Mechanistically, autospecific Treg cells prevented disease induct

Mechanistically, autospecific Treg cells prevented disease induction by blocking donor T-cell engraftment whereas allospecific Treg cells permitted long-term engraftment of donor T cells. Donor

T cells, while unresponsive to auto- and recipient alloantigens, retained the capacity to respond to third party alloantigens on ex vivo stimulation. These findings indicate that allospecific Treg cells may therefore be more clinically relevant as a cell therapy for cGVHD in the context of haplo-identical hematopoietic transplantation, as they allow persistence of donor T cells capable of responding to foreign antigens whilst preventing cGVHD-mediated autoimmunity. Chronic graft-versus-host disease BAY 57-1293 cost (cGVHD) is a major complication following allogeneic haematopoietic stem cell transplantation (HSCT) and represents a significant BMS-777607 concentration contributor toward morbidity and mortality associated with this procedure [1, 2]. cGVHD is complex and distinct from acute graft-versus-host disease (aGVHD) in terms of kinetics of disease onset, immunological mechanism of disease induction, and pathophysiology [3], affecting multiple target organs as a result of dysregulated alloimmune reactivity between donor and recipient immune compartments [4, 5]. Clinically, cGVHD presents as a myriad of symptoms

characteristic of autoimmune conditions such as systemic lupus erthymatosus (SLE) and Sjögren’s syndrome [6], which are distinct from aGVHD

and as such, patients do not respond well to effective drug therapies used to treat acute disease. There is therefore a pressing need to provide an alternative to managing or preventing cGVHD that would negate side effects associated with sustained steroid use and benefit steroid refractory patients [2]. Although the mechanistic basis of cGVHD remains to be fully elucidated, it is thought that following haplo-identical HSCT and the resulting donor-derived haematopoiesis, disease is driven primarily by donor T-cell recognition of processed recipient alloantigens presented by donor antigen presenting cells (APCs), via the indirect pathway of antigen presentation [7]. This is distinct to the main driver of ZD1839 price aGVHD disease, which is mediated by donor T-cell recognition of intact recipient alloantigens expressed by recipient APCs, via the direct pathway of antigen presentation [8]. During cGVHD, activation of alloreactive donor T-cell responses is associated with a loss of self-tolerance and immune dysregulation [9], which may be attributed to loss of recipient regulatory T (Treg)-cell subsets [10], activation of quiescent auto-reactive T cells present within the donor transplant [11], or loss of normal thymic negative selection processes.

The I-PSS total score and nocturnal urine volume significantly im

The I-PSS total score and nocturnal urine volume significantly improved only by furosemide

treatment. Navitoclax mw Conclusion: Furosemide treatment definitively improved nocturia with nocturnal polyuria. GJG treatment may also induce mild improvement of nocturnal polyuria, although further study is required to confirm its efficacy. “
“The purpose of our study was to evaluate the effect of alfuzosin and tadalafil as combination therapy compared with each monotherapy, in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). Men over the age of 50 years with LUTS secondary to BPH and an International Prostate Symptom Score (IPSS) 8 or higher, were randomized to receive 10 mg alfuzosin (n = 25), 10 mg tadalafil (n = 25) or the combination of both the drugs (n = 25) once daily for 3 months. Symptoms were assessed at baseline, 6 weeks Selisistat manufacturer and 3 months. The primary endpoint was the change in IPSS from the baseline. Secondary endpoints were changes in IPSS storage and voiding subscores, peak urinary flow rate, residual urine volume, IPSS quality of life score and erectile domain score. There were significant

improvements in all IPSS scores, peak urinary flow rate and IPSS quality of life score from baseline at both 6 weeks and 3 months in all the three groups (P < 0.003). Combination therapy was better than monotherapy in improving IPSS scores and reducing post-void residual urine volume (P < 0.005). Combination therapy was similar to alfuzosin regarding improvement

in maximum urine flow rate (P = 0.22), similar to tadalafil in improvement on erectile function (P = 0.22) and better than each monotherapy in improving the IPSS quality of life (P ≤ 0.015). Alfuzosin and tadalafil combination therapy provides greater symptomatic improvement as compared to either monotherapy in men with LUTS due to BPH. Benign prostatic hyperplasia (BPH) is a common disease of ageing men. It is clinically characterized by the progressive and bothersome developmentof lower urinary Epothilone B (EPO906, Patupilone) tract symptoms (LUTS). The incidence of moderate to severe LUTS in a large prospective cohort of United States men was about 44% and the progression rate was about 26.5%.[1] Currently, alpha-blockers and 5α-reductase inhibitors (5ARIs) represent the most effective treatment options for BPH. Although these drugs are effective, they are associated with side-effects, which include dizziness, hypotension and sexual dysfunction. These side-effects may be exacerbated by combination therapy. Erectile dysfunction (ED) and LUTS associated with BPH generally begin when men are in the fifth or sixth decade of life and become more common with increases in age. Regular sexual activity is normal in aging men and satisfaction with sex life is an important dimension of quality of life.

The mechanism for this defect

has not been described If

The mechanism for this defect

has not been described. If IL-12 negatively regulates memory cell development while IFN-α/β positively regulates this process, it remains puzzling how memory cells develop when both of these cytokines are secreted during intracellular pathogen infections. In mice, both IL-12 and IFN-α/β are sufficient to promote effector function in CD8+ T cells when activated in vitro, albeit IFN-α/β is not quite as potent as IL-12 in regulating cytokine expression.86,101 However, there seems to be less redundancy between IWR-1 research buy these two cytokine pathways in driving human CD8+ T-cell effectors. Recently, Ramos et al.102 compared the ability of IL-12 and IFN-α to promote cytokine secretion and lytic activity in primary naive human CD8+ T cells. In contrast to mouse, IL-12 induced robust lytic activity and secretion of IFN-γ and tumour necrosis factor-α, but treatment with IFN-α alone had little effect on these activities compared with cells activated under neutralizing conditions. Two recent studies claim that IFN-α enhances IFN-γ production103 and granzyme expression104 in human CD8+ T cells, but those reports

only compared IFN-α to neutralizing conditions. Indeed, IFN-α does marginally increase IFN-γ production over the baseline control, but this level is still 10-fold less than the magnitude of production induced by IL-12.102 Consequently, IL-12 appears to be the main signal driving the expression of effector Cabozantinib purchase cytokines. However, while IFN-α failed to regulate effector cell development, IFN-α enhanced the development of CD8+ central memory (TCM) cells.102 This activity was unique to IFN-α, because IL-12 promoted only effector cell (TEM) but not TCM development. These cells lack immediate effector function but rapidly acquire these responses following secondary stimulation, hence representing

a functional memory population. Interestingly, when naive cells receive signals from both IL-12 and IFN-α, both TEM and TCM cells develop simultaneously, and they are derived from subpopulations of cells that differentially progress through enough cell division. The IL-12 programmes TEM phenotypes in actively dividing cells, whereas IFN-α induces TCM development by limiting proliferation and terminal differentiation in a subset of cells. These points are summarized in Fig. 2. Regarding the mechanism of this developmental programme, Ramos et al.102 demonstrated that the development of distinct effector and memory phenotypes of human CD8+ T cells occurred through the reciprocal regulation of their respective cytokine receptors. Development of TCM was regulated by marked induction of the IFNAR with low expression of the IL-12R, whereas effector cells rapidly divided and progressively lost IFNAR while gaining IL-12R expression.

Burster, unpublished data) We note that a dihistidine motif is a

Burster, unpublished data). We note that a dihistidine motif is adjacent to the CatG cleavage site of MHC II molecules (Fig. 4a), which might regulate CatG access in a pH-dependent fashion. However, GW-572016 nmr the pH dependence does not explain why even high concentrations of CatG

added to B-LCLs at neutral pH failed to cleave DR molecules at the cell surface. The simplest interpretation of the latter result is that the CatG cleavage site of MHC II molecules is sterically inaccessible when the MHC II molecules are embedded in endosomal or cell surface membranes. The steric hindrance could, in principle, come from the proximity of the membrane itself, or from noncovalent associations with other proteins, both of which would be disrupted by detergent lysis. Partial steric masking may also explain why, in most experiments,

full-length DR embedded in detergent micelles was digested less completely than soluble recombinant DR ectodomains. Our results do not prove that CatG is never involved in MHC II degradation in vivo. For instance, CatG might conceivably act on MHC II molecules that have partially lost their native conformation at the end of their useful life. However, our findings do suggest that MHC II molecules have evolved resistance to endosomal proteolysis by a combination of mechanisms. The inherent resistance of MHC II ectodomains to many cathepsins is likely to be important. Other protease cleavage sites, such as the CatG cleavage site studied here, may be cryptic, either Depsipeptide because of charge characteristics that impair proteolytic learn more attack in acidic endosomal compartments, or because they are sterically inaccessible at APC membranes, or both. Steric inaccessibility of the CatG cleavage site may be particularly important in allowing antigen presentation to be maintained

in inflamed tissues, in which CatG is abundantly released into the extracellular space by activated neutrophils. Whether cryptic protease cleavage sites contribute to regulated turnover of MHC II molecules remains to be determined. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG; BU1822/1-1) to TB, SFB 518, GRK 1041-2, and Else Kröner-Fresensius-Stiftung to BOB, funding from Sidney Sussex College and the Arthritis Research Campaign (ref. 18543) to RB, and grants from the NIH and the Child Health Research Program (Stanford University) to EDM. We gratefully acknowledge A. Guzzetta for mass spectrometry and L. Stern for providing HLA-DR1 molecules made in E. coli and the CHAMP anti-DR antisera. Other purified MHC II molecules, HLA-DR2b, murine I-Ag7 and I-Ek, were kindly provided by K. Wucherpfennig, L. Teyton and M. Davis, respectively. CatG−/− mice were kindly provided by C. Pham. The authors do not have any conflicting interests. Data S1. Sequential digest of HLA-DR3. Data S2.

Pregnancies with medical complications or diseases were excluded

Pregnancies with medical complications or diseases were excluded. The placental villi tissues were collected during the suction curettage procedure. The placental villi from first-trimester pregnancies were carefully dissected

free of attached placental Gefitinib or myometrial tissue as well as visible blood clots and then washed twice in 0.9% NaCl as soon as the embryonic tissues were removed from the uterus. Samples were stored at −80°C and later processed to extract tissue protein. Biopsies were taken from the placental villi, and small blocks of tissue were obtained by cutting longitudinal sections of 3–5 mm maximum thickness. The blocks were immersed immediately for 2 hr in phosphate-buffered 2.5% gluteraldehyde. After overnight washing in a 0.1 m sodium phosphate buffer, the tissue blocks were post-fixed in 1% OsO4 in a 0.1 m phosphate buffer (pH 7.4) for 1 hr and stained with 1% uranyl acetate. Afterwards, the tissue blocks were dehydrated and flat-embedded in Durcupan (Fluka Chemic AG, Sweden). For electron microscopy (EM), ultrathin sections (60–70 nm) were stained with lead citrate, examined at 3700× and LY2157299 12500× magnification and photographed using a Zeiss 109 electron microscope (Carl Zeiss, Oberkochen, Germany). HTR-8/SVneo and HPT-8 cells were grown in Dulbecco’s modified Eagle’s medium/Ham’s F-12 medium supplemented

with 1% non-essential amino acids, 2 mm glutamine and 10% heat-inactivated foetal bovine serum in a 37°C incubator with 5% CO2. Complementary DNA (cDNA) to gC1qR was constructed in-frame using the BamHI/EcoRI sites of the pcDNA 3.1 vector. The resulting

gC1qR vector was then transfected into HTR-8/SVneo and HPT-8 cells according to the vendor’s protocol. Briefly, 500 pmol of gC1qR vector and 10 μL of Lipofectamine 2000 were diluted in 750 μL of OptiMEM (Life Technologies). After pre-incubation for 45 min at 37°C, the solutions were mixed and incubated for an additional 15 min at room temperature. The Lipofectamine 2000/gC1qR vector mixture was subsequently overlaid onto the cells and incubated for 2 hr. Finally, 1 mL of growth medium (20% FCS) per well was added for further cultivation of the cells. Reporter gene activities were normalized to total protein levels, and all of the results represent the average of triplicate experiments. We designed an siRNA to target the 408–426 nucleotide portion of human gC1qR mRNA; the forward sequence cAMP was 5′-AAC AAC AGC AUC CCA CCA ACA UU-3′. Using pGenesil-1 as the vector backbone, a gC1qR siRNA-expressing plasmid was constructed. Near the 5′ end of the two oligonucleotides were BamHI and HindIII restriction site overhangs; a 6-nucleotide poly-T tract recognized as an RNA pol III termination signal was located at the 3′ end of the siRNA template. The siRNA was synthesized, annealed and ligated into the BamHI and HindIII restriction sites of the pGenesil-1 expression vector. A vector containing siRNA for an unrelated gene was used as a negative control.

Moreover, morphological alterations of fungal cells were investig

Moreover, morphological alterations of fungal cells were investigated using scanning electron microscopy. All disinfectant solutions killed all remaining fungal cells on the specimens. Interestingly, 4% chlorhexidine did not remove these cells from the acrylic resin surface whereas sodium hypochlorite solutions (1% and 2%) provided almost complete biofilm removal. Furthermore, treating the specimens with sodium hypochlorite induced cell morphology

alterations, as seen in the residual fungal cells. Finally, according to our findings, it can be suggested that sodium hypochlorite solutions are the first choice as denture cleanser when compared with 4% chlorhexidine because those solutions not only killed C. albicans biofilms but also removed them from the Temozolomide heat-polymerised acrylic resin. “
“AMG-148, an oxathiolone-fused

chalcone derivative, exhibited in vitro antifungal activity against several strains of human pathogenic yeast, with minimum inhibitory concentration values within the range of 1–16 μg ml−1 and a fungicidal effect was observed at higher concentrations. Presence of major drug-effluxing membrane proteins Cdr1p, Cdr2p or Mdr1p, did not affect substantially the fungistatic activity of this compound against clinical Candida albicans strains. Studies on the mode of action revealed that AMG-148 inhibited chitin and β(13)glucan biosynthesis and was in vitro an inhibitor of β(13)glucan synthase. Inhibition of chitin biosynthesis was responsible for fungistatic activity, while the fungicidal effect was a consequence Hydroxychloroquine of disturbance of β(13)glucan check details synthase function. The chalcone derivative may be a useful lead compound for the development of novel antifungal agents. “
“Due to the increased number of immunocompromised patients, the infections associated with the pathogen of the genus Candida have significantly

increased in recent years. To grow, Candida albicans may form a germ tube extension from the cells, which is essential for virulence. In this work, we studied the effect of crude glycolic extract of Aloe vera fresh leaves (20% w/v) on growth and germ tube formation by C. albicans. The C. albicans growth was determined in the presence of different concentrations of A. vera extracts in Sabouraud dextrose broth medium. In the presence of A. vera extract (10% v/v), the pronounced inhibition in the C. albicans growth (90–100%) was observed. This inhibition occurred parallel to the decrease in the germ tube formation induced by goat serum. Our results demonstrated that A. vera fresh leaves plant extract can inhibit both the growth and the germ tube formation by C. albicans. Our results suggest the possibility that A. vera extract may be used as a promising novel antifungal treatment. “
“Colonisation may be the first step for the development of Candida infection.

15∼0 3 mL of PBS/mouse) was injected slowly into the area surroun

15∼0.3 mL of PBS/mouse) was injected slowly into the area surrounding the nostrils after i.p. injection of 0.25 mL of pentobarbital/ethanol/PBS (0.8 mL/2 mL/8 mL). The following antibodies were used in this study: mouse IgE and IgG Abs from Zymed (San Francisco, CA, USA); rat anti-mouse IgE and IgG Abs from Biosource (Camarillo, CA, USA); HRP-labeled IDH mutation goat anti-mouse IgE and IgG Abs from Nordic (Tilburg, the Netherlands)

and Cappel (Aurora, OH, USA); FITC-labeled rat anti-mouse CD14 (Sa2–8) Abs from eBioscience (San Diego, CA, USA); and Alexa Fluor 647-conjugated rat anti-mouse CCR3 (83103) Abs, PE-labeled rat anti-mouse CD3 (145–2C11), CD4 (RM4–4), CD11b/Mac-1 (M1/70), Ly-6G (1A8), CD45R/B220 (RA3–6B2), and IgM (R6–60.2) Abs and FITC-labeled rat anti-mouse Ly-6G (1A8), CD3 (145–2C11), CD8 (53–6.7), CD11b/Mac-1 (M1/70), and CD11c (HL3) Abs from PharMingen (San Diego, CA, USA).

Blood samples were taken by cardiac puncture under chloroform anesthesia at various time intervals after i.n. injection of cedar pollen extract-Cry j with or without complete Freund’s adjuvant. The whole blood was incubated in a CO2 incubator at 37°C for 1 hr, stood overnight at 4°C, and then centrifuged at 440 g for 20 min. The supernatant fraction was stored in microtubes at − 20°C prior to use. Mice were anesthetized with chloroform and then bled from the inferior vena cava. After exsanguination, they were decapitated along the line between the upper and lower jaws. The facial

skin was stripped from the head and the nose component separated from the rest of the head along the line of the eyeballs. A segment containing the tip selleck of the Glycogen branching enzyme nose and fore-teeth was severed from the rest of the specimen. After removal of the cheek muscles, cheek bones, and back teeth, NALT, which localize bilaterally on the posterior side of the palate, was separated from the rest of the nasal tissue by peeling the palate away. The excised palates were immediately placed into a 60 mm Petri dish containing stainless mesh on ice and 3 mL of ice-cold PBS with 5 mM EDTA. Using a dissection microscope (Nikon; Tokyo, Japan), the NALT was teased gently into the medium with syringe needles to release the cells, which were harvested by using siliconized Pasteur pipettes. Other lymphoid tissues such as submandibular, axillary, inguinal or mesenteric lymph nodes and Peyer’s Patches were removed aseptically; and single-cell suspensions prepared from them as described earlier (14). To evaluate lymphoid organ(s) responsive to i.n. injected allergen, we injected 2% Evans blue in PBS (2 mL/kg) i.n. and allowed it to permeate the neighboring lymphoid organs for 20 min. The mice were then anesthetized with chloroform and bled from the inferior vena cava. After exsanguination, NALT was separated from the rest of the nasal tissue and the skin covering the submandibular lymph nodes excised. The lymphoid organs stained by Evans blue were examined macroscopically.

This finding is consistent with the speculation [57] that intrave

This finding is consistent with the speculation [57] that intravenously administered DCs can acquire islet antigens in vivo (a process that would take place in the pancreatic lymph nodes) and, thus, can modulate effector and regulatory T cell responses to diabetes-relevant antigens even without deliberate prior antigen treatment. The original observation that DCs from the pancreatic

lymph nodes could prevent diabetes when transferred to NOD mice, while those from other sites could not, suggested the potential importance of the incorporation of beta cell antigens into DC-based therapeutics for this disease [5]. As reviewed recently [66], a variety of immunosuppressive and anti-inflammatory compounds, e.g. vitamin D3 and mycophenolate mofetil, this website can endow DCs with a tolerogenic functional phenotype. Cytokines such as IL-10 can behave similarly [67]

. This suggests a therapeutic strategy for type 1 diabetes in which tolerogenic DCs would be generated in CHIR-99021 in vivo vitro and then exposed to beta cell antigens prior to administration. Such an approach was employed recently by the von Herrath group [59], who utilized the rat insulin promoter (RIP)-LCMV model of type 1 diabetes in which disease is induced upon LCMV infection. BMDCs were generated in the presence of GM-CSF, IL-10 and normal mouse serum, and then pulsed with a viral peptide recognized by CD8+ T cells. When the pulsed DCs were administered intraperitoneally to mice 10 and 3 days prior to LCMV infection, only 45% of the animals developed diabetes, whereas 80% of those treated with unpulsed DCs became diabetic. A reduced expansion of viral-specific T cells in response to viral infection was also observed

in mice treated with peptide-pulsed DCs. This study supports the idea that ex vivo-generated tolerogenic DCs, when exposed to disease-relevant antigens, can deliver therapeutic benefit in type 1 diabetes. In a recent thoughtful review of DC-based immunotherapeutic strategies for human diseases, the disadvantages of ex vivo antigen loading of DCs were discussed [68]. These include a requirement for leukapheresis, the inability to manipulate DCs Dimethyl sulfoxide within their natural milieu and a requirement for a tailor-made ‘product’ for each patient, resulting in labour-intensive procedures and high costs. It is for reasons such as these that we [69] and others [70] are exploring the utility of in vivo delivery of beta cell antigens to DCs in the prevention and treatment of type 1 diabetes. DCs employ a variety of molecules, such as the Fc receptors, the macrophage mannose receptor (MMR) and DEC-205 [71], to execute receptor-mediated endocytosis of antigens. Of these, DEC-205 (Ly75/CD205) has the special ability to uptake and subsequently present antigen via both class I [35] and class II MHC pathways [72]. DEC-205 is a type 1 transmembrane protein homologous to MMR and phospholipase A2 [71].

16 Finally, the few NS populations that have been tested for GM a

16 Finally, the few NS populations that have been tested for GM are almost monomorphic for haplotype GM 1,17 5*. This represents an extreme differentiation compared with NC, which is explainable by rapid genetic drift through

isolation. Actually, NS populations are spread discontinuously over a vast geographic area extending from East (Ethiopia) to West (Mali) Africa throughout the Sahara Desert, and may have been submitted to repeated episodes of demographic contraction and gene flow with local neighbours, depending on climatic variation, which extensively modified the environments. Variation of GM has also been highly informative for anthropological studies in East Asia. A north–south genetic cline is clearly observed, with high frequencies of GM 1,17 21 and GM 1,2,17 21 and low frequencies of GM 1,3 5* in the north, the reverse situation being RAD001 observed

in the south. Here again, the linguistic information is relevant: we observe continuous genetic differentiations between (from one end of the cline to the other) Altaic, Japanese and Korean; North Tibeto-Burman; Northern Chinese (all Mandarin but Southeastern); Wu and Southeastern Mandarin; Southern Chinese and Southern Tibeto-Burman; and Austro-Asiatic, Tai-Kadai and Austronesian populations.17,18 However, contrary to the situation found in Africa, in East Asia the linguistic families are found in specific geographic areas and it is hard to establish whether the observed genetic patterns have mostly been shaped by linguistic or by geographic differentiations in the past. As discussed in more Carfilzomib ic50 detail below for the HLA polymorphism, GM genetic variation is compatible with the ‘pincer’ model of migrations from West Asia, suggesting that some populations followed a southern (maybe coastal) route through India to Southeast Asia, and others a route north to the Himalaya Mountains to Northeast Asia (although at a different period), both groups

of populations later intermixing through north–south migrations in East Asia. As for HLA, a higher level of internal diversity (higher heterozygosity) is observed in Northeast Asia compared with Southeast Asia, indicating higher levels Protein tyrosine phosphatase of gene flow, whereas Southeast Asian populations may have undergone rapid differentiation through genetic drift.19 Another crucial example pertains to the peopling history of Taiwan. In a previous study, we investigated the GM polymorphism of several Aboriginal populations from this island (Siraya, Pazeh, Taroko, Atayal, Tsou, Bunun and Puyuma, as well as Yami located in Lan-Yu island off the southeastern coast of Taiwan).20 We found a decrease in heterozygosity from (north)western to southern and southeastern regions (with a higher frequency of GM 1,3 (–23) 5* in the west, whereas GM 1,3 23 5* is (almost) fixed in the south and/or southeast).

pallidum The response of NK cells producing IFN-γ against microb

pallidum. The response of NK cells producing IFN-γ against microbial stimulation is highly significantly associated with KIR genotype [32]. Artavanis-Tsakonas et al. [23] reported that there was a significant association between KIR genotype and NK cell response to Plasmodium falciparum-infected erythrocytes and found that induction of IFN-γ synthesis Saracatinib was dependent on the direct contact between NK cells and the infected erythrocytes. Therefore, we speculate that IFN-γ productions

in response to syphilis maybe have association with KIR genotype, but this needs to be confirmed further. Here, we put forward two hypotheses by which KIR genotype might affect NK cell producing IFN-γ in responses to syphilis. First, signals produced from the interaction of KIRs with their ligands during T. pallidum infection might modulate the degree of activation of NK cells. Alternatively, binding of KIR by relevant HLA ligands during NK cell ontogeny might lead to greater or lesser education of NK cells. Additional studies examining KIR–HLA class I interactions in patients and

controls may be fruitful. “
“Activation of NK cells is a hallmark of infections with intracellular pathogens. We previously showed that the Nutlin-3a protozoan parasite Leishmania infantum triggered a rapid NK-cell response in mice that required TLR9-positive myeloid DC and IL-12, but no IFN-α/β. Here, we investigated whether IL-15 or IL-18 mediate the activity of IL-12 or function as independent activators of NK cells. In contrast to earlier studies that described IL-15 as crucial for NK-cell priming in response to TLR ligands, the expression of IFN-γ, FasL, perforin and granzyme B by NK cells in L. infantum-infected mice was completely preserved in the absence of IL-15, whereas the proliferative capacity of NK cells was lower than in WT mice. IFN-γ secretion, cytotoxicity PD-1 inhibiton and FasL expression of NK cells from infected IL-18−/− mice were significantly reduced compared with controls, but, unlike IL-12, IL-18 was not essential for NK-cell effector functions.

Part of the NK-cell-stimulatory effect of IL-12 was dependent on IL-18. We conclude that IL-15 is not functioning as a universal NK-cell priming signal and that IL-18 contributes to the NK-cell response in visceral leishmaniasis. The cytokine requirements for NK-cell activation appear to differ contingent upon the infectious pathogen. “
“Tumour-loaded dendritic cells (DCs) from patients with chronic lymphocytic leukaemia (CLL) matured using an α-type 1-polarized DC cocktail (IL-1β/TNF-α/IFN-α/IFN-γ/poly-I:C;αDC1) were recently shown to induce more functional CD8+ T cells against autologous tumour cells in vitro than DCs matured with the ‘standard’ cocktail (IL-1β/TNF-α/IL-6/PGE2;PGE2DCs).