The late-arterial CT is superior to the porto-venous CT for initi

The late-arterial CT is superior to the porto-venous CT for initial diagnosis and follow-up of hepatic fungal infection. “
“Cryptococcosis has emerged as an important public health problem in Africa, Asia and the Americas due to the increasing numbers of persons at selleckchem risk of this infection and the adaptation of its aetiological agents to new environments. The proper management requires early recognition of Cryptococcus neoformans/C. gattii species complex infection, familiarity with the use and limitations of diagnostic tests and knowledge of the available treatment options. This review will address these issues with the goal of providing sufficient information to suspect, diagnose and

treat patients with cryptococcosis based on Cuban data and review of the literature. “
“The use of anti-fungal agents has increased dramatically in recent years and new drugs have been developed. Several methods are available for determinations of their

specific biological activities, i.e. the standard method for minimum inhibitory concentration-determination is described in M-38 [Clinical and Laboratory Standards Institute document M-38 (CLSI M-38)]. However, alternative methods, such as the E-test, are currently available in Mycology laboratories. The susceptibilities of clinical isolates of Aspergillus spp. (n = 29), Fusarium spp. (n = 5), zygomycetes (n = 21) and Schizophyllum (n = 1) were determined for itraconazole, voriconazole and posaconazole, using the CLSI M-38-A broth dilution method and also by the E-test. A good overall agreement Enzalutamide concentration (83.7%) between the two methods for all drugs and organisms was observed. Analyses of voriconazole showed a better agreement (93%) between the methods than posaconazole and itraconazole (85% and 74% respectively). Aspergillus spp. were the most susceptible fungi

to the anti-fungal agents tested in this study. Posaconazole was the most active drug against filamentous fungi in vitro, followed by itraconazole and voriconazole. The latter (voriconazole) demonstrated no significant in vitro activity against zygomycetes. “
“We Phospholipase D1 report on in vitro antifungal activity and the structure–activity relationship of diphenyl diselenide [(PhSe)2] and its synthetic analogues, (p-Cl-C6H4Se)2, (m-CF3-C6H4Se)2 and (p-CH3O-C6H4Se)2, against 116 strains of pathogenic fungi. (PhSe)2 showed the highest inhibitory activity against Candida albicans (minimum inhibitory concentration of 4–32 μg ml−1), Candida dubliniensis (2–16 μg ml−1), Aspergillus spp. (0.5–64 μg ml−1) and Fusarium spp. (2–16 μg ml−1). Its minimum fungicidal concentration (MFC) varied among C. albicans (4–64 μg ml−1), C. dubliniensis (2–32 μg ml−1) and Fusarium spp. (4–64 μg ml−1). Antifungal activity was decreased by the introduction of functional groups to the (PhSe)2 molecule: (PhSe)2 > (p-CH3O-C6H4Se)2 > (m-CF3-C6H4Se)2 > (p-Cl-C6H4Se)2. “
“Limited data are available on temporal and geographic variation of occurrence and antifungal resistance of non-C.

7a,b) Ki67 staining was largely absent in wild-type mucosal tiss

7a,b). Ki67 staining was largely absent in wild-type mucosal tissue following DSS treatment and coincided with the extensive destruction and loss of tissue architecture (Fig. 3). In contrast, widespread and strong Ki67 staining was found throughout the crypts of colonic tissue taken from DSS-treated Bcl-3−/− mice, indicating significantly enhanced proliferation of Bcl-3−/−

epithelial cells following treatment (Fig. 7a). Immunofluorescence microscopy analysis of Bcl-3 protein in tissue sections was unsuccessful using commercially available antibodies; however, previous studies have demonstrated Bcl-3 mRNA expression in intestinal epithelial cells [25, 26]. Taken together, these data suggest that Bcl-3−/− mice develop less severe clinical and histopathological

colitis due to an increase in epithelial proliferation, which leads to regeneration High Content Screening of the damaged epithelium. Our data also demonstrate that this regeneration occurs despite the presence of ongoing inflammation in the colonic mucosa. In this study we investigated the expression of Bcl-3 in human IBD and also the role of Bcl-3 in DSS-induced colitis in the mouse. We found that Bcl-3−/− mice develop less severe colitis compared to littermate control wild-type mice. These findings were unexpected, given the previously described role of Bcl-3 as a negative regulator of inflammatory gene expression selleck compound [16] and the recent identification of reduced Bcl-3 expression as potential risk factors for CD [17]. However, the resistance of Bcl-3−/− mice to experimentally induced colitis correlates with our analysis of Bcl-3 expression in the colon of IBD patients, which was significantly increased when compared to healthy individuals. It is possible that the identified SNPs may lead to increased Bcl-3 expression rather than

decreased expression as predicted. Thus, our findings suggest that increased expression of Bcl-3 rather than reduced expression may be a potential risk factor for IBD. Our study also identifies a novel role for Bcl-3 in regulating intestinal Erlotinib mouse epithelial cell proliferation during DSS-induced colitis. Analysis of cytokine expression during DSS-induced colitis in Bcl-3−/− mice revealed a robust inflammatory response following DSS treatment characterized by significantly elevated levels of proinflammatory cytokines TNF-α, IL-6 and IL-1β. The levels of these cytokines was similar to wild-type mice, indicating that Bcl-3 does not act as a negative regulator of TNF-α, IL-6 and IL-1β expression in the context of DSS-induced colonic inflammation. Histological analysis supported this observation further, as significant oedema and leucocyte infiltration were present in Bcl-3−/− colonic tissue sections and to a similar degree to that seen in wild-type mice.

Conclusion:β-ARs were expressed in vimentin-positive ICs of the <

Conclusion:β-ARs were expressed in vimentin-positive ICs of the Vincristine human urinary bladder. As for β2- and β3-AR, there was no gender-related difference or age-related correlation in urothelium, ICs and detrusor muscles. In the human urinary bladder, β-ARs expressed in ICs may play a role in bladder physiology. “
“Depression and anxiety are common mental illnesses. It is recognized that depression/anxiety causes physical changes, including insomnia, anorexia, and bladder dysfunction. We aimed to delineate bladder dysfunction in patients with depression/anxiety by reviewing the literature. We performed a systematic review

of the literature to identify the frequency, lower urinary tract symptoms (LUTS), urodynamic findings, putative underlying pathology, and management of bladder dysfunction in patients with depression/anxiety. From a recent survey of a depression cohort (at a psychiatry clinic), the frequency of bladder dysfunction in depression is lower (up to 25.9%) than that in Parkinson’s disease (up to 75%) and stroke (up to 55%), whereas it is significantly higher Saracatinib supplier than that in

age-matched controls (around 10%). In both the depression cohort and the psychogenic bladder dysfunction cohort (at a urology clinic), the most common LUTS was overactive bladder (OAB), followed by difficult urination and infrequent voiding. Compared with severe LUTS, urodynamic findings were dissociated; i.e. urodynamic findings were normal except for increased bladder sensation without detrusor overactivity for OAB (50% of all patients), followed by underactive detrusor without post-void residual for difficult urination. The effectiveness of serotonergic or anti-cholinergic medication

for ameliorating OAB in the patients awaits further study. In conclusion, although the frequency of LUTS among the depression cohort is not elevated, Chloroambucil depression/anxiety is obviously a risk factor for OAB. This finding presumably reflects that the bladder is under emotional control. Amelioration of bladder dysfunction is an important target in treating patients with depression/anxiety. Major depression is a common mental illness with a prevalence of around 6% of the general population. It is characterized by feelings of sadness and despair, and causes significant morbidity.[1] Anxiety and stress-related disorders are also common, with estimations of their prevalence in the general population ranging from 2% to 20%. These disorders are characterized by excessive worry and irritability[2] mixed with symptoms of depression. It is well recognized that depression/anxiety causes not only mental but also physical changes. Physical changes associated with depression/anxiety include insomnia,[1] anorexia,[2] tachycardia,[3] sexual/erectile dysfunction,[4-6] bowel dysfunction,[7] and bladder dysfunction (mostly an overactive bladder [OAB, urinary urgency and frequency with/without urinary incontinence]).

Today, epidemiology has moved beyond the study of infections alon

Today, epidemiology has moved beyond the study of infections alone and has contributed to the link between rubber workers and bladder cancer [5], asbestos exposure and mesothelioma [62], ultraviolet radiation and skin cancer [41], and most notably, from the British Doctors study, tobacco in the etiology of lung cancer [17]. Epidemiology

is defined as the study of distribution and determinants of health-related Vemurafenib states and the use of such studies to address health-related problems. The main aim of the science is to discover potential causal relationships, which may be further tested with appropriate modifications to remove the possible trigger and assess the potential benefits. In 1965, Austin Bradford Hill detailed criteria for assessing evidence of causation (Table 1) [25]. It is important to stress that these are nothing more than a series of tests to apply to a hypothesis to determine its relative strength; they do not form a checklist that if all criteria are met, causality is proven. At this point, it is important to distinguish between true epidemiological studies and population-based mechanistic studies. Epidemiological studies are primarily designed to reveal relationships between exposures to substances,

such as alcohol selleck chemical and smoking, to outcomes, such as cardiovascular events or death. This contrasts with the larger population-based studies that are aimed at determining and measuring physiological or pathological processes, and exploring their relationships with morbidity, mortality, or surrogates thereof. The

utility of large populations Florfenicol and statistical methods established in epidemiology often results in these microvascular mechanistic studies being referred to as “epidemiological.” These large-scale studies have considerable overlap with epidemiology, notably in the application of the Bradford-Hill criteria of causation, study designs (Table 2), and statistical modeling to account for other known mechanistic processes and potential confounding, however, have the important distinction that these are exploring relationships between structure and/or function within one microvascular beds and outcomes, without looking directly at the impact of external influences. Cardiovascular disease, encompassing, but not limited to, atherosclerotic coronary artery disease, stroke, peripheral vascular disease, and hypertensive target organ damage, is the biggest cause of premature death and disability in the developed world [74], and much work has been performed to better understand its etiology. Despite this, much of the variance in these disease processes remains unexplained [75]. Furthermore, the exact mechanisms associating, for example, hypertension and atherosclerosis are unclear. A greater understanding of these etiopathogenic mechanisms may allow further drug development or nonpharmacological interventions to be applied to populations.

The empty vector was used to generate CAL-1-EV cells Lentiviral

The empty vector was used to generate CAL-1-EV cells. Lentiviral particles were produced in 293T cells by calcium phosphate transfection. Spin transduction of CAL-1 cells with 8 μg/mL Polybrene was performed at 1800 Gefitinib mw rpm for 90 min. GFP-positive CAL-1 cells were sorted under low-pressure conditions on the

FACSAria. For RNA interference, CAL-1 cells were transfected with 75 nM siRNA directed against NAB2 (siRNA ID: s9248; Ambion/Applied Biosystems) or the Silencer Selected Negative Control siRNA #1; Ambion/Applied Biosystems) together with 25 nM siGLO Transfection Indicator (Dharmacon) with transfection reagent DharmaFECT 4 (Dharmacon) according to the manufacturer’s protocol. Transfection efficiency was determined by flow cytometry (Supporting Information Fig. 3A), and silencing was confirmed at protein levels by western

blot (Supporting Information Fig. 3B). A total of 105 primary human pDCs were stimulated with 12.5 μg/mL CpG A (Invivogen) or left untreated for 4 h or overnight in complete medium in a 96-well plate for RT-PCR and flow cytometry or western blot analysis, respectively. CAL-1 cells (7 × 105) were seeded overnight in a 24-well plate in 2 mL medium. A total of 1.1 mL medium was replaced with 100 μL FBS-free RPMI medium containing 12.5 μg/mL CpG B or Ctrl CpG B, 5 μg/mL Imiquimod (Invivogen), or 100–200 ng/mL IFN-β (PBL Medical Laboratories) to prevent FBS-mediated NAB2 induction selleck compound ([14], data not shown). A total of 50 μM SB203580, 2.5 μM BAY11–7082, 5 μM PI-103 (Tocris Bioscience), 200 mM Rapamycin (Calbiochem) or DMSO alone, or 0.1 μg/mL B18R (eBioscience) were added to cells 30 min prior to CpG stimulation. After stimulation, supernatant was harvested for cytokine analysis and cells were washed once with PBS before further analysis. pDC cell sorting was performed with anti-CD45RA-FITC (BD Biosciences) and anti-CD123-PE (Miltenyi Biotec). Cell surface staining was performed aminophylline with Anti-CD40-PE (Beckman Coulter) or isotype control

IgG1-PE (BD Biosciences), and anti-TRAIL (2E5; Enzo Life Sciences), or control mouse IgG1 (BD Biosciences), followed by anti-mouse IgG1-Biotin (Enzo Life Sciences) and Steptavidin-allophycocyanin (BD Pharmingen). Dead cell exclusion was performed with propidium iodide. Intracellular IRF-7 staining was performed by fixation and permeabilization with Cytofix/cytoperm Solution (BD Biosciences) and PBS containing 0.5% saponin and 2% FCS, followed by staining with IRF-7 (H-246; Santa Cruz Biotechnologies) or isotype control (Imgenex) and anti-rabbit IgG Alexa 568 (Invitrogen). Flow cytometry was performed with FACS Calibur or LSRII (BD Biosciences). Analysis was performed with FlowJo software (Tristar).

This discrepancy raised concerns as to a possible difference betw

This discrepancy raised concerns as to a possible difference between human and mouse Th17 cells. Subsequent studies addressing the role of TGF-β in human Th17-cell differentiation confirmed an inhibitory effect of TGF-β at high doses, but emphasized the requirement of low doses of this cytokine for Th17-cell AG-014699 price differentiation [32-34]. The strict dose dependency of the TGF-β requirement and the finding of constitutive

TGF-β signaling in freshly isolated human T cells [35] raise the question of whether TGF-β is a limiting factor for Th17-cell differentiation in vivo or whether it may be required in vitro depending on the culture conditions. Interestingly, more recent studies in the mouse demonstrated that Th17-cell differentiation Protein Tyrosine Kinase inhibitor could occur also in the absence of TGF-β signaling, and only Th17 cells generated in the absence of TGF-β were found to be pathogenic in an EAE model [36]. These findings suggest that there may be different pathways for the generation of Th17 cells (and possibly Th1 and Th2 cells) and that our definition of a T-cell lineage based on a single cytokine and transcription factor may not be sufficient

to explain the complex heterogeneity of effector T cells. Given the heterogeneity of IL-17-producing T cells and the variety of cytokines involved in their differentiation, it would be important to develop new approaches based on the physiological function of these cells in the immune response. Since Th17 cells are key players in host defense, attempts were made to prime directly in vitro human naïve T cells against whole microbes, in order to induce Isoconazole Th17-cell differentiation in a more physiological system and identify the signals involved in driving this process. A method was developed that takes advantage of the complexity

of the microbes that provide, at the same time, a large number of antigens that can be recognized by specific naïve T cells and a variety of stimuli for innate receptors that lead to the upregulation of costimulatory molecules and the production of polarizing cytokines by antigen presenting cells [37]. Monocytes exposed to C. albicans or S. aureus efficiently primed human naïve CD4+ naïve T cells in vitro, which subsequently proliferated and differentiated into Th17 cells producing high levels of IL-17, IL-22, and expressing CCR6 and RORγt [37]. However, the cells primed by C. albicans had a hybrid Th17/Th1 phenotype, that is, they produced IL-17 and IFN-γ and expressed RORγt and T-bet, while cells primed by S. aureus produced IL-17, no IFN-γ, but did produce IL-10 but only in a narrow time window by strongly activated proliferating Th17 cells [37]. Strikingly, in vivo primed C. albicans or S. aureus specific memory Th17 cells isolated from immune donors had the same cytokine profile as the in vitro C. albicans or S. aureus primed Th17 cells, producing IL-17 plus either IFN-γ or IL-10, respectively.

Thus, the original question posed at the end of the 19th century

Thus, the original question posed at the end of the 19th century X-396 purchase regarding how the host perceives infection appears to have been solved. While they were the first to be discovered, TLRs are not the only pattern-recognition receptors (PRRs), and subsequent work has uncovered a plethora of recognition molecules. TLRs and C-type lectin PRRs are membrane-bound, found at the cell surface and in endosomes. Many additional PRRs are found in the cytoplasm, including the “retinoic acid inducible gene I-like receptors,” “nucleotide binding domain

leucine rich repeat containing receptors” (NLRs), and several other DNA sensors that signal through a crucial adaptor (STING, stimulator of IFN genes) associated with the ER membrane (reviewed in [[25]]). In fact, STING has recently been shown also to function as a direct sensor of cyclic di-GMP (a conserved signaling molecule restricted to bacteria) [[26]]. In addition, the pioneering work of the late Jürg Tschopp [[27]] highlighted the caspase 1-activating function of the “inflammasome,” formed in the cytosol after ligand-driven oligomerisation

of certain NLRs [[28]]. Once activated, caspase 1 controls maturation of members of the interleukin (IL)-1 family, and IL-1 is known to drive fever, a characteristic ofinflammation (reviewed in [[29]]). Unforeseen, a second paradigm shift (the first being the identified link between innate and adaptive immunity) has appeared on the horizon in recent years. There is now compelling evidence that germline-encoded PRRs not only perceive pathogen-induced inflammation, but INCB024360 cost also “sterile (auto)inflammation” by sensing metabolically altered self-components (reviewed in [[30, 31]]), including modified lipids [[32]] and proteins [[33]].These data have supported Matzinger’s view that “danger” as sensed by the innate immune system comes mainly “from the inside” [[34]]. Autoinflammatory responses have been linked, for example, to type 2 diabetes (see the clinically relevant effects

of IL-1 blockers [[35]]) and to certain aspects of this metabolic syndrome [[36]]. Furthermore, chronic autoinflammation is considered as hallmark PJ34 HCl of age-associated arteriosclerosis [[37]]. A third paradigm shift has arisen more recently. PRRs such as TLRs do not discriminate between commensals and pathogens in the gut microbiota. However, there is increasing evidence that TLR signaling in the intestinal epithelium shapes not only intestinal function (reviewed in [[38]]), but also the induction inflammatory Th17 T cells and that of regulatory T cells (reviewed in [[39]]). Thus, T-cell functions appear to be imprinted not only in the thymus but also in the gut. On the morning of 3rd October 2011, we celebrated the announcement that Ralph Steinmann along with Bruce Beutler and Jules Hoffmann had been awarded the Nobel Prize for Physiology and Medicine.

, 2009; Stübs et al , 2009), and the antigenic nature of ACGal ha

, 2009; Stübs et al., 2009), and the antigenic nature of ACGal has been confirmed by chemical synthesis (Stübs et al., 2010). These data imply that ACGal could improve serodiagnostics,

and may act as a basis for vaccine development. However, to date, it is unclear whether detection of or vaccination with ACGal would encompass LD-causing genospecies other than B. burgdorferi sensu stricto, B. afzelii, and B. garinii. On the other hand, the function of ACGal in B. burgdorferi is not elucidated, and the report that acylated cholesteryl α-d-glucosides in Helicobacter pylori are associated with immune evasion (Wunder et al., 2006) raises the question of whether ACGal are involved in the pathogenesis of LD. Therefore, in this study, we wanted to determine whether ACGal is a feature of other genospecies GSK1120212 in vivo of B. burgdorferi sensu lato, including those associated with all stages of LD as well as B. spielmanii as an agent of localized LD. The following Borrelia strains were grown under microaerophilic conditions in 9 mL of BSK-H medium at 33 °C as described previously (Preac-Mursic et al., 1986): B. burgdorferi s.s.

strain B31, B. afzelii PKo, B. bavariensis PBi, B. garinii A and TN, B. spielmanii PSig II, B. bissettii DN 127, B. lusitaniae Poti B2 and Poti B3, B. valaisiana VS 116 and UK, B. japonica HO 14, B. hermsii HS 1. The methods and materials for harvesting and extraction of bacteria have been described in detail earlier. In brief, the cells were harvested, lyophilized, and disintegrated using an ultrasonic rod and the lipids were extracted by a Folch extraction (Folch et al., 1957). The total lipids were dissolved and spotted in about equal amounts on a thin-layer chromatogram (TLC). Synthetic ACGal was applied as a reference (Stübs Carnitine palmitoyltransferase II et al., 2010). The chromatography was performed in chloroform/methanol 85 : 15 v/v.

The lipids were visualized on the TLC by molybdenum stain. The dried TLC was immersed in buffer and blotted onto a polyvinylidene difluoride (PVDF) membrane using a hot iron. The membrane was blocked with a skim milk/phosphate-buffered saline solution and incubated for 13 h at 4 °C with a 1 : 750 diluted serum of LD patients in the late stage. The membrane was incubated for 1.5 h at room temperature with a 1 : 50 000 dilution of a secondary, horseradish peroxidase-conjugated anti-human IgG antibody. The serum antibody binding was detected using enzymatic chemoluminescence to expose and subsequently develop X-ray films. Dot blots and Borrelia lysates were generated as described previously (Stübs et al., 2010): ACGal, Borrelia lysate and total lipids were spotted on PVDF membranes and incubated with pooled sera (n=4) from patients diagnosed with LD, syphilis as well as leptospirosis at 4 °C for 15 h. Detection with secondary antibodies was performed via chemoluminescence. The stained TLC (Fig. 1a) revealed that all analyzed Borrelia genospecies exhibited a similar lipid pattern.

Skin infections are common in immunosuppressed patients, and rare

Skin infections are common in immunosuppressed patients, and rare pathogens should be considered. 305 TACROLIMUS TOXICITY FROM NILUTAMIDE CO-ADMINISTRATION: A CASE REPORT A KENNARD, D JOHNSON, C HAWLEY Princess Alexandra Hospital, Brisbane,

QLD, Australia Background: Nilutamide is a nonsteroidal anti-androgen used in metastatic prostate cancer as a second line therapy in patients where androgen ablation has failed. To our knowledge, there is no prior reported drug interaction between nilutamide and tacrolimus, which is a principal immune suppressant employed in anti-rejection regimens in kidney transplantation. Case Report: A 62-year-old Caucasian, male kidney transplant recipient experienced a precipitous decline in renal function from baseline selleck chemicals llc creatinine 120 mmol/L to 172 mmol/L 8 days after starting nilutamide. This was accompanied by neurotoxic symptoms of tremor, new onset Ivacaftor mouse hyperglycaemia and elevation of trough tacrolimus concentrations from 5.6 to 12.6 μg/L. The man had a past history of kidney transplantation for end-stage renal failure secondary to IgA nephropathy. His immunosuppression regimen consisted of tacrolimus, prednisolone and mycophenolate mofetil. There had been no changes made to his medications

other than the commencement of nilutamide. Following cessation of nilutamide, the man’s renal function returned to baseline and his symptoms resolved within 6 days. No other specific treatment was given. Nilutamide is known inhibitor of P450 2C19, but, like steroid-based drugs, can also inhibit CYP3A4, which is involved in tacrolimus metabolism. Conclusions: After thorough evaluation for alternative causes of acute kidney injury, it is suspected that the episode of acute kidney injury reflects a previously undocumented drug interaction between nilutamide and tacrolimus. More frequent therapeutic monitoring of calcineurin inhibitor levels is recommended for transplant patients

receiving nilutamide therapy. 306 STONES, BONES, ABDOMINAL MOANS AND PARATHYROID’S GROWN K BLAZE, C QUINLAN, A WALKER Royal Children’s RAS p21 protein activator 1 Hospital, Melbourne, Victoria, Australia Background: A previously well 16-year-old girl presented with recurrent renal stones despite generous fluid intake and two lithotripsy procedures. Case Report: Despite successful lithotripsy she re-presented within one month post-procedure with painless macroscopic haematuria and repeat imaging consistent with stone recurrence. A metabolic work up revealed a marked hypercalcaemia with an elevated urinary calcium-to-creatinine ratio and hyperparathyroidism. She went on to have a cervical ultrasound suspicious for parathyroid adenoma posterior to the right lower lobe of the thyroid. A Tc 99m sestamibi scan confirmed the diagnosis. Conclusions: This demonstrates a case of primary hyperparathyroidism presenting as recurrent renal stones. Since excision of the parathyroid adenoma 2 years ago, this patient’s serum calcium and PTH have normalised and she has had no further stone recurrence.

These multifunctional lectins can hierarchically control a cascad

These multifunctional lectins can hierarchically control a cascade of immunoregulatory events including the expansion, recruitment, and function of regulatory T cells, the promotion of tolerogenic

dendritic cells, and the execution of T-cell death programs. In addition, galectins can control cell adhesion and signaling events critical for implantation and are involved in fundamental processes linking tissue hypoxia to angiogenesis. In an attempt to integrate the regulatory roles of galectins to immunological and vascular programs operating during pregnancy. Here we outline the regulated expression and function of individual members of the galectin family within the fetoplacental unit and their biological implications for the development and preservation of successful pregnancies. “
“The binding of NKG2D to its ligands strengthens learn more the cross-talk between natural killer (NK) cells and dendritic

cells, particularly at early stages, before the initiation of the adaptive immune response. We found that retinoic acid early transcript-1ε (RAE-1ε), one of the ligands of NKG2D, was persistently expressed on antigen-presenting cells in a transgenic mouse model (pCD86-RAE-1ε). By contrast, NKG2D expression on NK cells, NKG2D-dependent cytotoxicity and tumour rejection, and dextran sodium sulphate-induced colitis were all down-regulated in this mouse model. The down-regulation of c-Met inhibitor NKG2D on NK cells was reversed by stimulation with poly (I:C). The ectopic expression of RAE-1ε on dendritic cells maintained NKG2D expression levels and stimulated the activity of NK cells ex vivo, but the higher frequency of CD4+ NKG2D+ T cells in transgenic mice led to the down-regulation of NKG2D on NK cells in vivo. Hence, high levels of RAE-1ε expression on antigen-presenting cells would be expected to induce the down-regulation of NK cell activation by a regulatory T-cell subset.

“Bystander activation of T cells, i.e. the stimulation of unrelated (heterologous) T cells by cytokines during an Ag-specific T-cell response, has been best described for CD8+ T cells. In the CD8+ compartment, the release of IFN and IFN-inducers leads to the production of IL-15, which mediates the proliferation of CD8+ T cells, notably memory-phenotype CD8+ T cells. CD4+ T cells also undergo bystander activation, however, the signals inducing this TCL Ag-nonspecific stimulation of CD4+ T cells are less well known. A study in this issue of the European Journal of Immunology sheds light on this aspect, suggesting that common γ-chain cytokines including IL-2 might be involved in bystander activation of CD4+ T cells. Bystander activation of T cells was first described by Tough and Sprent, showing that different viruses, virus-mimetics such as poly(I:C) or bacterial products such as LPS induced IFN-α/β secretion, which led to the proliferation and expansion of unrelated (heterologous) polyclonal T cells 1, 2.