced amyloid precursor protein and were, therefore, susceptible to developing Alzheimer's disease, and lacked either the key inflammasome protein Nrlp3 or the apoptosis enzyme Caspase-1, which is activated by the inflammasome. Animals lacking either gene were protected to a large extent from developing neural changes and memory problems. The authors concluded that their data "show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease." Their work appeared in the Dec. 20, 2012, issue of Nature.

Response Stresses Immune System Enemies

Researchers from the University of California at San Diego have shown that tumor cells use a stress response, the unfolded protein response, to trick immune system cells into creating conditions that are favorable for tumor growth, rather than fighting the tumor cells. In the studies, the authors showed the unfolded protein response could also be transmitted from tumor cells to myeloid cells. Such "imprinted" myeloid cells secreted proinflammatory cytokines, and also increased their production of the immunosuppressive enzyme arginase. As a result of those changes, the myeloid cells were no longer able to present tumor antigens to killer T cells. Since the unfolded protein response is also important for survival and growth of the tumor cells themselves, the authors suggested that new therapies targeting that response "could offer a two-fold benefit: retardation of tumor cell adaptation and growth, and reversal of tumor-induced immune suppression and tolerance, which presently stand as barriers to immunotherapy." Their work appeared in the Dec. 18, 2012, issue of PLoS ONE.

Mutations Are Random; Their Locations Not

Researchers at the Chinese Beijing Genomics Institute – Shenzen and the University of California at San Diego have discovered that not all parts of the genome have an equal chance of acquiring mutations. That chance, in fact, may differ as much as 100-fold between different regions of the genome. In their study, the authors sequenced monozygotic twin pairs where both twins had autism, and compared their genomes to those of their parents. Using that method, they were able to identify an average of nearly 60 mutations that were shared in the twins but not present in either of their parents, meaning they had arisen in the germ line. They found that certain areas of the genome were far more likely to feature such mutations, including, surprisingly, protein-coding regions, or exons. The findings confirmed the idea that de novo mutations are a significant risk factor for autism, and more generally "suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans." Findings were published in the Dec. 21, 2012, issue of Cell.

Organ Donor Study Yields T-Cell Atlas

Researchers from Columbia University Medical Center have used tissues from organ donors to create an atlas of sorts of the distribution of T cells in the body. Much of what scientists know about T cells comes from the T cells in the blood, which are easy to study. But many T cells stay in the lymph and mucosal tissues where pathogens first enter the body. The authors looked at the characteristics of different T cells in the lymph and mucosal tissues in 45 individuals who had died suddenly from causes such as accidents, suicide or drug overdoses. They found that the proportion of naïve, active and memory T cells differed between tissues, and that some subtypes expressed different surface markers in tissues than they do in the blood. "In order to break new ground in the study of human immunology and develop effective vaccines and therapies that specifically target immune responses at the sites where they are needed," the authors argued, "it is essential to move beyond conventional studies of human peripheral blood and study immune responses in the tissue sites." In providing a baseline map, their study represented one step toward that goal. It appeared in the Dec. 20, 2012, advance online edition of Immunity.

Fragile X Premutation Significance Uncertain

A pilot study screening for the mutation that causes Fragile X syndrome, the most common genetic cause of mental retardation, has shown that alterations in the gene's promoter are more common than expected, but the public health implications of that finding are not clear. Fragile X syndrome is caused by a triplet expansion in the promoter region of the Fragile X mental retardation protein 1, or FMRP1. Whether or not a person with the expansion will develop Fragile X syndrome is partly dependent on the number of extra triplet repeats. More than 200 repeats will cause Fragile X syndrome, while 55 to 200 repeats is considered a premutation that increases its carrier's risk of having a child with outright Fragile X. A triplet repeat size of 45 to 55 is a gray zone, and the effects on health are not clear. A team from the University of California at Davis screened 14,000 newborns and found one full-blown case of Fragile X, but rates of the premutation were higher than expected, at about 1 per 200 females and 1 per 400 males. The authors concluded that "before newborn screening for Fragile X mutations is expanded nationally, further work is needed" to understand the medical consequences of premutations. Their work appeared in the Dec. 21, 2012, online issue of Genome Medicine.

Thyroid Hormone Affects Heart via Brain

Researchers at the Swedish Karolinska Institutet have discovered a group of brain cells that are sensitive to the effects of thyroid hormone, and in turn influence heart function. Thyroid hormone has profound effects on cardiovascular function and metabolism, which were long thought to be direct. But recent work has suggested that those functions may be indirect, via the brain. In their studies, the authors identified a group of neurons in the hypothalamus that were sensitive to thyroid hormone. In animals, destroying those neurons led to both hypertension and heart rate abnormalities. The findings may lead to new ways to treat cardiovascular disease. They appeared in the Dec. 21, 2012, issue of the Journal of Clinical Investigation.

pHLIPing Drugs into Damaged Heart Tissue

Scientists from the University of Rhode Island and Yale University have shown that so called pHLIPs, pH-sensitive peptides that home specifically to regions of low pH, can target ischemic heart tissue. Many disease states are associated with low extracellular pH in the diseased tissue, and pHLIPs can target tumor tissues, among others. (See BioWorld Today, April 25, 2006.) In the new experiments, the authors administered pHLIPs shortly before inducing ischemia, and showed that the peptides selectively targeted ischemic tissue. The authors found that "in contrast to other known targeting strategies, the pHLIP-based binding does not require severe myocardial damage," which means it might be useful for imaging, and for targeting therapeutics in diseases that lead to relatively mild restriction of blood flow, such as angina. The findings were published in the Dec. 17, 2012, online edition of the Proceedings of the National Academy of Sciences.

– By Anette Breindl, Science Editor