In contrast to colonic IFN-γ release, caecal IFN-γ was maximal at day 7 (Fig. 1). No significant changes in cytokine production were

noted in small intestinal tissues (data not shown). The results shown are derived from experiments with 129/SvEv mice; however, results indistinguishable from these were also produced with Swiss Webster mice. The imbalance in intestinal RGFP966 manufacturer cytokine release with a maximal production of proinflammatory cytokines prior to production of anti-inflammatory cytokines was associated subsequently with a transient intestinal histopathological injury at day 7 post-faecal slurry exposure (Fig. 2a). The increase in intestinal injury scores was seen in both colonic and caecal tissues and involved mainly an influx in lamina propria mononuclear cells (Fig. 2b). However, not all mice developed colonic or caecal injury; the injury score among individual mice ranged from 1 to 8 in colon and from 1 to 7 in the caecum. find more Higher scores were found primarily among the Swiss Webster

mice, whereas 129/SvEv mice scored generally lower. However, even those mice that were found to be microscopic disease-limited (i.e. histopathological injury score of 1 at day 7) demonstrated increased proinflammatory mucosal cytokine production. Colonic and caecal injury had subsided in most mice by day 14 (Fig. 2) and returned to base levels by day 28 (data not shown). Colonic epithelial permeability was not altered significantly in these mice when tested at days 3, 7 and 14 post-faecal slurry exposure. In fact, we observed a slight reduction in mannitol flux in colonic tissue when subjected to Ussing chamber analysis (Fig. 3). Thus, despite the temporary cytokine imbalance and brief inflammatory response in the large bowel, the intestinal epithelial barrier function appeared to be intact. To investigate systemic immune responses to ingestion of faecal slurry in these

axenic mice we assessed cytokine release in unseparated splenocytes stimulated with faecal lysates derived from specific pathogen-free (SPF)-raised mice. Maximal release of IFN-γ, IL-17 and IL-10 was measured at day 7 post-bacterial treatments (Fig. 4a, shaded bars). No increase in either TNF-α or IL-4 production Cobimetinib was noted in any of these antigen-stimulated spleen cell cultures. As expected, cytokine release following spleen cell stimulation with lysates from axenic mice that are devoid of bacterial components remained at baseline level (Fig. 4a, solid bars). Consistent with these results from stimulation with faecal lysates, we observed a similar increase in production of IFN-γ and IL-10 at day 7 in cultures stimulated with sonicates derived from pure cultures of three endogenous bacterial strains: Bacteroides vulgatus, Enterobacter cloacae and Lactobacillus reuteri (Fig. 4b).

The term of chronic traumatic encephalopathy (CTE) was recently introduced to

regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology and pathogenesis of CTE and Alzheimer’s

disease (AD), as well as the close association between traumatic brain injuries (TBIs) MK-2206 purchase and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested selleck compound that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia. “
“Embryonal tumors are a group of malignant neoplasms that most commonly affect the pediatric population. Embryonal tumor with abundant neuropil and true rosettes is a recently recognized rare tumor.

It is composed of neurocytes and undifferentiated neuroepithelial cells arranged in clusters, cords and several types of rosettes in a prominent neuropil-rich background. We describe a new case of this tumor. The patient, a 24-month-old female infant, was referred to the Meyer Children’s Hospital with a history Cyclin-dependent kinase 3 of right brachio-crural deficit associated with occasional episodes of headache and vomiting. Computed tomography scan and MRI revealed a large bihemispheric mass. The patient underwent two consecutive surgeries. The resultant surgical resection of the tumor was macroscopically complete. The postoperative period was uneventful. On light microscopy the tumor showed a composite morphology: embryonal tumor with abundant neuropil and true rosettes (specimen from the first surgery); medulloepithelioma with mesenchymal and epithelial areas (specimen from the second surgery).

An animated translation of a single orthoslice through a computer-generated model of the vesicle in Video S1a showing the isolation of the vesicle in the endothelial cytoplasm. Video S1c. Rotation through 360 degrees of the model and orthoslice shown in Video S1b. Video S2. An animated tomographic series through two unlabeled vesicles (encircled) which appear and disappear  throughout the series without connections to other vesicular compartments. Video S3. An animated tomographic series through a large membraneous compartment which is open to both luminal and abluminal surfaces.

Video S4. An drug discovery animated tomographic series through two labeled abluminal caveolae (arrows) showing their connection with the luminal membrane indicating the presence of a patent transendothelial

channel. Video S5a. A video of a single orthoslice translating through a surface-rendered model of the channel shown in Figure 7. The model has been smoothed. Conformity of the model’s surface with the terbium deposition indicates an accurate representation of the channel’s interior compartment. The green region represents the total volume sampled. Video S5b. A fly-through of the computer-generated model of a transendothelial channel shown in Video S5a. The virtual camera rotates 180 degrees in mid-channel selleck and emerges on the other surface looking back at the channel. “
“Please cite this paper as: Spindler and Waschke (2011). Beta-Adrenergic Methane monooxygenase Stimulation Contributes to Maintenance of Endothelial Barrier Functions under Baseline Conditions. Microcirculation18(2), 118–127. Objectives:  cAMP signaling within the endothelium is known to reduce paracellular permeability and to protect against loss of barrier functions under various pathological conditions. Because activation

of β-adrenergic receptors elevates cellular cAMP, we tested whether β-adrenergic receptor signaling contributes to the maintenance of baseline endothelial barrier properties. Methods:  We compared hydraulic conductivity of rat postcapillary venules in vivo with resistance measurements and with reorganization of endothelial adherens junctions in cultured microvascular endothelial cells downstream of β-adrenergic receptor-mediated changes of cAMP levels. Results:  Inhibition of β-adrenergic receptors by propranolol increased hydraulic conductivity, reduced both cAMP levels and TER of microvascular endothelial cell monolayers and induced fragmentation of VE-cadherin staining. In contrast, activation by epinephrine both increased cAMP levels and TER and resulted in linearized VE-cadherin distribution, however this was not sufficient to block barrier-destabilization by propranolol. Similarly, PDE inhibition did not prevent propranolol-induced TER reduction and VE-cadherin reorganization whereas increased cAMP formation by AC activation enhanced endothelial barrier functions under baseline conditions and under conditions of propranolol treatment.

Briefly, PBMCs were incubated with saturating concentrations of CD14 microbeads at 4 °C for 15 min, washed and suspended in PBS containing SCH772984 purchase 2 mm ethylenediaminetetraacetic acid and 0.5% bovine serum albumin (BSA). The cell suspension was then applied

to the autoMACS separator using the positive selection programme. The CD14-positive cells were eluted from the magnetic column; a purity of >98% was routinely obtained as confirmed by flow cytometry. Previous studies using mRNA profiling as readout have demonstrated that isolation procedures do not result https://www.selleckchem.com/products/rxdx-106-cep-40783.html in relevant activation of the isolated cells. Naïve PBMCs and naïve CD14+ monocytes were recuperated in culture for 24 h in DMEM supplemented with 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mm L-glutamine (DMEM+), with 10% heat-inactivated human male AB serum. Naïve PBMCs were cultured in 96-well plate (Nunc) at a concentration of 1 × 105 PBMCs per well according to standard procedures, whereas naïve CD14+ monocytes

were cultured in 24-well plate at a concentration of 1 × 106 cells per well. Both naïve PBMCs and naïve CD14+ monocytes were cultured in a cell/tissue incubator under 5% CO2 in air (pH7.4), at 37 °C and 95% humidity. After the 24 h of recuperation, medium was replaced with serum-free DMEM+ with additives according to the experimental conditions, and cells were cultured for an additional 24 h. Experimental conditions included stimulation with FVIIa [25 nm], TF [37 pm] + FVIIa

[25 nm], Thiamet G TF [37 pm] + FVIIa [25 nm] + FX [100 nm], FX [100 nm], FXa [10 nm] or Thrombin [300 nm]. These concentrations correspond with a FVIIa dose of 90 μg/kg body weight for FVIIa in case of treatment and known estimated physiological intravascular concentrations of TF [37 pm], FX [135 nm], FXa [13.5 nm] and thrombin [2–300 nm] [[23].] For reverse transcription–polymerase chain reaction (RT-PCR), RNA was isolated from naïve CD14+ monocytes with RNeasy Mini Kit (Qiagen, Germantown, MD, USA) according to the manufacturer’s instructions. RT-PCR was carried out using GeneAmp RNA PCR Core kit (Applied Biosystems, Carlsbad, CA, USA) according to the manufacturer’s instructions. DNase-treated RNA samples were reverse transcribed to complement DNA (cDNA) using recombinant Moloney murine leukaemia virus reverse transcriptase.

LPS-protected animals showed higher frequency and number of CD4+Foxp3+ T cells in the spleen and pLN, when compared to healthy controls (Figs. 5A and S4). Expression of CD25 by Foxp3+ Treg is believed to identify active Treg presumably exposed to IL-2 produced by effector cells. LPS-protected mice showed enrichment in the

proportion of Foxp3+ cells within the CD4+CD25+ compartment in pLN (Fig. 5B). In the spleen, the frequencies of Foxp3+ cells were increased in the CD4+CD25− (Fig. 5C) and not in the CD4+CD25+ cell subset (Fig. 5B), although the levels of Foxp3 expression within the latter were somewhat enhanced (Fig. S5). Together, these results suggest that LPS treatment promoted Treg activation. Analysis of thymocytes showed no significant difference in the frequency and number of CD4+Foxp3+ EGFR inhibitor cells in LPS-treated as Selumetinib research buy compared to healthy controls (Fig. S6), indicating that the LPS effects on Treg are restricted to the periphery. We conclude that LPS treatment promoted the activation and accumulation of CD4+ cells with a regulatory phenotype. The findings above suggested that enhanced Treg activity prevented effector cell diabetogenic potential activity in LPS-protected NOD mice.

According to this scenario, effector cells from LPS-treated animals would cause severe diabetes if unleashed from Treg control. To directly test this hypothesis we performed adoptive transfer of splenocytes isolated from either diabetic, healthy controls or LPS-treated mice, into alymphoid NOD/SCID animals. We first analysed female recipient mice that had received 5 × 106 total splenocytes obtained from 6- to 7-month-old NOD females (Fig. 6A). As expected, all female recipients of cells isolated from sick donors developed diabetes 7 weeks post-adoptive transfer. Intriguingly, disease onset was not significantly delayed in mice Metalloexopeptidase that had received cells from healthy donors and diabetes incidence reached 100% by 12 weeks post-transfer.

Similar results were obtained when NOD/SCID male received splenocytes prepared from 7-month-old diabetic or disease-free NOD males (Fig. S7A). These results confirmed that diabetes is transferable upon injection of total splenocytes while spontaneous resistance to diabetes seemed not. In contrast, mice recipient of cells isolated from LPS-treated donors developed diabetes more than 5 weeks later than any of the control groups. Notably, at 12 weeks post-transfer, when all control mice were readily sick, only two of 14 (14.3%) female recipient mice of LPS-treated donors were diabetic. Remarkably, in the same group, four of 14 mice were still not diabetic 25 weeks post-transfer. Similar experiments performed with males yielded comparable results (Fig. S7A). As recipient mice were not exposed to LPS, we conclude that LPS altered the lymphocyte composition in the protected donors.

Importantly, mcDC transfer induced CD8+ T cell

memory. When mice were challenged with OVA257–264-pulsed target cells 28 days after DC transfer, mcDC-treated mice showed robust killing of target cells. This antigen-specific killing was superior to the killing observed in CD8 DC-transferred mice (Fig. 3c). We next determined the induction of OVA323–339-specific CD4+ T cell responses by the different DC subsets. CD11b DCs, pDC and CD8 DCs showed poor priming of OVA323–339-specific CD4+ T cell responses as determined by ELISPOT for IFN-γ 10 days after DC transfer (Fig. 3d). Importantly, mcDC transfer resulted in a significantly stronger priming of IFN-γ-producing OVA323–339-specific CD4+ T cells (P < 0·05). We could not detect the cytokines IL-4 and IL-5 by ELISPOT upon mcDC transfer,

indicating that mcDCs induce CD4+ T cell responses of a Th1 phenotype. Comparable to the in vitro data, DC populations from find more PBS- and FLT3L-treated mice had the same capacity to activate endogenous CD4+ and CD8+ T cell responses, showing that the DC functions also remain unaltered in vivo by FLT3L treatment. To determine the capacity of the different DC populations to induce protective anti-tumour responses, mice received DC populations from FTL3L-treated mice that had been cultured with irradiated ActmOVA-Kbm1 T cells in vitro. Seven days after the transfer of 0·5 × 106 DC, mice were challenged on the left flank with EL-4-mOVA cells and on the right flank with EL-4 parental cells. In naive mice, EL-4 and EL-4-mOVA tumours grew with Selleckchem beta-catenin inhibitor comparable kinetics (data not shown). Pretreatment of the mice with CD11b DCs did not affect tumour growth of either EL-4 or EL-4-mOVA (Fig. 4a). Pretreatment of the mice with CD8 DCs delayed tumour growth of the EL-4-mOVA but not the parental EL-4 tumour. Strikingly, mcDC pretreatment protected the mice completely from EL-4-mOVA tumour challenge but not EL-4-tumour challenge (Fig. 4a), highlighting their potency to induce protective tumour-specific

immunity. Similar outcomes were seen when mcDC were Y-27632 purchase isolated from PBS-treated mice (Fig. 4b), which was expected given their similar capacity to prime endogenous T cell responses to cell-associated antigens in vivo. Moreover, the protection to EL-4-mOVA but not EL-4 parental tumour challenge demonstrated the specificity of the DC treatments. We next determined the therapeutic potential of tumour cell vaccine presentation by the different DC populations in tumour-bearing mice. Mice received EL-4-mOVA cells on one flank and the parental EL-4 on the other flank. As soon as palpable tumours had formed, mice were treated with purified DC that had been exposed to irradiated ActmOVA-Kbm1 cells in vitro. Treatment with CD11b DCs did not affect tumour growth, and both EL-4 tumour and EL-4-mOVA tumour growth was comparable with the tumour growth in untreated mice (Fig. 5a).

Culture of biopsy tissue and aspirated material was negative whilst on antibiotic therapy. Cystoscopy and bladder biopsy revealed suspicious erythematous patches and yielded a histological diagnosis of malakoplakia (see Fig. 1). Although at least three mid stream urine samples were sterile around the period of the cystoscopy, Klebsiella pneumoniae

was isolated from bladder wall tissue. Once the diagnosis of malakoplakia was made, we embarked on a co-ordinated strategy that included minimization of immunosuppressive medication together with aggressive and prolonged antibiotics. Mycophenolate mofetil was stopped; the prednisolone reduced learn more to 5 mg daily and tacrolimus was titrated to achieve concentrations of 2–4 μg/L. She received a further 12 weeks of intravenous piperacillin/tazobactam and from September 2012, followed by oral faropenem (150 mg, three times daily) and fosfomycin (3 g, weekly). Serial abdominal CT scans in March and October 2013 revealed reduction in graft oedema with reduction in size of the malakoplakia lesions to 15 mm followed by resolution of the lesion in the latter scan (see Fig. 2). Our patient’s urine has been sterile for more than 15 months, and repeat cystoscopy demonstrated regression of the

malakoplakia. All antibiotics were ceased selleck chemicals llc in November 2013. Despite her complicated course, her allograft function throughout has been excellent, consistently achieving eGFR above 55 mL/min per 1.73 m2. To our knowledge, this is the first reported case of malakoplakia in a renal transplant recipient affecting both the allograft and the bladder. This case is also notable for a successful outcome, for a condition often associated with poor graft survival, by employing a strategy combining minimization of immunosuppressive medications and prolonged antibiotics. Malakoplakia (from the Greek: malakos, soft; plakos, plaques, describing the macroscopic appearances) is a rare granulomatous inflammatory

disorder postulated to occur as result of disordered macrophage bactericidal activity, usually in the context of host immunodeficiency. Approximately 40% of cases are associated with established risk factors for poor immune function, including malignancy, autoimmunity, immunosuppressive therapy, chronic alcohol excess or general debility.[1] filipin Although the molecular pathogenesis is unknown, it is believed that abnormally low intracellular concentrations of cyclic guanosine monophosphate (cGMP), required for assembly of microtubules and lysosomal merger to phagocytic vacuoles, and similar deficiency of beta-glucuronidase, an enzyme critical for normal lysosomal function, underpins the process.[2-4] The subsequent intracellular accumulation of partially degraded bacteria prompts development of a granulomatous reaction, and accounts for the pathognomic MG bodies: calcified, basophilic, periodic acid-Schiff positive intracellular inclusions which often appear as targetoid or owl’s eye lesions.

The canonical member of the GlyAg family is polysaccharide A (PSA) from the capsule of B. fragilis. PSA is comprised of a tetrasaccharide repeating unit with both positively and negatively charged groups 17 that facilitate its ability to be presented by MHCII molecules 18. GlyAgs are endocytosed by professional APCs and trigger the production of NO 19, which is responsible for the oxidative cleavage of the antigen to low molecular weight fragments for MHCII-mediated presentation 20, 21. This NO-dependent oxidative DMXAA purchase processing and presentation mechanism is essential for GlyAg-specific T-cell recognition and activation. Animals lacking the iNOS

gene fail to form abscesses in response to GlyAg challenge 20. With NO-mediated oxidation at the root of GlyAg-induced abscess formation, we sought to understand the nature of the hyperresponsiveness in CGD. Using the gp91phox-deficient animal model of CGD, we discovered that the loss of a functional NADPH oxidase results in a ten-fold increase in sensitivity against GlyAg GDC-0068 in vivo challenge, with

CGD abscesses being consistently larger compared with WT C57BL/6 (WT) controls. Ex vivo experiments further reveal an earlier and more robust T-cell activation response against GlyAg that correlated with increased NO and iNOS protein production in CGD animals and increased GlyAg processing in CGD APCs. Remarkably, CGD hyperresponsiveness was transferrable to WT animals through adoptive transfer of neutrophil-depleted CGD APCs, demonstrating that increased abscess formation was a result of aberrant APC function and the resulting downstream T-cell activation, rather than changes in neutrophil or T-cell activity resulting from Abiraterone cell line changes in ROS production. Perhaps most significantly, we discovered that attenuation of iNOS activity with 1400W (N-(3-(aminomethyl)benzyl)acetamidine, 2HCl) effectively and safely reduced the incidence and severity of abscesses in CGD. These findings reveal that the abscess hyperresponsiveness in CGD is mediated at least in part through greater sensitivity to GlyAg

via an increase in NO-dependent T-cell activation and that treatment with 1400W could represent a novel approach to improving infection outcomes for CGD patients. GlyAg-mediated abscess formation in rodent models of sepsis is dependent upon MHCII presentation 20, 22, 23 and CD4+ T-cell activation 16, 23–26, while being exquisitely sensitive to NO production in responding APCs 19–21, 23. Given the dependence upon oxidation, we measured the impact of the CGD mutation on GlyAg-specific responses. CGD and WT mice were challenged i.p. with either 200 μg GlyAg containing undiluted sterile cecal contents (SCC) (dilution=1), SCC alone, or dilutions of each inoculum. On day 7, the number of mice with at least one abscess was scored (Fig. 1A). CGD animals were ten-fold more sensitive to GlyAg challenge compared with WT control animals (C1/2=four-fold dilution for WT; 40 for CGD).

Table 1 provides a summary of the relationships among the levels of various inflammatory mediators throughout the protocol. The results demonstrated significant correlations among selected mediators, with CRP levels being independent of the other inflammatory biomarkers. However, the acute phase reactants, BPI and LBP, showed the most consistent relationship as markers of systemic inflammation throughout the pregnancy and ligature-induced disease. Table 2 provides a similar assessment BTK inhibitor in relating the inflammatory mediators to serum antibody levels to oral bacteria at baseline, mid-pregnancy and delivery.

Using a forward stepwise regression to assess the level of antibody specificity that best predicted the individual systemic inflammatory analyte levels, the results provided some interesting outcomes. Generally PGE2, RANTES and BPI levels were unrelated to the antibody responses. CRP, IL-8, MCP-1 and LBP showed significant relationships to this website antibody response profiles at baseline. IL-8 and MCP-1 levels maintained a relationship to

specific antibody profiles through mid-pregnancy, including both antibody specificities and direction. IL-6 levels were related to specific antibody patterns at mid-pregnancy and delivery. Examination of the overall systemic antibody responses indicated that responses to F. nucleatum, P. gingivalis, A. actinomycetemcomitans and C. rectus were associated most frequently with variations in inflammatory mediator levels. Finally, we attempted to model the oral clinical disease expression via a specific profile of systemic inflammatory responses. The results in Table 3 provide a summary of these analyses. Levels

of IL-6, IL-8 and LBP demonstrated a significant profile across the entire population irrespective of the sampling interval. Separating these comparisons into the individual sampling times demonstrated that none of the analytes profiled the oral clinical presentation at baseline. However, at mid-pregnancy, PGE2 and RANTES were related significantly to the oral disease, with only ifoxetine BPI levels as a significant correlation of oral disease at delivery. Interestingly, throughout the experimental protocol, the profiles of serum mediators were less dependent upon the sampling interval, and patterned more closely the actual clinical presentation of the animals throughout the course of the study (Table 3). As more attention is being directed towards chronic diseases in the human population, new concepts of aetiology and resulting loss of tissue/organ function continue to develop. Many of these chronic diseases have been identified to have components of chronic inflammation, both locally and systemically, that contribute to inducing collateral damage of the host resulting in the clinical symptoms.

The high levels of IL-23 expression seen in the gut may suppress Treg responses via γδ T cells to allow adaptive immunity to ensue in response to a gut-related infection. There is one obvious question arising from these studies: are the target cells of IL-23 in the experimental setting of

autoimmune neuroinflammation merely αβ T cells or also γδ T cells? Studies using adoptive transfer of myelin oligodendrocyte glycoprotein (MOG)-specific IL-23R−/− T cells concluded that only αβ T cells are relevant [32]. However, many current adoptive transfer protocols rely on prior in vivo immunization Palbociclib chemical structure and it cannot be excluded that during this priming period, IL-23-responsive innate immune cells such as γδ T cells shape the developing αβ T-cell response by modulating the local cytokine milieu. In order to unequivocally clarify this question, a conditional IL-23R

allele would be necessary. Despite their low numbers, γδ T cells have been shown to be major contributors to IL-17 production not only during CNS inflammation, but also in other models of autoimmune disease. In a model of CIA, γδ T cells were responsible for the majority of IL-17 expression. In this particular setting, IL-17 expression was induced by IL-23- and IL-1-triggered signaling in γδ T cells [89]. Very recently, the pathogenic role of the IL-23–γδ axis has been highlighted in another disease model, namely imiquimod-driven psoriatic skin inflammation [90, 91]. This finding is of particular importance, since 4-Aminobutyrate aminotransferase psoriasis has so far been considered to be a CD4+ T-cell-mediated disease, with treatment learn more strategies aiming at targeting conventional CD4+ Th17 cells. However, the data by Yan and colleagues [88] suggest that γδ T cells are the predominant source of IL-17 not only in the mouse model, but also in psoriatic lesions from human patients and it is known that IL-17 contributes greatly to psoriatic disease progression [92-95]. Shortly after IL-23 was identified

as the major pathogenic messenger in EAE [25], various human immunopathologies previously ascribed to the action of IL-12-activated Th1 cells were probed for the involvement of IL-23. Consequently, it was shown by several groups in mouse models of IBD that IL-23 is indispensable for immune-mediated destruction of the intestine [52, 96, 97]. Furthermore, in a genome-wide association study in IBD patients, several single nucleotide polymorphisms in the IL23R gene were associated either with resistance or susceptibility to IBD [48]. Interestingly, polymorphisms in the IL-12Rβ1 and the IL-12p40 subunit did not associate significantly with the disease. Given the therapeutic options, this observation intensified efforts to understand the exact role of IL-23 in intestinal inflammation. Initially, most of the research focused on the involvement of Th17 cells, which were identified at the same time, and were also shown to contribute to the disease in various mouse models.