The neutrophilia

in BALF, which is often found in IPF and pulmonary stage IV in sarcoidosis, could be responsible for the elevated MRP14 levels seen in patients. However, BALF MRP14 levels were associated much more strongly with pulmonary stage in sarcoidosis than the neutrophil percentage. This suggests that MRP14 is a more specific biomarker for pulmonary disease severity in sarcoidosis than the amount of neutrophils in BALF. In addition, we observed a correlation between MRP14 and BALF neutrophils in IPF patients, but it was small, and no such correlation was found in sarcoidosis patients. The lack of correlation with neutrophils in sarcoidosis indicates that high BALF MRP14 levels learn more do not simply reflect the presence of neutrophils in the lung, although all the MRP proteins together make up approximately 50% of the neutrophils cytosolic protein content [22]. Previous reports on a possible chemoattractant role for MRP14 are ambiguous. A study by Ryckman et al. [10] selleck chemicals reported that MRP8, MRP14 and the heterocomplex MRP8/14 caused neutrophil chemotaxis in vitro and in vivo, and the same group also reported that antibodies against MRP14 blocked neutrophil recruitment [23]. However, other studies reported that MRP14 was not a chemoattractant for neutrophils and even repelled neutrophils [24,25]. Our data do not support a possible chemoattractant role for MRP14, but do not rule out the possibility

that MRP14 is a chemoattractant for neutrophils under specific conditions; for instance, in some IPF patients. An mRNA expression study in rabbits showed that after neutrophils migrate from the blood to inflammatory Sinomenine sites the mRNA expression of MRP14 increases rapidly [26]. In addition, neutrophilic MRP14 is phosphorylated and translocated to the membrane during human neutrophil activation [27]. This suggests that MRP14 levels during inflammatory reactions are not dependent on the number of neutrophils present, but rather on their activity. Activated neutrophils can cause lung injury, epithelial cell apoptosis and basement membrane loss [28,29]. Neutrophils are also thought to mediate the transition from acute to chronic inflammation that may precede fibrosis [30]. Both neutrophils and macrophages have been reported to have an altered phenotype in the lungs of sarcoidosis patients [31,32]. It is possible that MRP14 is a marker for an activated subset of leucocytes. Further research is needed to reveal whether MRP14 expression is upregulated in neutrophils and alveolar macrophages in interstitial lung diseases. It is intriguing to speculate about the exact role of MRP14. It may influence the functioning of leucocytes in several ways. For instance, a study by Newton and Hogg showed that MRP14 could be involved in the attachment of neutrophils to the endothelium, and could thus facilitate their migration [24].

Moreover, infection of BMDCs

with a plasmid-cured apathogenic Yersinia enterocolitica strain lead to DC Protein Tyrosine Kinase inhibitor swelling in a MOI (multiplicity of infection) dependent manner (data not shown) indicating that bacterial LPS is responsible for DC swelling in response to contact with bacteria. Additionally, LPS-induced DC swelling was dependent on the LPS concentration used (data not shown). Moreover, we found that LPS-induced DC swelling (Fig. 1a) and CCL21-directed migration (Fig. 1b) were impaired in TLR4-deficient DCs when compared to WT DCs. These results indicate that the observed cell swelling is critically dependent on TLR4 signaling upon LPS binding. Our results are supported by another in vitro study demonstrating that stimulation of TLR4 by LPS, but neither stimulation of TLR2 by PamCys or heat-killed gram-positive bacteria nor activation of BMDCs by different cytokines (TNFα, IL-10) induce the loss of podosomes, and thereby enhance the migratory capacity of DCs [6]. However, it cannot completely be excluded that LPS-induced DC swelling occurs independently of DC migration. Moreover, cell swelling itself is not causative for DC migration since BMDCs treated with 20% H2O for 4 hr did not migrate along a chemokine gradient (data not shown). It has been described

that treatment with LPS for 24 hr increases the expression of CCR7, the receptor of the chemokines CCL19 and CCL21, on DCs [22]. Hence, possibly differences in the CCR7-expression on DC between WT and TLR4−/− DC might affect CCL21-directed INCB024360 datasheet migratory activities of these two cell types. As a consequence, BMDCs of WT and TLR4−/− mice were treated or not with LPS for 4 hr, double-stained with fluorescent antibodies against CD11c and CCR7, respectively, and analyzed by flow cytometry (data not shown). No differences were detected in the CCR7 expression rates between WT and TLR4-deficient DC kept in medium without LPS (12.5 ± 3.4% Verteporfin purchase vs. 12.4 ± 4.3%). However, after incubation with LPS (500 ng/mL) for 4 hr, CCR7 expression on DC was higher in WT than in TLR4−/− DCs (25.2 ± 4.8% vs. 17.4 ± 4.0%) suggesting that the LPS-induced

increase in CCR7 expression in WT DC contributes to LPS-induced migration. Intracellular Ca2+ acts as a key regulator of actin assembly thereby affecting the migratory activity of DCs [19]. For example, within minutes after exposure of DCs to gram-negative bacteria or LPS the cytosolic Ca2+ levels increase involving both mechanisms, entry of extracellular Ca2+ and the release of Ca2+ from intracellular stores [7, 20]. Elevated Ca2+ in turn causes extensive actin-based cytoskeletal rearrangement including loss of podosomes thereby facilitating the conversion of DCs to a migratory phenotype [6]. After treatment of DCs with LPS, we observed an increase in [Ca2+]i within 30–120 min (Fig. 2b). Increased [Ca2+]i in migrating cells may result from activation of mechanosensitive Ca2+ channels by the growing lamellipodium at the front part and gradual cell swelling [19].

“
“Summary  Alternative treatments for seborrhoeic dermatitis are needed because of the increasing risk of anti-fungal resistance

to existing therapies. To investigate the efficacy, safety and tolerability of topical scalp treatment with K301 solution. Two multi-centre, randomised, double-blind studies were conducted. Study I: 4 weeks of once-daily treatment with either one form of K301 (a or b) or placebo, followed by 4 weeks of maintenance treatment three times-per-week. Study II: 4 weeks of K301 (a) or placebo once-daily. Study I: 98 patients enrolled (K301a + b, n = 51; placebo, n = 47) and 83 completed; 201 entered Study II (K301a, n = 136; placebo, selleck compound n = 65) and 195 completed. Erythema and desquamation sum score at 4 weeks, mean (SD) values were 2.4 (2.0) for K301a + b and 3.2 (2.2) for placebo in Study I (P = 0.025) and 2.5 (1.9) for K301a and 3.2 (1.8) for placebo in Study II (not significant). In both studies, 4-week desquamation

scores were significantly improved for K301 vs. placebo (P < 0.05). Both studies showed significant improvements in symptomatic investigator and patient assessments for K301 over placebo after 4 weeks (P < 0.05). Treatment-related adverse events were generally mild and included some smarting or burning upon application. The K301 was well tolerated and associated with clinically meaningful improvements in seborrhoeic selleckchem dermatitis endpoints. “
“Histoplasmosis occurs in specific endemic areas, including the mid-western United States, Africa and most of Latin America. Sporadic cases have also been reported in China. The aim of this study was to summarise the epidemiological and clinical data of histoplasmosis in China. We searched the PubMed, CBMdisk and CNKI databases to identify publications related to histoplasmosis in China. Case reports/series on patients with histoplasmosis were included. A comprehensive Anacetrapib literature review identified additional cases. The relevant material was evaluated and reviewed. Overall, 300 cases of histoplasmosis

were reported in China from 1990 to 2011, and 75% were from regions through which the Yangtze River flows. Most of the patients were autochthonous infections. Of these, 43 patients had pulmonary histoplasmosis and 257 patients had disseminated histoplasmosis. Common underlying diseases included HIV infection, diabetes mellitus and liver diseases. Fever was the most frequently reported clinical feature in disseminated histoplasmosis, followed by splenomegaly and hepatomegaly. Cases of histoplasmosis had a prominent geographical distribution in China. Histoplasmosis should be considered in the diagnosis of patients with relevant symptoms and a history of travel to or residence in these areas. “
“The aim of this study was to evaluate the effects of photodynamic therapy (PDT) using rose bengal or erythrosine with light emitting diode (LED) on Candida albicans planktonic cultures and biofilms. Seven C.

Alternatively Metformin spliced transcripts of human IL-7Rα were reported in leukaemic cells from children with acute lymphoblastic leukaemia (ALL) [21]. Another study observed increased production of the soluble form of the IL-7Rα protein due to a twofold increase in alternatively spliced transcripts that eliminated exon 6 [19]. Moreover, serum levels of sIL-7Rα have been associated with the Hap2 haplotype (counting rs6897932T), also associated with

autoimmune disease [22]. Investigation of health controls demonstrate that an increase in sIL-7Rα is associated with the rs6897932 SNP, also found to be related to relapse in the present study with an approximately threefold increase in the median levels between the TT and CC genotype and intermediate levels for the CT genotype [23]. The functional impact of sIL-7Rα on IL-7 activity

is not known in vivo, but it was recently shown that in vitro, the native sIL-7R does interfere in optimal IL-7/IL-7Rα-signalling by significant inhibition of STAT5 and Bcl-2 phosphorylation [24]. It is likely that increased levels of sIL-7Rα may be associated with reduced IL-7 activity due to diminished expression of IL-7Rα on the cell surface. In addition, the soluble form of IL-7Rα may bind IL-7 in solution and may therefore act as a decoy receptor [25]. This may affect the IL-7-dependent thymic production of T cells, including the rate of regulatory T cell production CH5424802 in vivo that has been associated with T cell alloreactivity in HCT [26]. The biological significance of this in relation to HCT, however, deserves further investigation because IL-7 levels have been shown to be considerably elevated during the PLEKHM2 early phase after HCT [27]. Recently, it was demonstrated that IL-7Rα Hap 2 (counting rs6897932T) is associated with faster CD4+ T cell reconstitution following antiretroviral therapy (ART) for HIV infection and that these individuals have lower circulating soluble IL7Rα [28]. Furthermore, the potential of sIL-7Rα to influence TSLP signalling should be explored in

future studies. TSLP is important for the development of regulatory T cells. A reduction in TSLP signalling could lead to reduced production of Tregs and thereby increased GvHD and TRM. In conclusion, there is accumulating evidence for an association between various IL-7Rα SNPs and adverse outcome in HCT. In this study, we show for the first time that the donor type of IL-7Rα rs6897932 may be associated with the risk of relapse in patients undergoing HCT for haematological malignancies. In addition, the functional impact we know of rs6897932 on the release of sIL-7Rα in health controls and a potential biological mechanism for the immune-modulating function of the SNP. These data provide further evidence of a role of the IL-7 pathway in outcome of HCT and impact of non-synonymous SNPs on IL-7Rα function. Marianne B.

While CpG pre-treatment resulted in enhanced CD8+ T-cell expansion and survival compared with peptide immunization alone, the population

size of the resultant surviving T-cell pool was still much lower than the T-cell response to radiation-attenuated parasites 2. Since this lower response is not due to lack of recruitment of antigen-specific T cells into the effector phase (based on percentage of CFSEbright cells at day 3, Fig. 2B), an exaggerated amount of cell death still appeared to be occurring with CpG treatment. Others have demonstrated that soluble peptide antigen can be found systemically on the surface of non-professional APC following peptide immunization 10, 11, suggesting that naïve and recently primed T cells may repeatedly engage their antigen in an inappropriate context on the “wrong” kind of cells. Given that 40–60% of resting LN cells are B cells, it is possible, LDK378 if not likely, that T cells engage their cognate antigen on the surface of B cells following peptide immunization. Since previous studies have shown that B cells could have detrimental effects on the development of CD8+ T-cell responses 24–28, we examined the effects of these cells on the response to soluble peptide immunization. For this purpose, we immunized WT

and B-cell-deficient (JHT) BALB/c mice with peptide following adoptive transfer of TCR-Tg cells and pre-immunization with Selumetinib CpG. Ten days after peptide immunization, the frequencies of TCR-Tg cells recovered from the spleens of B-cell-deficient mice were much greater than those observed in WT mice (Fig. 5A and B). This striking phenotype was dependent upon pre-immunizing with CpG, as peptide immunization alone in B-cell-deficient mice did not result in increased T-cell survival (Fig. 5C), indicating that homeostatic mechanisms cannot account for the phenotype observed with the mutant host. Enzalutamide clinical trial Importantly, these experiments were done with low numbers of TCR-Tg T cells (2×103per mouse), minimizing possible artifacts that may be introduced with a high precursor frequency of naïve T cells. To confirm that the B cells played an inhibitory

role in T cell priming with CpG and peptide, B-cell-deficient mice were reconstituted with 3×106 sort-purified B cells from normal BALB/c mice prior to immunization. This reconstitution resulted in near complete reversal of phenotype, with an 85% reduction in the frequency of antigen-specific CD8+ T cells recovered from these mice compared with non-reconstituted B-cell-deficient mice (Fig. 5D). Similar results were obtained by adoptive transfer of non-sorted spleen cells containing 3×106 B cells from normal BALB/c mice as a source of unmanipulated B cells (Supporting Information Fig. 5). Thus, in the context of immunization with soluble peptide and CpG, B cells are detrimental to the survival of CD8+ T cells.

Soluble CD23 is also found in the saliva of Sjögren’s syndrome

patients41,42 and in the plasma of patients with systemic lupus erythematosus,41,42 though in the case of systemic lupus erythematosus the effect of sCD23 is likely to be mediated via its interaction with CD21 on autoimmune B cells rather than via integrins on monocytic cells.43 The finding of high sCD23 levels in such syndromes has made both sCD23 protein itself and its various receptors attractive targets for therapeutic intervention. This aspiration is supported by data from rodent systems where anti-CD23 mAbs have been shown to both prevent initial and ameliorate existing BAY 80-6946 solubility dmso arthritic disease,25,26 and by the success of Lumiliximab, a humanized macaque anti-CD23 antibody, in treatment of B chronic lymphocytic leukaemia,44 a disease characterized by strikingly high plasma sCD23 levels.45 A different strategy, employing a CD23-binding peptide identified by phage display technology, also shows promise in preventing onset of adjuvant-induced arthritis

and reducing severity of established disease in rats.46 The identification of αVβ3 as an sCD23 receptor linked to TNF-α release in human monocytes18 suggested that antibodies to this integrin might be useful in autoimmune inflammatory disease.47 The Etaracizumab MK-8669 mouse mAb (Abergrin, Vitaxin),48,49 a humanized form of the LM609 anti-αVβ3 reagent, was shown to be potent in inhibiting angiogenesis.50,51 However, Etaracizumab was also assessed in psoriatic arthritis but was not found to have a therapeutic effect and this is potentially explained by the fact that the parent LM609 mAb does not inhibit sCD23-driven TNF-α release from monocytes,18 a finding that implies that the mAb does not influence the site on the integrin responsible for control of cytokine release. Our data that showed LM609 did not induce cytokine production from either THP-1 or U937 cells (Fig. 3) were also in agreement with this

suggestion. Etaracizumab retains significant Casein kinase 1 promise, however, and is currently in trials for therapy of metastatic melanoma.52 It is important to bear in mind that most previous studies on integrin function have been performed in adherent cells. The possibility of an alternative mode of integrin signalling illustrated by sCD23 is particularly interesting in the context of haematopoietic cells, including monocytes, which are non-adherent cells, but nonetheless express a wide range of integrins, and are the precursors of a number of adherent, terminally differentiated cells, such as macrophages and osteoclasts. The differentiation of monocytes into adherent counterparts is the result of paracrine or autocrine signalling in response to cytokines, such as those released by the interaction of sCD23 with integrins.

Indeed, we did not find soluble FcαRI in the serum of FcαRIR209L/FcRγ Tg mice (Fig. 1d). The results in WT FcαRI Tg mice demonstrated that expression of FcαRI on mouse monocytes/macrophages was detrimental [21]. The mechanism underlying spontaneous IgA nephropathy (IgAN) onset in WT FcαRI Tg mice is probably linked to

mouse serum IgA, which is predominantly polymeric (70–80% of total serum IgA), contrary to the situation in humans [21]. We next analysed the ability of FcαRIR209L/FcRγ to bind to human and mouse IgA. No specific binding of mouse monomeric IgA was observed, whereas binding of mouse polymeric IgA (>390 kD) from line 604 to FcαRI was significant (Fig. 1f). These experiments indicated that 3-Methyladenine purchase FcαRI could bind polymeric but not

mouse monomeric IgA. We then found that polymeric mouse IgA which could bind weakly to FcαRIR209L/FcRγ transfectants was sufficient to induce strong inhibitory signals and blocked TLR-4 signal triggered by LPS (Fig. 1g). These findings suggested that the association of FcαRI and FcRγ blocks the shedding of FcαRI, and weak phosphorylation of iITAM by low-affinity mouse polymeric IgA is protective against cell activation and prevents IgAN development. In the present study, we observed that monovalent targeting of FcαRI was inhibitory in an in vivo model of TLR-9 signalling-accelerated nephritis, showing a possible explanation of www.selleckchem.com/products/bmn-673.html inhibitory mechanisms. First, TLR-9 and probably proinflammatory cytokines including MCP-1 and TNF-α are thought to activate macrophage

MAPKs (p38, ERK1/2 and JNK) and NF-κB/AP-1 pathways, promoting gene expression and cytokine production (MCP-1, RANTES and MIP-1a) [21,22], leading to cytokine-mediated inflammation and nephritis [23]. Consistent with this, the present study showed that both MAPKs (p38, JNK and ERK1/2) and NF-κB/AP-1 are activated significantly in the inflamed kidneys enhanced by TLR-9 activation via CpG-ODN (not shown). Our observation (Figs 2–4) that TLR-9 orchestrates the production of an array of potential mediators of renal injury makes it an attractive target for the prevention or treatment of acute renal injury. Phosphoprotein phosphatase Indeed, pharmacological blockade of MAPKs activation, specifically ERK and p38, improved disease activity and the histological disease score in experimental kidney diseases [24]. Our mechanistic analysis revealed that monovalent targeting of FcαRI regulates CpG-ODN-induced activation of MAPKs, primarily ERK1/2, p38, JNK and NF-κB/AP-1 activation via TLR-9, leading to down-regulation of TNF-α and MCP-1 (Figs 8–11). These data suggest that abolished activation of p38, ERK1/2 and JNK via TLR-9 stimulation through FcαRI targeting in the FcαRIR209L/FcRγ Tg is sufficient to regulate increased cell activation and control of HAF-CpG-GN.

Monocytes were isolated from peripheral blood by centrifugation Proteasome activity over Ficoll-Hypaque followed by adherence to plastic flasks. To detect CD1 induction, fresh monocytes were treated with lipids (1 μg/mL) and stained with 10 μg/mL of Abs binding to CD1a (OKT6), CD1b (BCD1b3.1), CD1c (F10/21A3.1) or CD1d (CD1d42) isotype control (P3), followed by a FITC-labeled goat anti-mouse IgG (BioSource International) and analyzed by a FACScalibur flow cytometer (BD Biosciences) with CellQuest and FlowJo software (Tree Star). Monocytes were

pretreated with an anti-TLR-2 mAb (T2.5) or isotype control (T2.13) 34 in serum-free medium for 30 min at room temperature and for 20 min at 37°C before adding lipids (1 μg/mL). After 2 h, monocytes were washed 3 times and resuspended in fresh RPMI medium with 10% FBS containing 10 μg/mL of the anti-TLR-2 mAb or control mAb, and cultured for 72 h prior to by flow cytometric analysis using fluorescein-labeled CD1a (CB-T6, Ancell) or CD1c (M241, Ancell) or isotype control Abs (MOPC-21, BD Pharmingen). To measure CD1a-induced T-cell activation, activated monocytes were incubated with 50 000 CD1a autoreactive

T cells (BC2) in 96-well plates for 24 h, followed https://www.selleckchem.com/products/gsk2126458.html by measurement of interferon-γ by capture ELISA (Invitrogen). Human monocytes were treated with triacyl-CSK4 for 2 h; 50 μL of each supernatant were screened for IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-18, IFNα, TNF-α and GM-CSF by a multiplexed sandwich-ELISA system (Pierce Endogen). To confirm the presence of cytokines detected in the initial screen, IL-1β was measured by sandwich ELISA Astemizole using the M421B capture mAb (2 μg/mL) and the biotin-labeled mAb M421BB, with a streptavidin–horseradish peroxidase (Pierce Endogen). GM-CSF was detected in sandwich ELISA after

capture (Pierce Endogen M500A-E) and development with biotinylated anti-GM-CSF (M501B) and avidin AKP. To measure secreted factors, experiments were carried out in a 3-step protocol whereby monocytes (i) were pulsed with TLR agonists and washed, (ii) cultivated in media to obtained conditioned supernatants enriched with soluble factors, and (iii) conditioned supernatants were transferred to fresh cells for measurement of CD1 in the presence or absence of reagents that block cytokine function. For pulsing, fresh monocytes were treated with synthetic 3-bis(palmitoyloxy)-(2-RS)-propyl-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys(4)-OH, triacyl-CSK4,100 ng/mL, EMC Microcollections, Germany) in 24-well plates (106 cells and 1 mL of media per well), for 10 min to 6 h followed by three washes. For conditioning supernatants, fresh media (1 mL per well) was added and the cells (106 well) were cultured for an additional 3 days. For the measurement phase, fresh monocytes (106/well) were cultured (0.9 mL/well) with previously conditioned media for 3 days before flow cytometric analysis.

A few research groups have adapted clinical DENV isolates to the murine host to obtain adapted strains that are able to induce disease resembling human infection. Atrasheuskaya et al.[63] showed that young BALB/c mice (4-weeks old) were found to be sensitive BAY 73-4506 to the challenge with a

mouse-adapted DENV-2 (strain P23085, GenBank: AY927231.1). They developed clinical manifestations such as arching of the back, ruffling of the fur and slowing of activity. The presence of DENV-2 virus in the blood was confirmed by RT-PCR and mice showed severe weight loss ending in limb paralysis and 100% mortality. The most important changes in production of pro-inflammatory markers were seen in TNF-α, which quickly increased 24 hr before death. This model supports the notion that activation of the innate immune response is partially responsible for mortality in DENV-2 virus infection. In line with this hypothesis, anti-TNF-α treatment significantly reduced the mortality rates.[63] Similarly, BALB/c mice-infected intraperitoneally with a DENV-2 isolate demonstrated liver damage, as determined by high AST and ALT levels that peaked at day BTK inhibitor 7 post-infection.[64]

Our group described a DENV infection model in adult BALB/c or C57BL/6 mice (≥ 8 weeks old), using the mouse-adapted DENV-2 strain (P23085), from Atrasheuskaya et al.[63] The adapted virus given systemically (intraperitoneally) induced inoculum-dependent lethality that was preceded by major manifestations of severe DENV infection in humans such as mechanical hypernociception (an index of pain), thrombocytopenia, haemoconcentration, increased vascular permeability, hypotension, increased levels of cytokines and chemokines, tissue haemorrhage, viraemia and recovery of viral load in target organs of infection.[65-71] Viral replication and lethality were abolished after in vitro or in vivo neutralization using the anti-DENV-2 monoclonal antibody 4G2.[68] Moreover, the adapted DENV-2 strain was not found in the brain of intraperitoneally infected mice.[71] This model of DENV-2 infection in immune competent

mice provides an important tool to study host–virus interactions and mechanisms associated with severe disease manifestation, so contributing to the elucidation of Bcl-w DENV pathogenesis.[65, 67-70] However, a possible drawback of the model is that it uses a single strain that was adapted by multiple passages in mice. All eventual modifications of the virus to the murine host are currently under investigation because they may cause a disease that is significantly different to that of the original virus in humans.[19] Table 1 summarizes the most studied mouse models of dengue infection available in the literature. Mice develop functional human immune system, including adaptive immunity; infection of human cells lineages; study of ‘human’ response to infection.

The ‘instructive’ model hypothesized that all fates could be adopted by every naïve cell. By now, the ‘instructive’ model has been validated by showing that cells that had been partially differentiated towards

the Th2 phenotype could be re-educated to become Th1 cells [91, 106]. Many different signals have been described as being potentially instructive for Th cells, and much study has gone into which signals induce which phenotype. But how does the adaptive immune response choose a correct phenotype? The adaptive immune system of B and T lymphocytes is built on top of the so-called innate immune system composed of intracellular responses, neutrophils, granulocytes and natural killer cells. The members of the innate immune system

detect the presence of pathogens by evolutionary conserved signals that are usually called pathogen-associated molecular patterns (PAMPs) [107]. One important class of cellular find protocol receptors that can detect the presence of PAMPs are the Toll-like receptors (TLR), which discriminate between bacterial, viral and several other types of PAMPs [1, 108]. The innate system therefore uses evolutionary conserved information and is probably selected to mount an appropriate immune response buy Dabrafenib to particular pathogens. Because innate cells and infected cells secrete cytokines, these cytokines provide a key to the developing Th0 cells to adopt a particular phenotype [99]. Thus, the local

context of cytokines created by the innate immune GNA12 responses can instruct helper T cells to make an appropriate decision. One notorious example of Th decision-making is the priming with formalin-inactivated and alum-adjuvated RSV vaccine (FI-RSV). In the 1960s, a trial with this vaccine failed because it predisposed for enhanced disease rather than preventing it [109]. This was attributed to the generation of Th2 responses rather than the more appropriate Th1 response. Subsequent mouse studies into RSV have shown that immunization with the RSV fusion protein (F) or the RSV attachment protein (G) induces Th1 or Th2 responses when challenged with RSV [110]. Again the Th2 type response was associated with enhanced disease, including a marked eosinophilia reminiscent of that seen in FI-RSV-primed mice. Induction of these skewed Th2 responses can be abrogated by the insertion of a CD8 epitope derived from the RSV M2 protein into the G protein or by simultaneous priming of mice with G and M2 proteins prior to RSV infection [111]. This demonstrates that the presence or absence of a CD8+ T-cell epitope could play a role in determining the type of immune response against a pathogen. The absence of a CD8+ epitope appears to predispose for the formation of Th2 immunity. Conversely, in the presence of a CD8+ T-cell response, the CD4 T cells adopt a Th1 phenotype.