As shown in Fig. 4, HO-1 transcript levels do not correlate with the SLEDAI-2K score, (r = −0·24, P = 0·12, Pearson’s correlation test). We also evaluated whether there was a correlation between HO-1 levels and key parameters of the disease, such as anti-DNA antibody levels, anti-Ro antibody levels and complement levels.

However, no significant correlation was observed between HO-1 transcript levels and any of the parameters measured (data not shown). In addition, when HO-1 protein levels and SLEDAI-2K were plotted, no significant correlation was observed (data not shown). In addition, the dose of prednisone was also included among the parameters evaluated and no significant correlation was found (data not shown). The anti-inflammatory

role of HO-1 has been widely reported in several disease processes.38–40 The relevance of HO-1 as an immunomodulator has been Maraviroc ic50 suggested by studies showing that HO-1 knockout mice display an exacerbated immune response and high levels of pro-inflammatory T helper type 1 cytokines.41,42 In addition, HO-1 has been involved in the modulation of the function of several cell types of the immune system, such as DCs, T cells and monocytes.30,32,43 However, to our knowledge, the role of HO-1 during SLE pathogenesis has not been previously evaluated. Therefore, here we have measured the levels of HO-1 in different subsets of immune cells obtained from peripheral blood of patients with SLE, to define HO-1 www.selleck.co.jp/products/Fludarabine(Fludara).html Selleckchem Doxorubicin as a relevant molecule in the aetiology of the disease, as well as a potential therapeutic target for treating this autoimmune disease. Our results show that HO-1 transcripts and protein levels are significantly reduced in monocytes from patients with SLE, compared with healthy controls. These differences are specific for this particular cell population, because no significant differences were found in DCs or T cells. Our results

suggest an unbalanced monocyte function linked to reduced HO-1 activity in SLE. These findings could not only impair the tolerogenic capacity of monocytes, but also enhance their immunogenicity. As a result of these alterations, monocytes with low HO-1 expression could contribute to the autoimmune deregulation associated with SLE. Although monocytes from SLE patients did not show an increase in antigen-presenting activity in SEA assays, it is possible that the previously described defective T-cell function for these patients could account for this result. Moreover, the results obtained in DCs from FcγRIIb knockout mice strongly suggest that HO-1 down-regulation could be a key step in the promotion of autoimmunity. Several studies have shown that monocytes obtained from patients with SLE can display altered functionality.

L-3 expressed on AP-61 cells may be involved in

the interaction with DENV. Seppo et al. found two GSLs, zwitterionic and acidic GSLs, in the Drosophila melanogaster embryo (21). However, learn more they could not detect Nz3, which is similar to L-3. Moreover, nLc4Cer has not so far been detected in neutral GSLs of AP-61 cells. Since insect cells do not contain β-N-acetylgalactosaminyl-transferase, which produces Gal β-(22, 23), it can be deduced that nLc4Cer will not be found in these cells. In comparing the GSLs that can bind to dengue virus on TLC plates, the β-GlcNAc residue was noted to have a similar carbohydrate moiety to those of L-3 and nLc4Cer. A previous study reported that β-HexNAc is important in the process of DENV binding to host cells (7). The core structure of two DENV-2-binding

GSLs, L-3 and nLc4Cer, which are predominantly found in GSLs, is different from those of N- and O-linked glycoproteins. The SCH772984 research buy host range of DENV is restricted to only humans and mosquitoes. Since DENV is propagated in mosquitoes and characteristically transmitted to humans, GSLs such as L-3and nLc4Cer may play important roles in virus transmission. This paper was supported and funded by Mahidol University and a Southeast Asian Ministers of Education Organization/Regional Tropical Medicine and Public Health scholarship. Part of this work was supported by Core Research and Technology (Japan Science and Technology Agency), Japan and the Department of Virology, Armed Forces Research Institute of Medical Sciences, Thailand. “
“Transplantation is a successful treatment for end-stage organ failure. Despite improvements in short-term outcome, long-term survival remains suboptimal because of the morbidity and mortality associated with long-term use of immunosuppression. There is, therefore, a pressing need to devise protocols that induce tolerance in order to minimize or completely withdraw immunosuppression in transplant recipients. In this review we will discuss how regulatory

T cells (Tregs) came to be recognized as an attractive way to promote transplantation tolerance. We will summarize the preclinical data, supporting the importance Progesterone of these cells in the induction and maintenance of immune tolerance and that provide the rationale for the isolation and expansion of these cells for cellular therapy. We will also describe the data from the first clinical trials, using Tregs to inhibit graft-versus-host disease (GVHD) after haematopoietic stem cell transplantation and will address both the challenges and opportunities in human Treg cell therapy. Other Articles Published in this Series T cell depletion in paediatric stem cell transplantation. Clinical and Experimental Immunology 2013, 172: 139–47. Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now? Clinical and Experimental Immunology 2013, 172: 148–57.

In order to study the predictive factors of graft loss, patients were divided into two groups: those who experienced graft loss and those who did not during the study. Obesity

and other commonly associated factors of graft loss were assessed (Table 8). Cox regression analysis was used to study the impact of obesity and other covariates MAPK Inhibitor Library chemical structure such as age of recipient, pre-transplant DM, post-transplant DM, human leucocyte antigen mismatch and history of acute rejection on graft outcome. Obesity (odds ratio (OR) = 3.09), acute rejection (OR = 5.68), pre-transplant DM (OR = 3.21) and age of recipient (OR = 1.06) were all significant independent risk factors associated with development of graft failure (Table 9). Because DGF was more common in the obese group (33.3% vs 15%), the effect of obesity on graft survival might be related to a higher incidence of DGF. However, the results of each individual predictive factor remained unaffected even check details if DGF was introduced in the multivariate analysis. Obesity is an established risk factor of cardiovascular disease and is

associated with increased mortality in the general population.17 Many survival studies in haemodialysis patients, however, have shown the ‘reverse epidemiology’, namely, low values of BMI are associated with increased mortality, whereas higher values of BMI are associated with improved survival in dialysis patients.18,19 On the other hand, the published work analyzing the impact of obesity in renal transplant recipients had conflicting results.3–5,20–22 In our population, with a median follow-up period of 73 months, there was a significant association between obesity and graft loss or mortality after transplant. This is in accordance with the results of the study by Chow et al.10 However, it would be necessary to study the impact of BMI on the survival rates of our dialysis patients before excluding obese patients from kidney transplant, because the overall patient

outcome could be even worse if obesity had a larger impact on survival for those who maintained on dialysis than those who underwent kidney transplant. Amine dehydrogenase Obesity is a significant risk factor of coronary artery disease in patients on chronic haemodialysis (relative risk = 5.09).23 Moreover, it is also associated with increased risk for development of post-transplant DM, hypertension and hyperlipidaemia which, like in the general population, are risk factors for cardiovascular mortality and morbidity after kidney transplant. Modlin et al. demonstrated that there was a greater incidence of post-transplant DM in obese renal transplant recipients when compared with matched non-obese recipients (12% vs 2%) and that cardiac diseases are the leading cause of deaths (39.1%) in obese patients.

Allergen, adjuvant and anaesthetics.  Chicken egg ovalbumin (OVA), grade VII, was from Sigma-Aldrich, St. Louis, MO, USA. The Al(OH)3 adjuvant (Alhydrogel) was from Brenntag Biosector, Denmark. Two different types of anaesthetics were used; Isoflurane (Isoba vet; Intervet/Schering-Plough Animal Health, Lysaker, Norway) and a cocktail named ZRF, consisting of Zoletil Forte (Virbac International, Carros Cedex, France), Rompun (Bayer Animal Health GmbH, Leverkusen, Germany) and Leptanal (Janssen-Cilag International NV, Beerse, Belgium) and isotonic saline. Isoflurane gas was administered as a 3.5% mixture with

medical O2 in a coaxially ventilated open mask to effect. see more The ZRF cocktail contains 18.7 mg AZD2281 cost Zolazepam, 18.7 mg Tiletamine, 0.45 mg Xylazine and 2.6 μg fentanyl per ml and was administered to effect with a nominal dose of 0.1 ml/10 g i.p. Intraperitoneal sensitization study.  Groups of mice received first sensitization at ages 1, 6 and 20 weeks and are hereafter referred to as 1-, 6- and 20-week-old mice. The mice were sensitized by i.p. administration of 0, 0.1, 10 or 1000 μg OVA in 1 mg Al(OH)3 in Hank’s balanced salt solution (HBSS) in a 0.1-ml bolus. Two weeks later, they were boosted i.p. with the corresponding dose, but without Al(OH)3 in 0.1 ml. All mice in the

1000-μg groups suffered from severe anaphylactic chock and died or were killed upon booster administration. One week later, a blood sample Clomifene was taken from the remaining groups, which

were then anaesthetized with isoflurane and challenged by i.n. instillation of 10 μg OVA in 35 μl HBSS per day for 3 days. Three days after the last challenge, the mice were anaesthetized with ZRF before the chest was opened and blood drawn by heart puncture. Lung-draining mediastinal lymph nodes (MLNs) were collected, lungs lavaged and the lymph nodes and bronchoalveolar lavage fluid (BALF) kept on ice. Intranasal sensitization study.  Groups of 1-, 6- and 20-week-old mice were sensitized i.n. [13] with 10 μg OVA with 120 μg Al(OH)3 in HBSS on days 1, 2 and 3 (Table 1). On days 22, 23 and 24, they were boosted i.n. with 10 μg OVA in HBSS. All i.n. exposures were performed under isoflurane anaesthesia. On day 27, blood was drawn by heart puncture. Nose- and lung-draining lymph nodes [superficial cervical (SLNs) and MLNs, respectively [14]] were collected and kept on ice; lungs were lavaged and thereafter collected for histopathology. The BALF was also kept on ice. In a concurrent study, control groups of age- and sex-matched mice were immunized i.n. with OVA alone without Al(OH)3 (Table 1). This OVA-only exposure did not induce sensitization or any significant responses, when compared with OVA + Al(OH)3-treated mice. For clarity, the OVA-only groups are not presented, except for a few observations. Determination of instillation volumes in the intranasal sensitization study.  The mice of the different age groups were exposed according to Table 1.

The Treg percentages were significantly higher in all the experiment groups compared to the control groups. These changes were deduced by applying TGF-β1 neutralizing antibody into the co-culture system. Our results indicated that the

CD4+ T cells can be induced into CD4+CD25+FoxP3+ T cells by BMMCs via TGF-β1. Regulatory T cells (Tregs) can suppress immune responses to donor alloantigens, and have the potential to play an important role in both inducing and maintaining transplant tolerance in vivo[1]. The transcription factor forkhead box P3 (FoxP3) is the recognized master gene governing the development and function of both natural and induced Tregs, especially in mice [2–4]. Mast cells (MCs) have long been recognized as major players in allergy [5], but see more in recent years MCs have been identified as being responsible for a far more complex range of functions in the innate and adaptive immune responses [6–9]. However, the role of mast cells JQ1 manufacturer in the generation of adaptive immune responses, especially in transplant immune responses, is far from being resolved [10]. Recently,

Lu et al. found that mast cells may be essential intermediaries in Treg-mediated transplant tolerance [11]. While the mechanisms involved are still not well understood, some previous studies have shown that MCs can serve as a source of transforming growth factor (TGF)-β1 [12], which is required for introduction and maintenance of Treg cells both in vitro and in vivo[13–16]. Therefore, this study was designed to test the hypothesis that bone marrow-derived mast cells (BMMCs) can induce CD4+ T cells to CD4+CD25+FoxP3+ Tregs via TGF-β1 HSP90 in vitro. C57BL/6 (H-2b) mice were maintained and housed at the animal facilities of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Bone marrow cells were obtained from C57BL/6 mice. The cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 10 mM Hepes, 50 µM 2-mercaptoethanol, penicillin/streptomycin/L-glutamine, 10 ng/ml mouse interleukin (IL)-3 (Peprotech, Rocky Hill, NJ, USA) and

10 ng/ml mouse stem cell factor (SCF) (Peprotech) at 37°C in a humidified atmosphere containing 5% CO2. Every 7 days, the non-adherent cells were transferred into fresh enriched medium. After 4 weeks, the purity of the mast cells was assessed by flow cytometry. Spleen cells were obtained from C57BL/6 mice. T cells were isolated from the spleen cells with CD3 T cell isolation kit (Miltenyi, Bergisch Gladbach, Germany). Purity of CD3+ T cells typically exceeded 95%. To determine the purity and the characteristic of BMMCs, BMMCs were collected after 4 weeks’ culture. They were dropped onto a slide and stained with toluidine blue (1%, pH = 1) for 10–20 s. The slide was then washed with distilled water for about 2 min. The cells were observed under a microscope.

Serum NGF levels varied greatly. Serum

NGF concentrations in healthy humans are not normally distributed. About 10% of healthy people have relatively high NGF concentrations.68,69 We also noted the same findings of serum NGF levels in OAB patients, but not in normal controls. The high serum NGF levels in healthy humans in other studies might result from underlying systemic conditions that affect serum NGF levels. C-reactive protein (CRP) is a protein found in the blood, the levels of which rise in response to inflammation. CRP is synthesized by the liver in response to factors released by fat cells (adipocytes).70 Serum CRP level can be used as a nonspecific marker of systemic inflammation. Chronic prostatic inflammation has been hypothesized to be associated with the learn more pathogenesis of benign prostatic hyperplasia. However, the association between histological prostatic inflammation and LUTS is relatively weak.71 Rohrmann et al.72 reported that men with serum CRP levels >0.30 mg/dL were more likely to show three or four symptoms

(i.e. nocturia, incomplete emptying, hesitancy, and weak stream) from the Third National selleck Health and Nutrition Examination Survey (NHANES III). Another report using longitudinal data from the Olmsted County study73 showed that patients with higher serum CRP levels were approximately two times more likely to exhibit a rapid increase in storage LUTS and almost 2.5 times more likely to show a rapid decrease in peak flow rate. Kupelian et al.74 reported a significant association between serum CRP level and overall International Prostate Symptom Score (IPSS) in both men and women included in the Boston Area Community

Health (BACH) survey. We Etoposide ic50 also reported the serum CRP levels are associated with residual urgency symptoms in patients with benign prostatic hyperplasia after medical treatment.75 In women, serum CRP was also found to elevate in OAB patients. CRP levels were significantly higher in women with OAB-wet than in those with bladder oversensitivity and in the normal control group. Women with voiding dysfunction also had a non-significantly higher CRP level. Further analysis revealed that body mass index and maximum flow rate were two independent factors influencing CRP levels. However, serum CRP level is not considered a suitable biomarker for discriminating female non-SUI LUTD. As patients with OAB may have frequent detrusor contractions during the storage phase, it is possible that sustained isometric detrusor contractions could result in increased muscle bulk and hence increased detrusor wall thickness (DWT) or bladder wall thickness (BWT). It has been hypothesized that DWT increases in patients with DO.

Contrary to the findings in mice [37,52], the autochthonous pig strain PR4 of B. choerinum did not interfere effectively with Salmonella and was not able to protect gnotobiotic pigs against subsequent infection with S. Typhimurium. Probiotics, including bifidobacteria, were shown to be able to down-regulate expression of genes in the S. Typhimurium pathogenicity islands SPI-1 and SPI-2 [53], and protective Maraviroc solubility dmso bifidobacterial properties after prolonged exposure have been described in conventional mice [54]. We speculate that this microbe needs more time to form an effective biofilm

on the intestinal epithelium, as has been shown in gnotobiotic rats [55]. Bifidobacteria are associated more with the colon than ileum, which is the major site of

Salmonella translocation, and their beneficial effect is caused rather by their metabolic products and the mechanisms of tolerance they induce [56]. This could be the major reason why the association of gnotobiotic pigs with B. choerinum for 24 h was not protective against a subsequent infection with S. enterica serovar Typhimurium. Further studies of the formation of biofilms by bifidobacteria and their impact on Salmonella pathogenity in gnotobiotic pigs are an Staurosporine interesting target of future study. We thank our colleagues Ms Marie Zahradnickova, Ms Jana Machova, Ms Jarmila Jarkovska and Ms Hana Sychrovska for their technical assistance. We are grateful to Professor M. Bailey (University of Bristol, UK) for his kind help in preparation of the manuscript. This work

was supported financially by grant no. 523/07/0572 of the Czech Science Foundation, Ardeypharm GmbH (Herdecke, Germany) and the Institutional Research Concept AV0Z50200510 of the Institute of Microbiology. U.S. –E. coli Nissle 1917 is the active component of the probiotic preparation Mutaflor® (Ardeypharm GmbH). The other authors have no conflict interests. “
“Modulation and suppression of the immune response of the host before by nematode parasites have been reported extensively and the cysteine protease inhibitor (CPI or cystatin) is identified as one of the major immunomodulators. In the present study, we cloned and produced recombinant CPI protein from the murine nematode parasite Heligmosomoides polygyrus (rHp-CPI) and investigated its immunomodulatory effects on dendritic cell (DC) function and immune responses in mice. Bone-marrow-derived CD11c+ DC (BMDC) that were exposed to rHp-CPI during the differentiation stage showed reduced MHC-II molecule expression compared with BMDC that were generated in normal culture conditions. The BMDC generated in the presence of rHp-CPI also exhibited reduced expression of CD40, CD86 and MHC-II molecules and reduced interleukin-6 and tumour necrosis factor-α cytokine production when stimulated with Toll-like receptor ligand CpG.

25 These selleck screening library experiments suggest that adjuvants alter the Ag-specific CD4

T-cell repertoire by modifying the TCR affinity threshold that limits CD4 T-cell clonal selection.5 One question raised by our studies is whether MPL-based emulsions inherently focus Ag-specific CD4 T-cell repertoires toward high-affinity clonotypes or whether additional factors contribute to the skewing of the PCC-specific CD4 T-cell responses. The immunodominant peptide of PCC (PCC88–104) is an unusual I-Ek binder that lacks one critical MHC anchor residue29 and forms weakly stable complexes with I-Ekin vitro.30 To investigate the importance of pMHCII stability in the TCR repertoire selection by the MPL-based emulsion, we recently characterized the Ag-specific CD4 T-cell responses elicited by four altered cytochrome Selleckchem Midostaurin c peptides with different binding stability for I-Ek.31 Upon immunization with MPL, peptides forming low stability complexes with I-Ek, such as PCC88–104, focused CD4 T-cell responses towards high-affinity clonotypes expressing the public 5C.C7β chain,

while higher stability peptides broadened the TCR repertoire to lower affinity clonotypes expressing different rearrangements in their CDR3β (Fig. 1b).31 Hence, both the adjuvant and the half-life of pMHCII complexes determine the clonotypic diversity of the responding CD4 T-cell compartment. How vaccine adjuvants alter the specificity and many clonotypic diversity of the CD4 T-cell response remains an open and important question. Because of the diversity of adjuvants used and the complexity of the cellular events involved in pMHCII presentation, several different mechanisms may be involved in the adjuvant control

of the CD4 T-cell immune repertoire (Fig. 2). In the following sections, we will discuss selected mechanisms by which adjuvants could alter Ag processing and presentation and thereby change the immune repertoire of CD4 T-cell responses. Although most adjuvants contain TLR agonists, TLR agonists and vaccine proteins are usually not physically coupled. Medzhitov and colleagues have shown that Ag and TLR agonists need to be present in the same phagosome cargo to induce optimal pMHCII presentation and stimulation of CD4 T cells.32 This TLR control of pMHCII presentation not only determines the density of pMHCII complexes on the surface of APCs but also biases the specificity of the CD4 T-cell repertoire towards peptides associated with TLR agonists.33 The choice of adjuvant vehicles is likely to have an important impact on the co-delivery of Ag and TLR agonists to the same phagosome and should therefore regulate the efficiency of pMHCII presentation (Fig. 2a). While the impact of pMHCII density on the CD4 T-cell repertoire is poorly understood, our latest studies, using variable doses of peptide Ag, suggest that low levels of pMHCII focus CD4 T-cell responses towards high-affinity clonotypes.

5 years. Intermediate risk predicted overall hazard ratio (HR) (2.157, P = 0.039) and cardiovascular mortality (HR= 5.023; P = 0.004) versus low risk, but ‘high’ risk did not. High risk (vs low risk) predicted cardiovascular events (HR = 2.458, P = 0.05). Besides, the addition of ABI < 0.9 (P = 0.021) and baPWV (P = 0.014) to a FRS model significantly improved the predictive MK-2206 supplier value for overall mortality. In hemodialysis patients, intermediate risk but not high risk categorization by FRS predicted overall and cardiovascular mortality, and high risk predicted cardiovascular events. ABI < 0.9 and baPWV provided additional

predictive values for overall mortality. Future study is needed to develop hemodialysis-specific equations and assess whether risk refinement using ABI < 0.9 and baPWV leads to a meaningful change in clinical outcomes.

“
“All chronic kidney disease (CKD) patients (CKD Stage 3–5; CKD Stage 5D (both peritoneal dialysis (PD) and haemodialysis (HD)). a. That therapeutic https://www.selleckchem.com/products/dabrafenib-gsk2118436.html iron be used to correct diagnosed iron deficiency (1D). c. That to achieve target haemoglobin levels in patients with CKD (2C), HD (2B) and PD (2D) the following iron indices should be targeted by increasing or decreasing iron therapy: Regular monitoring helps to predict iron overload and the overshoot of target Hb. (Ungraded) Suggested frequency of testing iron indices (Ungraded) CKD Stage 1–2 CKD Stage 3–5 CKD Stage 5D PD HD As clinically indicated ∼3 monthly ∼3 monthly ∼1–3 monthly In recent

years, since the publication of adjusted Hb targets (refer to KHA-CARI guideline ‘Haemoglobin Cyclin-dependent kinase 3 Levels in Patients using ESAs’) and the demonstration that higher dosing of ESAs to achieve Hb targets is associated with an excess of cardiovascular events,[1] more emphasis has been placed on reasons for renal anaemia and the subsequent ESA resistance that may occur. The use of iron as a means of treating renal anaemia has assumed greater importance and particularly in people who have a higher demand for iron when on ESAs. Ten per cent of patients receiving ESAs are unresponsive.[2] Pro-inflammatory cytokines antagonize the action of ESAs by exerting an inhibitory effect on erythroid progenitor cells and disrupting iron metabolism (a process where hepcidin has a central role). Iron deficiency is also common in pre-dialysis CKD. In the NHANES III study less than one-third of the CKD non-dialysis patients had TSAT% >20% and ferritin >100 μg/L,[3] suggesting that iron homeostasis disruption begins relatively early in CKD progression. In many patients with CKD, as with patients with other chronic inflammatory diseases, poor absorption of dietary iron and the inability to use iron stores contribute to the anaemia.[4] Detection is also complicated by the lack of sensitivity of peripheral indices.

If a relatively low level of self-tolerance in the CD8+ T-cell and B-cell compartments were to prove generalizable, it would provide an even stronger rationale to expect that addition of foreign helper epitopes to cancer vaccines would allow potent CD8+ T-cell and B-cell responses. In this issue of the European Journal of Immunology, Snook et al. [18] test whether strong CD4+ self tolerance and weaker or absent CD8+ T-cell and B-cell tolerance is a generalizable principle that is widely applicable in the design of cancer vaccines. Selleck Erlotinib The authors refer to this state of differential tolerance as “split-tolerance,” akin to the split-tolerance

often seen in allogeneic bone marrow transplantation [19]. Snook et al. [18] begin by examining the response to a key target for colorectal cancer vaccines, guanylyl cyclase C (GUCY2C), using immunization with an adenovirus expressing GUCY2C alone or also expressing an MHC class II-restricted influenza hemagglutinnin helper Venetoclax order epitope (S1) [18]. They show that CD4+ T cells are tolerant of self GUCY2C but that B cells and CD8+ T cells respond robustly to GUCY2C and generate CD8+ T-cell memory if provided the linked S1 helper epitope [18]; these responses were prevented by CD4+ T-cell depletion. As expected, in knockout mice lacking

GUCY2C the CD4+ T cells were not tolerant and the S1 epitope was not required in order to generate B- and T-cell responses to GUCY2C. Immunization of BALB/c mice with adenovirus containing both GUCY2C and the S1 helper epitope generated a CD8+ T-cell-dependent reduction in lung metastases arising from GUCY2C-expressing

CT26 colorectal cancer cells and substantially extended survival (nearly eightfold for longer) compared with survival following immunization without the S1 epitope. Surprisingly, this protective immunity did not result in any detectable autoimmunity to healthy self-tissues that express GUCY2C [18] and therefore identification of the mechanisms leading to differential recruitment of effector cells to tumors as opposed to healthy host tissues warrants substantial investigation. The ability to manipulate recruitment would alleviate the potential dangers of achieving a maximal antitumor response. Perhaps most importantly, Snook et al. show that their conclusions are generalizable based on similar findings with different mouse strains and tumors/tumor antigens (e.g. melanoma and breast cancer antigens Trp2 and Her2, respectively), as well as additional helper epitopes such as the synthetic pan DR epitope known as PADRE [18]. In addition to the potential clinical utility, these studies highlight the underappreciated concept of differences in the level of self-tolerance of lymphocyte subsets to specific self-antigens. A key conceptual feature of the T-cell help mechanism in general and employed here is that the foreign helper (CD4+) and effector (CD8+ and B-cell) tumor epitopes must be linked (Fig. 1), meaning that they must be presented by the same antigen-presenting cell.