in cost-utility analysis reflected more or less in keeping with published data (Table 5).[38]

However, this study made an assumption that the treatment was beneficial. In our opinion, this lifetime risk estimation in conjunction with CHADS2 index may be a useful tool in informed decision-making process for anticoagulation therapy. Warfarin has a notoriously narrow therapeutic window and carries significant risk if not closely monitored. There is increasing NVP-AUY922 manufacturer appreciation that kidney impairment could also decrease non-renal clearance and alter the bioavailability and response to drugs predominantly metabolized by the liver.[39, 40] Moderate and severe kidney impairment was associated with a reduction in warfarin dose requirements.[41] Initiation and maintenance of warfarin therapy is challenging because of the multitude of factors that influence PF 2341066 its pharmacokinetics and pharmacodynamics. The risk of haemorrhage is especially increased during the first 30–90 days after initiation of oral anticoagulation because initial therapy often results in INR value >3.0.[20, 42] Reinecke et al. proposed that checking INR three times a week during the first month and checking at least every fortnight

for long term.[25] The prevalence of warfarin use among HD patients was reported to be 8–25%, with up to 70%.[21, 43] Despite common use of warfarin, the exact bleeding risk due to warfarin in HD patients with AF is largely unknown. Elliott et al. systemically reviewed the rates of bleeding episodes in HD patients treated with warfarin for any indication (mainly for venous access thrombosis) and concluded that warfarin use doubled the risk for major bleeding.[44] This systematic review concluded that both low- and full-intensity anticoagulation use in HD patients was associated with a significant bleeding

risk. The other comorbidities contributing to the increased bleeding risks of the patients may not be taken into account in these studies and this was the major limiting factor. A full-intensity anticoagulation TCL therapy study in the same systematic review showed that 20 times higher bleeding rates in HD patients exposed to warfarin.[45] In Holden et al. study, warfarin was found to increase significantly the risk for bleeding up to three times and aspirin by four times.[46] In Chan et al. study, a significant higher bleeding rate was associated with warfarin or clopidogrel use (vs non-use) whereas the rates of bleeding between patients on aspirin and no mediation were statistically and clinically no different.[21] The results of both Holden et al. and Chan et al. studies indicated that the combination of warfarin and aspirin resulted in the highest incidence of major bleeding episodes.[21, 46] Olesen et al. concluded in his a large observational study that compared with non-user, warfarin mono-therapy (HR 1.27; 95% CI 0.91–1.77; P = 0.15), aspirin mono-therapy (HR 1.63; 95% CI 1.18–2.26; P = 0.

65 Not surprisingly, NGAL measurements as an outcome variable are currently included in several ongoing clinical trials formally listed in ClinicalTrails.gov. The approach of using NGAL as a trigger to initiate and monitor novel therapies, and as a safety biomarker when using potentially nephrotoxic agents, is expected to increase. It is also hoped that the use of predictive and sensitive biomarkers such as NGAL as endpoints in clinical

trials will result in a reduction in required sample sizes, and hence the cost incurred. A number of studies have demonstrated the utility of early NGAL measurements for predicting the severity and clinical outcomes of AKI. In children undergoing cardiac surgery, early post-operative plasma NGAL levels strongly correlated with duration and severity of AKI, length HM781-36B mouse of hospital stay

and mortality.66 In a similar cohort, early urine NGAL levels highly correlated with duration and severity of AKI, length of hospital stay, dialysis requirement and death.67 In a multicentre study of children with diarrhoea-associated haemolytic uraemic syndrome, urine NGAL obtained early during the hospitalization predicted the severity of AKI and dialysis requirement with high sensitivity.68 Early urine NGAL levels were also predictive of duration of AKI (AUC 0.79) click here in a heterogeneous cohort of critically ill paediatric subjects.51 In adults undergoing cardiopulmonary bypass, those who subsequently required renal replacement therapy (RRT) were found to have the highest

urine NGAL values soon after Oxymatrine surgery.30–37 Similar results were documented in the adult critical care setting.53–59 Collectively, the published studies revealed an excellent overall AUC-ROC of 0.78 for prediction of subsequent dialysis requirement, when NGAL was measured within 6 h of clinical contact.41 Furthermore, a number of studies conducted in the cardiac surgery and critical care populations have identified early NGAL measurements as a very good mortality marker,30–32,54,55,59 with an overall AUC-ROC of 0.71 in these heterogeneous populations.41 Furthermore, there is now evidence for the utility of subsequent NGAL measurements in critically ill adults with established AKI. Serum NGAL measured at the inception of RRT was an independent predictor of 28-day mortality, with an AUC of 0.74.69 With respect to the sample source, the majority of AKI biomarkers described thus far have been measured in the urine. Urinary diagnostics have several advantages, including the non-invasive nature of sample collection, the reduced number of interfering proteins, and the potential for the development of patient self-testing kits.

Conceivably, under conditions of high antigen concentration, the duration of T-cell–APC contacts is longer and sufficient to elicit a chronic inflammatory response. Hence, it has been suggested that the presence of antigen at a relatively low concentration may be protective against inflammation.[54] Further experimentation is required to address this question, as well as the questions of how long are cytokines produced by T cells in antigen-rich versus antigen-poor see more tissue environments and are effector cytokines retained locally or can they be delivered to several different distant sites. Similar

to the above-described patterns of recirculation and migration of naive, effector and memory CD4+ T cells, recent studies have

also analysed the patterns of recirculation and migration of NKT cells in vivo in mice (Table 4).[60] The pathogenic and protective effects of NKT cell subsets following agonist stimulation in vivo are determined mainly by their timing of activation, structures of lipid antigens recognized, interactions with different Proteases inhibitor DCs and profiles of cytokine secretion. Using structural variants of αGalCer that do not interfere with TCR recognition, it was recently shown that distinct types of CD1d-bearing DCs may regulate the different profiles of cytokines secreted, e.g. Th1-type (IL-12, IFN-γ), Th2-type [IL-4, IL-9, IL-10, IL-13, granulocyte–macrophage colony-stimulating factor (GM-CSF)] or

Th17-type (IL-17A, IL-21, IL-22), by NKT cells in vivo.[32, 60] The list of cytokines secreted by NKT cells include IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, IL-21, tumour necrosis factor-α, IFN-γ, transforming growth factor-β and GM-CSF. Hence, depending on the type of specific interactions between subsets of NKT others cells and DCs, the cytokines secreted by activated NKT cells may either activate or suppress adaptive immune responses. Since the strength of a TCR signal may influence the cytokine profile (Th1- or Th2-type) produced, understanding how the TCRs of NKT cell subsets bind to their ligands and subsequently cross-regulate each other’s activity is essential for the development of improved strategies of immune regulation for intervention in autoimmune diseases (Table 5). Considerable recent evidence in favour of a regulatory function of both type I and type II NKT cells suggests that both NKT cell subsets are attractive targets to test in novel immunotherapeutic protocols.[7-14, 61-63] A valuable animal model in which to study the pattern of recirculation and migration of NKT cells in vivo is a mouse in which the green fluorescent protein (GFP) gene is knocked into a lineage-specific gene yielding a heterozygous mouse in which certain leucocytes are fluorescently labelled.[61] The salient features of NKT cell recirculation and migration obtained in such a mouse model are highlighted in Table 4.

55,56 Associations between the presence of shorter (GT)n repeats and less susceptibility to different autoimmune diseases have been reported.57,58 Consistent with this notion is the observation that patients with rheumatoid arthritis display higher ratios between longer (GT)n and shorter (GT)n repeats than do healthy patients and hence

fewer HO-1 transcripts and less protein expression.59 Therefore, although we have only observed decreased HO-1 expression in monocytes from patients with SLE, it is possible that HO-1 microsatellite polymorphisms, such as Gefitinib in vivo (GT)n, could play a role in the expression of this enzyme. Further research is required to evaluate this hypothesis. Although our results show a decrease in HO-1 levels on monocytes from patients with SLE, we could not detect a correlation between HO-1 levels and the SLEDAI in these patients. However, we observed that all of the six patients with the highest SLEDAI displayed low levels of HO-1 in their monocytes (Fig. 4). It is possible that the lack of correlation between disease activity and HO-1 levels could be the result of the small number of patients included and that most of them did not have a very active disease. Nevertheless, the fact that HO-1 expression remains low independent

of the activity of the disease does not exclude this molecule as an interesting new therapeutic target for treating patients with SLE. Indeed, the chemical induction of HO-1 in MRL/MpJ-Faslpr (MRL/lpr) mice, an animal model of SLE, decreases the symptoms of Urease disease in part by a reduction LY2606368 cell line of nitric oxide synthase expression in the kidney and spleen and by a reduction in IFN-γ serum levels,60 supporting a potential use of HO-1 as a therapeutic target in patients with SLE. We would like to thank Dr Aquiles Jara and Sandra Vilches for providing blood samples from kidney-transplanted patients

and to Ana Karina Jimenez for kindly coordinating the clinical visits and laboratory work of patients with SLE and healthy subjects. We also thank the generous collaboration of all the patients with SLE who participated in this study. This work was supported by grants from FONDECYT 1085281, 1070352, 1110518, 3070018, ECOS-CONICYT C07S01, Biomedical Research Consortium and Millennium Institute on Immunology and Immunotherapy P04/030-F, IMBIO programme, l’Agence de la Biomédecine, Ministère de la Recherche, Fondation CENTAURE, Fondation Progreffe. AAH is a CONICYT fellow and AMK is a Chaire De La Région Pays De La Loire De Chercheur Étranger D’excellence. A patent application for the use of CO and HO-1 modulation to treat SLE has been submitted. Figure S1. Normal levels of HO-1 on monocyte-derived DCs from SLE patients. Figure S2. Surface HO-1 expression in monocytes, lymphocytes and DCs from SLE patients. Figure S3. Expression of MHCII and CD86 in monocytes from SLE patients. Figure S4. Reduced HO-1 expression in monocytes and dendritic cells from RA patients. Figure S5.

From superoxide, other ROS, such as hydrogen peroxide, can be generated. The exact mechanism of pathogen killing within the phagosome is not known. From the killing defect seen in CGD phagocytes, it is clear that ROS play an important role, but whether this is a direct role through formation of hypochlorous acid from hydrogen

peroxide and chloride, catalysed by myeloperoxidase, or an indirect role through facilitating the release of proteolytic enzymes from the granules in the phagocytes [2], or a combination of these mechanisms, remains to be established. Most CGD pathogens share the property Alpelisib concentration of producing catalase; as such, they degrade the hydrogen peroxide that they themselves generate. It has therefore see more been suggested that catalase-negative organisms, by supplying the CGD phagocytes with microbial hydrogen peroxide, might complement the hydrogen peroxide deficit in CGD phagocytes, thus inducing killing of the microbes themselves. Catalase production was thus thought

to be an important microbial pathogenicity factor in CGD. However, this hypothesis must be viewed in the context that the majority of all pathogens contain catalase (with the important exception of streptococci). This view has been challenged further by the retained virulence of Aspergillus and staphylococci rendered genetically deficient for catalase production [3, 4]. In addition, individuals with the quite common deficiency of myeloperoxidase do not suffer from CGD-like symptoms. The genes encoding the five NADPH oxidase components are CYBB (located on the X chromosome)

for gp91phox, and the autosomal genes CYBA for p22phox, NCF1 for p47phox, NCF2 for p67phox and NCF4 for p40phox (Table 1). About 70% of the CGD patients have a mutation in CYBB (most of them hemizygous males, Protirelin but a few heterozygous females with skewed expression of their mutation are also known). The remainder of the patients have a mutation in NCF1 (about 20%), in CYBA (about 5%) or in NCF2 (about 5%). Only one patient is known with a mutation in NCF4. A mutation in any of these five genes can cause CGD. If the mutation leaves some residual NADPH oxidase activity intact, the clinical expression of the disease is less serious [5] and the chance of survival of the patient is larger [6] than in the case of total oxidase deficiency. This depends upon the gene mutated, the type of mutation and the position of the mutation within the gene. In general, mutations in NCF1 lead to a milder form of CGD (later presentation, milder clinical expression, better chance of survival) than mutations in any of the other genes. For genetic counselling and prenatal diagnosis, mutation analysis of the CGD genes is mandatory. Treatment should be started immediately after CGD has been definitely diagnosed, or even before.

9 and 17.1%; 85.7 and 14.3%; 80.5 and 19.5%; and 90.8 and 9.2% respectively, in women with endometriosis (P = 0.004), women with minimal/mild endometriosis (P = 0.148), women with moderate/severe endometriosis (P = 0.002) and control group. Conclusion  The data suggest that in Brazilian women polymorphism PTPN22 (C1858T) may be an important genetic predisposing factor for endometriosis,

especially, in advanced disease. “
“Anaplasma phagocytophilum is an emerging tick-borne pathogen. Great genetic diversity of A. phagocytophilum has been described in animals and ticks. The present study is focused on the genetic variability of the groESL operon of A. phagocytophilum in human patients in Slovenia. During 1996–2008, there were 66 serologically confirmed patients with human granulocytic anaplasmosis. click here Of these, 46 were tested with a screening PCR for a small part of the 16S rRNA gene of A. phagocytophilum and 28 (60.9%) were positive. Positive samples were additionally tested with a PCR

targeting the groESL operon and a larger fragment of the 16S rRNA gene. All amplicons were further sequenced and analyzed. The homology RXDX-106 solubility dmso search and the alignment of the groESL sequences showed only one genetic variant. Sequence analysis of the 16S rRNA gene revealed 100% identity among amplicons. Slovenia is a small country with diverse climate, vegetation, and animal representatives. In previous studies in deer, dogs, and ticks, great diversity of the groESL operon was found. In contrast, in wild boar and in human patients from this study, only one genetic variant was detected. The results suggest that only one genetic variant might be pathogenic for humans or is competent enough to replicate in humans. To support this theory, other genetic markers and further studies need to be performed. Anaplasmosis comprises a group of emerging tick-borne diseases. It is mostly mild and self-limiting

disease. The causative agent Anaplasma phagocytophilum is a pathogen known to cause disease not only in humans but also in ruminants, horses, and dogs. Anaplasma phagocytophilum shows differences in clinical severity, disease manifestation, reservoir competency, and antigenic diversity. Deer have been suggested as a reservoir animal. The heterogeneity Thiamet G of the groESL operon, as well as other genes of A. phagocytophilum, in animals and in a tick vector Ixodes ricinus has been described elsewhere. Only few studies report PCR-confirmed human cases of anaplasmosis. The present study is focused on the genetic variability of the groESL operon of A. phagocytophilum in human patients in Slovenia. Between the years 1996 and 2008, blood samples of human patients with clinical signs of anaplasmosis were tested for the presence of anaplasmal DNA. DNA was extracted from acute blood samples of patients that seroconverted or had at least a fourfold rise in antibody titer against A. phagocytophilum antigen. For initial screening of all samples, PCR for a small part of the 16S rRNA gene of A.

However, not all studies yielded uniform results [13, 14], and it is until yet unclear which subset of patients with iDCM/non-ischaemic DCM does best benefit from IA therapy. Even if IA is used only once, the level of anti-cardiac antibodies remains low over time [10]. Likewise, a single course of IA treatment shows an increase in left ventricular function over a 6-month period comparable to that after repeated IA treatments

at monthly intervals [11]. A recent study suggests that IA therapy not only removes cardiotoxic autoantibodies from circulation, but also modifies Selleckchem Adriamycin T cell–mediated immune reactions. In this study, IA therapy, which was performed in 10 patients with iDCM, was associated with a significant increase in regulatory T cells (CD4+CD25+CD127low) and a decrease of activated T cells (CD4+/CD69+ and CD8+/CD69+ cells) and CD28+ T cells (co-stimulatory cells) selleck products [12]. Regulatory T cells (Tregs; formerly known as T suppressor cells) are important negative immune modulators, constituting

of approximately 5% of peripheral CD4+ T cells. They suppress the activation, proliferation and/or differentiation of CD4 and CD8 T cells, B cells, natural killer cells and dendritic cells, thus controlling the immune responses to self-antigens or to pathogens [15]. Depletion or dysfunction of Tregs alone is sufficient to cause autoimmune diseases, vice versa their reconstitution efficiently suppresses autoreactive T cells [16, 17]. Furthermore, Tregs suppress the proliferation of B cells; a depletion of Tregs results in an abnormal humoral response with an increased production of autoantibodies [18]. In mice challenged with coxsackievirus B3, adoptive transfer of Tregs protects against the development of myocarditis by suppressing the immune responses to cardiac Carteolol HCl tissue [19]. It is reasonable to assume that changes in T cell regulation and activity in response to IA are linked to inflammatory processes within the myocardium and subsequently myocardial function. In this prospective study, we investigated the correlation between the level of circulating Tregs and improvement

of myocardial contractility in response to IA therapy in a consecutive series of patients with iDCM. This study suggests that low levels of Tregs before IA therapy identify a subset of patients who do benefit best from this therapy during a 6-month follow-up. The study population comprises 35 patients recruited in the cardiovascular division of St. Josef-Hospital and BG Kliniken Bergmannsheil, hospitals of the Ruhr-University of Bochum, Germany. Patients (N = 18) were admitted for immunoadsorption. Inclusion criteria were congestive heart failure (CHF) (NYHA II – IV) secondary to chronic iDCM, reduced left ventricular systolic function (EF < 35%), stable medication for CHF for at least 3 months and angiographic absence of coronary artery disease.

Although HMGB1 stimulation prevented engraftment of WT islets, TLR2/4−/− islets engrafted in all animals, normalizing serum glucose levels with similar kinetics to untreated WT islets (Fig. 7D). Our results delineate several new insights into the pathogenesis R788 chemical structure of early islet graft failure, including the notable result that TLR2 and TLR4 are key participants in this process. We demonstrated that stimulation via either TLR2 or TLR4 initiated a proinflammatory milieu, likely via chemokines and cytokine release at the graft site, associated with graft apoptosis

and early graft failure (Fig. 2), but did not directly affect islet viability or function in vitro (Fig. 1). In experiments mimicking physiological islet injury by adding exocrine debris (Fig. 3) or by alloimmune response (Fig. 4), TLR2/4−/− islets reduced proinflammatory cytokine production and/or improved islet survival. Recipient T cells and principally CD8+ T cells mediated the graft destruction, because TLR-stimulated islets restored euglycemia

in CD8−/− mice (Fig. 5). Although the specific T-cell targets are not known, our data demonstrate Metformin datasheet that the CD8+ T cells did not require DC (Fig. 6). The data newly revealed that HMGB1, a highly conserved chromosomal protein, could be released from islets in response to hypoxic stress or transplantation and that through signaling via TLR2 and TLR4 this endogenous Florfenicol DAMP prevented primary

engraftment (Fig. 7). These studies extend our previous report in mice 10 and of others in humans 13 that isolated pancreatic islets produce chemokines, following short-term culture, and high pretransplant CCL2 concentrations correlated with poor islet graft function. Our previous data showed that the damage to the islets could not be completely accounted for by the interaction of CCL2 with its receptor CCR2, suggesting a role for other cytokines or chemokines 10. Our current findings explain this previous study by implicating islet-expressed TLR as the mechanistic link between pre and peri-transplant events and increased expression of proinflammatory genes, attracting macrophages and T cells. Although we demonstrated that early islet graft loss occurred in CD4−/− but not in CD8−/− recipients (Fig. 5), indicating a pathogenic role for CD8+ T cells, the specific mechanisms underlying this observation remain to be elucidated. We speculate that the local inflammation associated with the transplant procedure, compounded by the absence of CD4+ Treg in CD4−/− animals facilitates activation of autoreactive CD8+ T cells. The primed CD8 cells are attracted to the inflamed graft, where they elicit effector functions that mediate injury and amplify the local inflammation.

Necrosis and kidney damage were assessed with H&E-stained kidney tissue 24 h after transplantation. Acute tubular necrosis score (ATN) was decreased significantly in the immunosuppressive treatment group compared with the control group (4 ± 0·63

in control; rapamycin 2·2 ± 0·41; FK506 2 ± 0·63; rapamycin + FK506 1·2 ± 0·41; P < 0·001 versus control; Fig. 2a). Figure 2b PF-01367338 in vivo shows a representative image of H&E stain for the evaluation of renal injury in each treatment group. The use of rapamycin plus tacrolimus (group 4) was associated with a lower level of acute tubular necrosis (ATN) compared with rapamycin alone (P < 0·05), but no statistical difference was observed in comparison with tacrolimus. Also, the number of apoptotic nuclei in renal medulla was determined as evidence of kidney injury. In the control group, the number of TUNEL-positive cells was higher compared with the immunosuppressive treatment groups (control: 138·7 ± 24·8; rapamycin: 22·3 ± 4·5; FK506: 54·8 ± 8·3 and rapamycin + FK506: 17·5 ± 5; P < 0·001 versus control, Fig. 3a and b). As normal kidney control, the number of positive apoptotic nuclei in sham animals was lower than 6/mm2 located only in deep medullary epithelial tubules (data not shown). The use of rapamycin alone or rapamycin plus tacrolimus showed a lower number of apoptotic nuclei cells with respect to

tacrolimus treatment (P < 0·05 and P < 0·01, respectively). Finally, a statistically significant difference in the expression of Bcl2 was detected in selleck chemicals kidney tissue by immunohistochemistry. In accordance with our previous results, Bcl2 levels in the control group were lower than in the immunosuppressive treatment group (control: 1·8 ± 0·5; rapamycin: 16·01 ± 4; FK506: Nutlin-3 molecular weight 9 ± 2·6 and rapamycin + FK506: 6 ± 1·25; P < 0·01 and P < 0·05 versus control, respectively)

(Fig. 3c). These results suggest that preconditioning of the donor with rapamycin and tacrolimus or a combination of both is associated with lower kidney damage after transplantation. In order to determine if the immunosuppressive treatment affected the complement function, the C3 levels in recipient animals were assessed. C3 plasma values in immunosuppressive treatment were significantly lower than control group levels (control: 495 ± 94 pg/ml; rapamycin: 166·7 ± 57·1 pg/ml; FK506: 165 ± 66·3 pg/ml and rapamycin + FK506: 103·3 ± 33·3.; P < 0·001 versus control, Fig. 4a). No differences were found among the various immunosuppressive treatment groups (P > 0·05). In addition, the local expression of C3 within the grafts was analysed. Immunohistochemical analysis of graft tissue 24 h after transplantation revealed that local expression of C3 was higher in the control group compared with the immunosuppressive treatment group (control: 53·98 ± 4·5; rapamycin: 10·62 ± 3·2; FK506: 2·27 ± 0·7 and rapamycin + FK506: 1·58 ± 0·54.

Indeed, we observed greater IFN-γ production by expanded rat CD8α+ iNKT cells, compared with that of DN and CD4+ iNKT cells, as it has been reported for expanded human CD8α+ iNKT cells [6]. The genetic basis for the low iNKT cell frequencies of F344 rats compared with that in mice remains unclear. However, different expression

levels of CD1d by thymocytes, which would affect iNKT cell selection, can be excluded since thymocytes of both species have nearly identical CD1d levels [13]. The same is true for the recognition signal sequences, which are identical for all AV14 gene segments Trichostatin A ic50 of mice and rats and for AJ18 genes differ in only two nucleotides (Supporting Information Fig. 1E and data not shown). The low frequency of iNKT cells probably explains the lack of a direct identification of thymic F344 iNKT cells. Although frequencies of peripheral and thymic iNKT cells do not necessarily correlate [32], an extrapolation from frequencies of C57BL/6 liver and thymic iNKT cells would predict

for F344 rats a frequency in the range of 0.01% of total thymocytes and 0.08% for CD8β-pregated cells. In humans, gating of vehicle-CD1d stained cells into a “dump” channel has been instrumental for better characterization of very low frequencies (about 0.01%) of (thymic) Lumacaftor supplier iNKT cells [32]. So far, this approach is not feasible since in this study the rat CD1d dimers used are detected with a secondary reagent (fluorochrome-labeled anti-mouse Ig), which binds both vehicle and α-GalCer-loaded dimers. Nevertheless, the identification of canonical iNKT-TCRα sequences among AV14AJ18 PCR products clearly indicates the existence Sorafenib of iNKT cells in the F344 thymus. The differences observed in iNKT cell numbers between F344 and LEW rats in this study are not completely understood, but cannot be accounted to strain-specific differences

in the amino acid sequence of the mature CD1d protein or its expression levels, which are identical for both rat strains [13]. Nonetheless, since the first step necessary for the development of iNKT cells is the rearrangement of the A14 and AJ18 gene segments, the lack of iNKT cells in LEW inbred rats might be the consequence of a very inefficient production of iTCRα chains by thymocytes. Furthermore, LEW and F344 rats do differ in their Tcrb haplotypes. In particular, BV8S2 and BV8S4 are distinct in their CDR2β. Consequently, they could very well affect iNKT-TCR affinity and, thereby, iNKT cell development as well [12].