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Abstract Background Ablation of the low-affinity receptor subunit for leukemia inhibitory factor (LIFR) causes multi-systemic defects in the late gestation fetus. Because corticosterone is known to have a broad range of effects and LIF function has been associated with the hypothalamo-pituitary-adrenal axis, this study was designed to determine the role for LIFR in the fetus when exposed to the elevated maternal glucocorticoid levels of late gestation. Uncovering a requirement for LIFR in appropriate glucocorticoid response will further understanding of control of glucocorticoid function. Methods Maternal adrenalectomy or RU486 administration were used to determine the impact of the maternal glucocorticoid surge on fetal development in the absence of LIFR. The mice were analyzed by a variety of histological techniques including immunolabeling and staining techniques (hematoxylin and eosin, Alizarin red S and alcian blue). Plasma corticosterone was assayed using radioimmunoassay. Results Maternal adrenalectomy does not improve the prognosis for LIFR null pups and exacerbates the effects of LIFR loss. RU486 noticeably improves many of the tissues affected by LIFR loss: bone density, skeletal muscle integrity and glial cell formation. LIFR null pups exposed during late gestation to RU486 in utero survive natural delivery, unlike LIFR null pups from untreated litters. But RU486 treated LIFR null pups succumb within the first day after birth, presumably due to neural deficit resulting in an inability to suckle. Conclusion LIFR plays an integral role in modulating the fetal response to elevated maternal glucocorticoids during late gestation. This role is likely to be mediated through the glucocorticoid receptor and has implications for adult homeostasis as a direct tie between immune, neural and hormone function.

The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1T946) that is associated with multiple autoimmune diseases. The effect of this polymorphism on both viral sensing and autoimmune pathogenesis remains poorly understood. Here we found that human peripheral blood mononuclear cells (PBMCs) and cell lines expressing the risk variant IFIH1T946 exhibited heightened basal and ligand-triggered production of type I interferons. Consistent with those findings, mice with a knock-in mutation encoding IFIH1T946 displayed enhanced basal expression of type I interferons, survived a lethal viral challenge and exhibited increased penetrance in autoimmune models, including a combinatorial effect with other risk variants. Furthermore, IFIH1T946 mice manifested an embryonic survival defect consistent with enhanced responsiveness to RNA self ligands. Together our data support a model wherein the production of type I interferons driven by an autoimmune risk variant and triggered by ligand functions to protect against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity.

Testing drugs for anti-aging effects has historically been conducted in mouse life-span studies, but are costly and time consuming, and more importantly, difficult to recapitulate in humans. In addition, life-span studies in mice are not well suited to testing drug combinations that target multiple factors involved in aging. Additional paradigms for testing therapeutics aimed at slowing aging are needed. A new paradigm, designated as the Geropathology Grading Platform (GGP), is based on a standardized set of guidelines developed to detect the presence or absence of low-impact histopathological lesions and to determine the level of severity of high-impact lesions in organs from aged mice. The GGP generates a numerical score for each age-related lesion in an organ, summed for total lesions, and averaged over multiple mice to obtain a composite lesion score (CLS). Preliminary studies show that the platform generates CLSs that increase with the age of mice in an organ-dependent manner. The CLSs are sensitive enough to detect changes elicited by interventions that extend mouse life span, and thus help validate the GGP as a novel tool to measure biological aging. While currently optimized for mice, the GGP could be adapted to any preclinical animal model.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although [CD4.sup.+] T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for [CD8.sup.+] T cells in disease pathogenesis. We previously showed that an MHC class I-restricted epitope of myelin basic protein (MBP) is presented in the CNS during [CD4.sup.+] T cell-initiated EAE. Here, we investigated whether naive MBP-specific [CD8.sup.+] T cells recruited to the CNS during [CD4.sup.+] T cell-initiated EAE engaged in determinant spreading and influenced disease. We found that the MBP-specific [CD8.sup.+] T cells exacerbated brain but not spinal cord inflammation. We show that a higher frequency of monocytes and monocyte-derived cells presented the MHC class I-restricted MBP ligand in the brain compared with the spinal cord. Infiltration of MBP- specific [CD8.sup.+] T cells enhanced ROS production in the brain only in these cell types and only when the MBP-specific [CD8.sup.+] T cells expressed Fas ligand (FasL). These results suggest that myelin-specific [CD8.sup.+] T cells may contribute to disease pathogenesis via a FasL-dependent mechanism that preferentially promotes lesion formation in the brain., Introduction Multiple sclerosis (MS) is an autoimmune disease of the CNS that affects approximately 2.3 million people worldwide (1). MS is characterized by inflammatory multifocal lesions, plaques of demyelination, and [...]

Heterozygous signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections and predisposition to humoral autoimmunity. To gain insights into immune characteristics of STAT1-driven inflammation, we performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome and age-matched controls. Affected individuals exhibited dysregulated CD4+ T cell and B cell activation, including expansion of TH1-skewed CXCR3+ populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated Stat1 GOF transgenic mice (Stat1GOF mice) and confirmed the development of spontaneous humoral autoimmunity that recapitulated the human phenotype. Despite clinical resemblance to human regulatory T cell (Treg) deficiency, Stat1GOF mice and humans with STAT1 GOF syndrome exhibited normal Treg development and function. In contrast, STAT1 GOF autoimmunity was characterized by adaptive immune activation driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. However, in contrast to the prevailing type 1 IFN-centric model for STAT1 GOF autoimmunity, Stat1GOF mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-γ) signals abrogated autoimmunity. Last, germline STAT1 GOF alleles are thought to enhance transcriptional activity by increasing total STAT1 protein, but the underlying biochemical mechanisms have not been defined. We showed that IFN-γ receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-γ as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome. Editor's summary: Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations lead to immune dysregulation and predispose affected individuals to humoral autoimmunity, but the underlying mechanisms are not fully understood. Here, Largent and colleagues performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome, finding expansion of TH1-skewed CXCR3-positive cell populations that correlated with serum autoantibody titers. A Stat1 GOF transgenic mouse model developed spontaneous autoimmunity characterized by absence of Treg dysfunction and by adaptive immune activation driven by type 2 interferon signaling. Further, deletion of the interferon-γ receptor normalized STAT1-dependent inflammation, suggesting that agents that block interferon-γ signaling may constitute a potential treatment for patients with STAT1 GOF syndrome. —Melissa Norton [ABSTRACT FROM AUTHOR]

Adoptive transfer of regulatory T cells (Tregs) is therapeutic in type 1 diabetes (T1D) mouse models. Tregs that are specific for pancreatic islets are more potent than polyclonal Tregs in preventing disease. However, the frequency of antigen-specific natural Tregs is extremely low, and ex vivo expansion may destabilize Tregs, leading to an effector phenotype. Here, we generated durable, antigen-specific engineered Tregs (EngTregs) from primary human CD4+ T cells by combining FOXP3 homology-directed repair editing and lentiviral T cell receptor (TCR) delivery. Using TCRs derived from clonally expanded CD4+ T cells isolated from patients with T1D, we generated islet-specific EngTregs that suppressed effector T cell (Teff) proliferation and cytokine production. EngTregs suppressed Teffs recognizing the same islet antigen in addition to bystander Teffs recognizing other islet antigens through production of soluble mediators and both direct and indirect mechanisms. Adoptively transferred murine islet-specific EngTregs homed to the pancreas and blocked diabetes triggered by islet-specific Teffs or diabetogenic polyclonal Teffs in recipient mice. These data demonstrate the potential of antigen-specific EngTregs as a targeted therapy for preventing T1D. Engineering immunosuppression: Antigen-specific regulatory T cell (Treg) therapy has been proposed as a treatment strategy for autoimmune diseases such as type 1 diabetes (T1D). However, isolating, expanding, and reinfusing antigen-specific Tregs from individuals with T1D has proven to be a challenge. Here, Yang et al. bypassed this requirement by generating engineered, antigen-specific human Tregs (EngTregs) by simultaneously introducing a T1D-associated T cell receptor and stably expressing FOXP3 in the cells. EngTregs, which suppressed both antigen-specific and bystander immune responses, were able to block diabetes onset in mice, suggesting that EngTregs may be an effective strategy to prevent diabetes in humans. [ABSTRACT FROM AUTHOR]

Multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus, are associated with an allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), which encodes [...]

Most patients who die from cancer succumb to treatment-refractory advanced metastatic progression. Although the early stages of tumor metastasis result in the formation of clinically silent micrometastatic foci, its later stages primarily reflect the progressive, organ-destructive growth of already advanced metastases. Early-stage metastasis is regulated by multiple factors within tumor cells as well as by the tumor microenvironment (TME). In contrast, the molecular determinants that control advanced metastatic progression remain essentially uncharacterized, precluding the development of therapies targeted against it. Here we show that the TME, functioning in part through platelet endothelial cell adhesion molecule 1 (PECAM-1), drives advanced metastatic progression and is essential for progression through its preterminal end stage. PECAM1-KO and chimeric mice revealed that its metastasis-promoting effects are mediated specifically through vascular endothelial cell (VEC) PECAM-1. Anti-PECAM-1 mAb therapy suppresses both end-stage metastatic progression and tumor-induced cachexia in tumor-bearing mice. It reduces proliferation, but not angiogenesis or apoptosis, within advanced tumor metastases. Because its antimetastatic effects are mediated by binding to VEC rather than to tumor cells, antiPECAM-1 mAb appears to act independently of tumor type. A modified 3D coculture assay showed that anti--PECAM-1 mAb inhibits the proliferation of PECAM-1--negative tumor cells by altering the concentrations of secreted factors. Our studies indicate that a complex interplay between elements of the TME and advanced tumor metastases directs end-stage metastatic progression. They also suggest that some therapeutic interventions may target late-stage metastases specifically, mAb-based targeting of PECAM-1 represents a TME-targeted therapeutic approach that suppresses the end stages of metastatic progression, until now a refractory clinical entity. metastasis | endothelium | tumor microenvironment doi/ 10.1073/pnas.1004654107

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs (1). The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelin-specific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation (2). We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 ([T.sub.H]17) to T helper type 1 ([T.sub.H]1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the [T.sub.H]17:[T.sub.H]1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the [T.sub.H]17:[T.sub.H]1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when [T.sub.H]17 cells outnumber [T.sub.H]1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of [T.sub.H]17:[T.sub.H]1 ratios induce spinal cord parenchyma) inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord., Experimental autoimmune encephalomyelitis (EAE) is an animal model that shows many similarities to multiple sclerosis (3). However, rodent EAE differs from multiple sclerosis by manifesting as ascending flaccid paralysis, reflecting [...]

Previous research has shown that techniques of molecular biology can be used to attach the interferon-gamma gene to the insulin gene in mice to induce diabetes. The gene attachment was performed so that the insulin gene promoter would turn on interferon-gamma as well; the rationale is that this would occur only within the insulin-producing beta cells of the pancreatic islets, and thus these cells specifically would produce interferon-gamma within the living mouse. However, it is not clear from the original experiments whether the destruction of the beta cells and the subsequent diabetes were a result of some primary effect of the interferon gene or a result of the stimulation of the destruction of the beta cells by the mouse's own immune system. New experiments demonstrate that the presence of the interferon-gamma stimulates an immune reaction against the beta cells and destroys them. This was demonstrated by showing that normal, histocompatible, beta cells were also destroyed when implanted into the diabetic mice. This effect was clearly mediated by T cells. Furthermore, when lymphocytes from the affected mice were removed and challenged with normal beta cells, they destroyed these cells. The results suggest that the presence of interferon-gamma apparently breaks the normal tolerance of the immune system for the body's own pancreatic beta cells, which then begins the sequence of events leading to cell destruction. (Consumer Summary produced by Reliance Medical Information, Inc.)