Reviews & Analysis

A new combinatorial approach harnesses the power of immuno- and virotherapy in a vesicular stomatitis virus (VSV) vector carrying a cDNA library that expresses normal human prostate antigens, thus providing proof of principle that this vaccine can induce prostate tumor rejection in mice (pages 854–859). This strategy might bypass many of the issues associated with conventional cancer immuno- or virotherapy.

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

Humans with a missense mutation in LRP5 (encoding lipoprotein receptor-related protein 5) have a high bone mass phenotype, which has now been recapitulated in mice conditionally expressing this Lrp5 variant in terminally differentiated bone osteocytes (pages 684–691). These results suggest that LRP5 acts locally to increase bone mass, thereby opening avenues for new therapeutics for osteoporosis and bone injury by manipulating LRP5 signaling.

A mouse model of Joubert syndrome helps identify a crucial role for Wnt signaling in early cerebellar proliferation and midline fusion (pages 726–731). Reduced activity of this pathway causes cerebellar hypoplasia reminiscent of the cerebellar malformation observed in humans with Joubert syndrome.

Peptidoglycan recognition proteins (PGRPs) are a key part of the innate immune system's defense against bacteria. PGRPs are now shown to act through a conserved secretion stress–sensing two-component system, which leads to membrane depolarization and the release of cytotoxic hydroxyl radicals. Thus, PGRPs exploit an ancient bacterial stress response to elicit cell death, and this pathway may be targeted to produce improved antimicrobial drugs (pages 676–683).

Estrogen receptor α (ERα)-positive breast cancers often find a way to circumvent endocrine therapies such as tamoxifen. A newly described ERα kinase, lemur tyrosine kinase-3 (LMTK3), may provide both a diagnostic advance and a new therapeutic target to fight these resistant, aggressive tumors.

Some individuals with estrogen receptor–α (ER-α)-positive breast cancer do not respond to tamoxifen treatment. Increased expression of the ubiquitin ligase CUEDC2 may contribute to this endocrine resistance by reducing theamounts of ER-α (pages 708–714).

The success of organ transplantation is severely hindered by immune-mediated rejection, but the steps involved in this process remain poorly defined. A new imaging study now reveals the sequence of events and immune cells involved in graft rejection in a mouse model, providing insights into the points at which the immune system could be rationally targeted to prevent transplant rejection (pages 744–749).

Although attention deficit hyperactivity disorder (ADHD) is a highly heritable and common psychiatric disorder, few susceptibility genes have been identified. A new multidisciplinary genetic study in humans and mice reveals GIT1 (encoding G protein–coupled receptor kinase–interacting protein-1) as a previously undescribed ADHD susceptibility gene in humans and provides new insights into the underlying mechanisms of this condition (pages 566–572).

Although leukocyte activation in fat tissue promotes obesity-related insulin resistance, a role for B cells has been unclear. A new study in obese mice shows that they enter the fat tissue to activate T cell function and boost inflammation, exacerbating the metabolic disease (pages 610–617).

Interleukin-2 receptor-α (IL-2Rα) on antigen-presenting dendritic cells (DCs) is now shown to trans-present IL-2 to T cells during the earliest stages of T cell activation (604–609). The resulting T cell proliferation is blocked by daclizumab, an IL-2Rα–specific antibody used to treat multiple sclerosis and prevent transplant rejection, highlighting the importance of understanding individual variability in immune responses to daclizumab treatment.

Moderate to severe asthma is difficult to treat because recurring bouts of inflammation in the lungs induce fibrosis, which reduces lung elasticity, gas exchange and responses to conventional therapy. A recent study identifies the tumor necrosis factor family member LIGHT as an essential mediator of airway fibrosis in a mouse model of chronic asthma (pages 596–603).

Hepatitis C virus puts about 130 million people worldwide at risk for severe liver disease, but no vaccine or broadly effective therapy yet exists. A new study identifies receptor tyrosine kinases as host factors required for hepatitis C virus entry—potentially opening the door for new antiviral strategies (pages 589–595).

Thiazolidinediones (TZDs) target peroxisome proliferator–activated receptor-γ (PPAR-γ) and are widely prescribed to treat type 2 diabetes but are associated with substantial weight gain. This side effect of TZDs is now shown to be mediated via brain PPAR-γ. These findings suggest an important role for brain PPAR-γ in obesity and have major implications for the clinical use of TZDs (pages 618–622 and 623–626).

Alum is the most widely used vaccine adjuvant, but its mechanism of action remains largely unknown. A recent study shows that alum interacts directly with membrane lipids on the surface of dendritic cells, triggering signaling cascades that promote CD4⁺ T cell activation and humoral immune responses (pages 479–487).

Axonal damage causes neurological defects in multiple sclerosis. In vivo imaging in mouse models of multiple sclerosis now shows a reversible and sequential process of focal axonal degeneration (FAD) (pages 495–499), suggesting the use of neuroregenerative as well as neuroprotective drugs as potential therapies for multiple sclerosis.

A new study shows that a candidate schizophrenia pathway, neuregulin-1–ErbB4 signaling, inhibits Src-mediated enhancement of synaptic N-methyl-D-aspartate receptor (NMDAR) function (pages 470–478). These results suggest that Src can have a pivotal role in NMDAR hypofunction in schizophrenia and thus might have potential therapeutic implications for this complex neuropsychiatric disorder.

A new study shows how SRC, a nonmembrane tyrosine kinase, is a common signaling node in trastuzumab resistance caused by different mechanisms in HER2-positive breast cancers (pages 461–469). A SRC inhibitor restored trastuzumab sensitivity in vitro and in mouse tumor models, suggesting a new way to tackle drug resistance in breast tumors.

Retinoic acid receptors inhibit chondrogenesis, but their ability to block the cartilaginous scaffold of heterotopic endochondral ossification has not been explored. A study in mice shows that agonists of retinoic acid receptor-γ potently inhibit heterotopic endochondral ossification, suggesting therapeutic potential in people with this condition (pages 454–460).

By the time diabetes is diagnosed, irreversible pathology is typically present, challenging therapeutic intervention. A reliable test for predicting diabetes risk could allow earlier implementation of intervention measures. Increased blood concentrations of amino acids are now suggested to predict risk of diabetes (pages 448–453), and amino acid profiling might also provide mechanistic insights into this disease.