The aim of this study was to investigate whether diabetes and insulin resistance affect B-1 cells and their production of natural IgM. We found that diabetic db/db mice have Epigenetics Compound Library datasheet lower levels of peritoneal B-1a cells and a decreased

IgM response to pneumococcal immunization and TLR-4 activation. Furthermore, our in-vitro studies showed that glucose in high concentrations reduces B-1 cell IgM secretion and differentiation into antibody-producing cells concurrent with proliferation arrest and increased apoptosis. Specific pathogen-free C57BL/6 mice were purchased from Taconic (Skensved, Denmark). For isolation of peritoneal B-1 cells, male and female C57BL/6 mice were fed a normal chow diet. As a model for insulin resistance, 8-week-old male C57BL/6 mice were assigned randomly to a low glycaemic control diet or a high-fat diet (Harlan

Laboratories, Madison, WI, USA) for 12 weeks. On a caloric basis, the low glycaemic control diet contained 16·8% fat, 60·9% carbohydrate and 22·3% protein (3·3 Kcal/g), whereas the high-fat diet contained 60·3% fat, 21·3% carbohydrate and 18·4% protein (5·1 Kcal/g). The diets contained comparable amounts of vitamins and minerals. Male db/db mice and control mice (+/+ or +/db) on a C57BL/6 background from Jackson Laboratories (Bar Harbor, ME, USA), and db/db and wild-type controls (+/+) on a BKS background from Taconic, were maintained on a normal chow diet. For in-vivo assessment FK506 mouse of the effect of TLR-4 agonist, 10–12-week-old db/db mice (on a C57BL/6 background) and controls oxyclozanide were injected intraperitoneally with 0·34 mg/kg of the TLR-4 agonist Kdo2-Lipid A (Avanti Polar Lipids, Inc., Alabaster, AL, USA) or vehicle. For immunization studies, 10–12-week-old db/db mice and controls (on a C57BL/6 or BKS background) and C57BL/6 mice maintained on diets for 3 months were injected intraperitoneally with 11·5 μg of a 23-valent vaccine (Pneumovax; Sanofi Pasteur MSD, Lyon, France), containing 0·5 μg each of 23 types of polysaccharides from S. pneumoniae

or saline. As indicated for each experiment, body weight, plasma insulin, glucose and antibody titres were followed in longitudinal blood samples. Before blood sampling, mice were fasted for 4 h. Plasma glucose in blood samples from fasted, non-anaesthetized animals was determined with a glucose dehydrogenase method by using HemoCue® B-glucose microcuvettes (HemoCue®, Ängelholm, Sweden) and insulin was determined by a mouse insulin enzyme-linked immunosorbent assay (ELISA) (Mercodia, Uppsala, Sweden). Plasma triglycerides and cholesterol were measured using Konelab 20 Autoanalyzer (Thermo Electron Corporation, Vantaa, Finland). All mice were housed in a controlled environment and all experimental protocols were approved by the animal ethical committee in Gothenburg.

Levels of KLF4 can be manipulated by diverse agonists such as statins, resveratrol, bortezomib and dietary compounds, so these factors could be influential for TAM re-education.[130] Although still learn more preliminary, the association among c-Myc, STAT6 and M2 polarization has been proposed by recent studies. As reported, c-Myc up-regulated IL-4-mediated STAT6 activation and elevated the expression of 45% of the genes correlated with alternative activation of macrophages.[131] In contrast, c-Myc inhibition blocked the expression of some pro-tumoral genes.[131] Other proteins and signalling pathways known

to promote M2-like properties of macrophages are also the potential targets for tumour therapy. They include peroxisome Aurora Kinase inhibitor proliferator-activated receptor (PPARs), HIFs, Ets family member 2 (Ets2), Decoy receptor

(DcR3) and mammalian target of rapamycin (mTOR). First, PPAR-γ can promote M2 type differentiation of human macrophages by acting as a transcriptional inhibitor of NF-κB.[132] PPAR-α plays a role in macrophages by antagonizing M1 polarization and supporting M2 polarization.[133] As synthetic inhibitors of PPAR-α/γ have now been identified, the evaluation of their role in TAM-targeted therapy is essential. Second, HIFs are a hopeful target because of their over-expression in TAMs residing in the hypoxic tumour microenvironment and their ability to induce the production of angiogenic factors, including VEGF, platelet-derived growth factor-β, NOS2, fibroblast growth factor 2, IL-8 and cyclooxygenase-2.[134] In fact, macrophage-targeted depletion of HIF-1α reduced tumour

growth in mice.[135] Therefore, it would be interesting to see whether blocking HIFs could slow or halt tumour recovery. Third, Ets2 is a direct effector of the M-CSF signalling pathway, and so facilitates the formation of M2 macrophage. Zabuawala et al.[136] demonstrated that an Ets2-driven transcriptional program in TAMs could promote Montelukast Sodium the angiogenesis and metastasis of murine breast cancer. Interestingly, an Ets2-TAM gene signature consisting of 133 genes retrospectively predicted overall survival of breast cancer patients.[136] Investigations of DcR3 and mTOR are also interesting.[137, 138] Several anti-tumour drugs that are able to suppress M2 macrophages will be introduced as follows. (i) Histidine-rich glycoprotein (HRG): HRG can skew TAMs to M1 type by down-regulation of PIGF, a member of the VEGF family, and can combat tumour malignancy by enhancing immunity and vessel normalization.[26] Macrophages are a direct target of HRG; and re-education of TAMs is essential for HRG-mediated anticancer effects.[26, 139] (ii) Copper chelate (CuNG): A novel CuNG was demonstrated to modulate the cytokine profile of TAMs isolated from chemotherapy-resistant or radiotherapy-resistant cancer patients.

This means that males can be found much more often in patients below 30 years. Interestingly, this is also true if we exclude all 1457 patients with X-chromosomal inheritance (Fig. 1b). In contrast, from 30 years onwards, females were reported more frequently, resulting in an almost doubled probability for observing PID in women

compared to men aged 50–80 years. The documented prevalence for single diseases varies considerably between countries (Table 3). The minimal reported click here prevalence is highest in France, with 5:100 000 inhabitants. In France, CVID reaches a prevalence of close to 1:100 000 inhabitants, but there were relatively few patients with sIgA deficiency compared to Spain, where the prevalence is above 1:100 000. The calculated incidence rates show variations between countries and over time (between the 4-year groups) (see Fig. 2). France and Spain have the highest overall documented incidence rates, with France showing a somewhat balanced course over the years which peaks at 16·2 in 1999–2002 (Fig. 2a). For many diseases, France reported the highest incidence rates, e.g. for SCID: 1·6 (1999–2001, Fig. 2b), AT: 1·2 (1995–1998) and CGD: 0·8 (1991–1994). Italy shows the highest incidence for DGS (2·8, 1999–2002), WAS (1, 1995–1998) and agammaglobulinaemias (1·1,

1995–1998). SIgA deficiency has an exceptionally high incidence of 6·7 in Spain (1999–2002). The rates Poziotinib in vivo for CVID (Fig. 2c) vary strongly over time for each country, with a maximum of 2·3 in the Netherlands. Interestingly, the incidence of IgG subclass deficiency (Fig. 2d) is mainly below 0·5, but we see a marked increase particularly in France from 1987 onwards, peaking at 3 in 1999–2002. The drop of the curve in Fig. 2c and d for the time-periods after 2003 can be ascribed to the fact that these diseases both have a high share of late-onset patients. A total of 27·9% of all registered patients were diagnosed

at 16 years of age or later. This proportion Farnesyltransferase was particularly high in antibody deficiencies, where 40·2% of patients were diagnosed after the age of 16, and complement deficiencies (55·5%). In CVID, which forms the largest single PID entity, the proportion was above 70%. Statistically significant overall trends towards a shorter diagnostic delay could be identified for some of the diseases. These are partly restricted to single countries. We observed such positive trends for IgG subclass deficiency and agammaglobulinaemias both in the total cohort and in Spain. Figure 3a and b depicts this result for agammaglobulinaemic patients: they were more often prone to a very long delay (>5 years and >10 years, respectively), in particular for the period before 1990 compared to the following periods. We furthermore observed positive trends for AT in Turkey and WAS in the United Kingdom. In contrast, no significant trend could be identified for CVID (Fig.

The lower detection limit of these was 16 pg/mL for all assays. Samples

below the detection levels were assigned a theoretical value of one-half the detection limit. WT and knockout mice were infected i.v., via the lateral tail vein, with 1 × 104 CFU C. albicans ATCC strain 90028 as previously described [22]. Mice were observed twice daily for signs of disease and lethality. The kidney fungal burden was determined exactly as previously described [22]. Cytokine levels and log CFU were expressed as mean ± standard deviation of the mean (SD) of several determinations, each conducted on a different animal in an independent experiment. Differences in cytokine levels and organ CFUs were assessed by one-way analysis of variance and the Student’s-Keuls-Newman test. Survival data were analyzed check details with Kaplan–Meier survival plots followed by the log rank test (JMP Software; SAS Institute, Cary, NC) on an Apple Macintosh computer. When p values of < 0.05 were obtained, differences were considered statistically significant. We thank S. Akira, G. Brown, B. Beutler, S. Bauer, and T. Taniguchi for providing KO mice. This work was partially supported by the Programma Operativo Nazionale PON01_00117/8 from the Ministero dell'Istruzione,

dell’Università e della Ricerca of Italy and by Progetti di Ricerca d’Ateneo A.013.BIO200809 and A.013.MAN200809 from the University of Messina granted

to CBi and C-X-C chemokine receptor type 7 (CXCR-7) GM, respectively. The authors declare no financial or commercial conflict of interest Disclaimer: EPZ-6438 purchase Supplementary materials have been peer-reviewed but not copyedited. “
“Deposition of Schistosoma mansoni eggs in the intestinal mucosa is associated with recruitment of mucosal mast cells (MMC) expressing mouse mast cell protease-1 (mMCP-1). We investigated the involvement of mMCP-1 in intestinal barrier disruption and egg excretion by examining BALB/c mice lacking mMCP-1 (Mcpt-1−/−). Tissue and faecal egg counts from 6 weeks until 12 weeks post-infection (w p.i.) revealed no differences between wild type (WT) and Mcpt-1−/−mice. Using chamber experiments on ileal tissue revealed that at 8 w p.i., the epithelial barrier and secretory capacity were severely impaired, whereas no difference was found between WT and Mcpt-1−/−mice in this respect. However, a fragmented distribution of the tight junction (TJ) protein occludin, but not of claudin-3 or ZO-1, was observed in WT mice at 8 w p.i., while no changes in TJ integrity were seen in Mcpt-1−/−mice. Therefore, we conclude that in contrast to the situation in Trichinella spiralis-infected mice, in schistosomiasis, mMCP-1 is not a key mediator in egg excretion or impairment of the intestinal barrier. The marked decrease in ileal secretory capacity during S.

Hyperphoshorylated IRAK-1 and activated TRAF6, in turn, induce transforming growth factor-β-activated kinase 1 (TAK1) [15]. The TAK1 multiprotein signalosome recruits the IκB kinase (IKK) complex resulting in final activation of transcription factors such as NF-κB family members [16]. Recently, IRAK4- and MyD88-deficiency were described INCB018424 chemical structure as autosomal recessive disorders. The clinical picture of these primary immunodeficiencies is indistinguishable and, thus, requires a genetic diagnosis. Patients deficient in the MyD88 adapter molecule

or the IRAK4 kinase fail to activate NF-κB and display an impaired cytokine response to nearly all TLR agonists, except for TLR3 ligand poly(I:C). Furthermore, TGF-beta inhibitor these patients

have an increased susceptibility to infections caused by pyogenic encapsulated bacteria, mainly Gram positive Streptococcus pneumoniae and Staphylococcus aureus [17-20]. These clinical cases highlight the importance of both MyD88 and IRAK4 in TLR-mediated immune responses. Although it is well established that IRAK4 plays a crucial role in the control of innate immune response, many aspects of IRAK4 deficiency and its precise function in MyD88-dependent signaling during bacterial infections remain elusive. Analysis of the human IRAK4 structure demonstrated the presence of an active Ser/Thr kinase domain [21]. Moreover, Cheng et al. [22] reported an autocatalytic phosphorylation of IRAK4 protein, why suggesting that IRAK4 acts as the first proximal kinase, which then phosphorylates IRAK1. Nevertheless, only little is known about its precise catalytic function or its enzymatic targets and interaction partners. The scope

of this study was, therefore, to assess the function of the IRAK4 kinase in anti-bacterial host defense in human peripheral blood monocytes. Interestingly, we found that IRAK4 modulates TLR-induced cytokine synthesis, thus representing a switch between pro- and anti-inflammation. This prompted us to clarify the molecular mechanism and our data highlight the involvement of the PKB/Akt pathway in the induction of TLR-triggered IL-10 secretion. Patients deficient in IRAK4 have been described to be more susceptible to infections with pneumococci and staphylococci [18]. In views of the clinical implications of IRAK4-deficiency we studied the function of IRAK4 in anti-bacterial host defense in human monocytes. For this purpose, we established an siRNA-based approach for IRAK4 knockdown, achieving significantly reduced irak4 mRNA levels as well as diminished IRAK4 translation (Fig. 1A and B). MyD88 silencing did not affect IRAK4 expression, thus proving specificity of the knock-down (Supporting Information Fig. 1A). Notably, cell viability was unaffected by transfection (Supporting Information Fig. 1B).

Compliance with the GFD was assessed every 15 days by careful examination

of a patient’s food diary (control level 1) followed, whenever possible, by a specific medical interview (control level 2). At the same time-points, a blood sample was obtained to detect EMA as a further index of adherence to the GFD (control level 3). All patients in this group presented excellent compliance with the GFD and completed the clinical phase of the study. Conversely, the NFR characterization was performed exclusively on 11 of 20 patients in this group who, after a reasonable period on a GFD, agreed to undergo a second duodenal biopsy. By preliminary evaluation, the subgroup click here of 11 patients appeared to be gender- and age-reflective of the overall group. Group 2.  Group 2 comprised treated CD patients (31 male/56 female, mean age 31·3, range 19–54 years) on a GFD from at least 12 months, and showing serum EMA-negative results. During the study, all patients continued to take a GFD and were followed regularly for 12 months. Compliance with the GFD was assessed every 15 days as described for group 1. Group 3.  Group 3 comprised healthy subjects (five male/10 female, mean age 28·7, range 18–55 years) not affected by CD or other autoimmune disease, and with no consanguinity

with CD patients. At study entry their sera were collected and stored at −70°C until tested. Two of the subjects in this group showed an NFR-like pattern in the absence of serum EMA. For ethical reasons, the

latter two subjects were not submitted to duodenal biopsy to exclude a subclinical form of CD. However, they agreed to undergo a GFD and to be monitored for 12 months. Adherence to Navitoclax ic50 the GFD was assessed every month as described for group 1. Both treated subjects presented excellent compliance to the GFD and completed the study. CD patients were selected from among the out-patients admitted to our gastrointestinal unit from January 2006 to December 2007 who showed clinical features described for groups 1 or 2, and who agreed to undergo the study protocol. The diagnosis of CD was made Bay 11-7085 in accordance with the procedure adopted worldwide [34], based on clinical case identification, serological screening and duodenal biopsy histology. Healthy subjects were selected among the blood donors admitted to our hospital from January 2006 to December 2007 who showed clinical features described for group 3, and who agreed to undergo the study protocol. The diagnosis of CD was excluded in individuals not clinically suspicious, with serum EMA-negative results. Because the suitability of oat as part of a GFD is still controversial [2], all the GFDs administered in this study included the withdrawal of any oat-based product. All procedures followed in this study were in accordance with the ethical standards of the institutional committee responsible for human experimentation. Furthermore, informed consent was obtained from each study participant.

Most available data are not from an Australian or New Zealand source. The effects on quality of life of different management pathways on patients, carers and staff still need to be addressed. The number

of patients with end-stage kidney disease (ESKD) is growing, with the greatest increase over the last decade among those who are elderly, dependent and with multiple comorbidities.[1, 2] As a consequence, the annual acceptance rate for renal replacement therapy (RRT) in Australia is rising with the highest prevalent dialysis groups being the 65–74 years age cohort (24%) and the over 75 years old age group (24%).[3] It is also noteworthy, that in the past 5 years, the greatest percentage increase in acceptance onto dialysis has been in the over 75 years old age group.[3] Although ANZDATA (Australian and New Zealand Dialysis and Transplant Registry) provides data on the stock and flow of elderly patients on see more RRT, there exists no registry data GDC-0449 research buy of the number of elderly patients reaching chronic kidney disease (CKD) stage V who choose not to dialyse. Results from the Patient INformation about Options for Treatment (PINOT)

study showed that 14% of incident stage V CKD patients chose a non-dialysis pathway[4] but this does not account for the undefined number of people who, in consultation with their physician and family choose not to dialyse and are never referred to nephrology services in the first instance. The Australian Institute of Health and Welfare (AIHW) study suggests that for every patient (usually elderly) who dies on RRT another dies without having the desire for or access to RRT.[5] We have reached an important mafosfamide crossroad in the provision of dialysis services where technology has

improved to such a degree that there exists few limitations in the ability to commence dialysis irrespective of age or comorbidities. However, in conjunction with this change in practice, there is increasing recognition among nephrologists and renal service providers that dialysing those with increasing dependence and multiple comorbidities may not improve survival and may adversely affect their quality of life. Few qualitative studies[6, 7] have explored the factors that elderly ESKD patients consider when making treatment decisions but some of the factors identified to date include survival, quality of life and burden of treatment. Elderly ESKD patients who commence dialysis in Australasia have a considerable comorbid burden (70% with cardiovascular disease, 60% coronary artery disease, 33% peripheral vascular disease, 24% cerebrovascular disease). Elderly ESKD patients who commence dialysis in Australasia often start without established access (46%) and one-third are referred late. There is little information about the characteristics of elderly ESKD patients in Australasia who are managed with non-dialysis pathways.

In addition, the HTLV-2 tax/rex mRNA levels were found to be increased in the HIV-1/HTLV-2 co-infected population [15] and high HTLV-2 proviral loads

correlated selleck chemicals llc with long-term non-progression to AIDS [14]. Tax1 and Tax2, the regulatory proteins of HTLV-1 and HTLV-2, activate viral and host cellular gene transcription and are essential for viral replication; in addition they have considerable effects on the level of clinical disease expression [16-18]. Tax1 induces multiple functions in the host cells (e.g. modulation of cell cycle checkpoint, interference with DNA repair, induction of cellular senescence, inhibition of apoptosis) and interacts with numerous cellular proteins regulating the activation of multiple signalling pathways [e.g. cyclic adenosine Buparlisib ic50 monophosphate (AMP)-responsive

element-binding protein (CREB), serum response factor (SRF), mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), activator protein 1 (AP1), transforming growth factor (TGF)-β, nuclear factor (NF)-κB], whereas Tax2 has only been identified to interact with proteins involved mainly in the NF-κB canonical pathway [19]. The canonical and non-canonical NF-κB activation pathways have distinct regulatory functions. In the canonical pathway, the NF-κB/Rel family of transcription factors exist in the cytoplasm bound and inhibited by IκB proteins. Cellular stimulation by a variety of inducers (e.g. cytokines, mitogens, free radicals, Tax1, Tax2) results in phosphorylation, polyubiquitination and proteosomal degradation of IκB allowing translocation of the active Baricitinib dimer p65/RelA-p50 to the nucleus inducing the transcription of target genes (chemokines, cytokines and adhesion molecules) promoting cell survival,

immune regulation and inflammatory responses [18, 20]. In the non-canonical pathway, p100/RelB complexes are inactive in the cytoplasm. Signalling through a subset of tumour necrosis factor (TNF) receptors (e.g. LTβR, CD40, BR3) phosphorylates IKKα complexes which, in turn, activate p100 leading to its ubiquitination and proteosomal processing to p52. The transcriptionally competent p52/RelB complexes translocate to the nucleus and induce target gene expression that regulates the development of lymphoid organs and the adaptive immune responses [18, 20]. Tax1 and Tax2 mediate activation of key cellular pathways involved in cytokine and chemokine production via the NF-κB pathway [20], but the ability of Tax2 to induce cytokine gene expression have been reported to be lower than Tax1 [21]. The NF-κB pathway is constitutively activated in HTLV-1-infected cells due to the persistent dissociation of IκB from the NF-κB/IκB complex induced by Tax1 [22].

Among various miRNA, miR-155 has been associated with the regulation of different immune-related processes, such as haematopoiesis,14 B-cell and T-cell differentiation,15 cancer16 and innate immunity.12 The miR-155 is processed from an exon of a non-coding RNA transcribed from the B-cell Integration Cluster located on chromosome 21, showing strong sequence homology Cytoskeletal Signaling inhibitor among humans, mice and hens, and is highly expressed in cells of lymphoid and myeloid origin.17 Recently, miR-155 has been identified

and characterized as a component of macrophage and monocyte response to different types of inflammatory mediators, such as bacterial lipopolysaccharide (LPS), interferon-β (IFN-β), tumour necrosis factor-α (TNF-α) and polyriboinosinic-polyribocytidylic acid [poly(I:C)].12,18,19 Many of the miR-155 target transcripts identified so far are pro-apoptotic and anti-inflammatory proteins, such as the Fas-associated death domain protein, IκB kinase ε, inositol 5-phosphatase 1 and the suppressor of cytokine signalling-1 (SOCS-1). SOCS-1 belongs to a family SP600125 supplier of proteins known to regulate the response

of immune cells to cytokines and other inflammatory stimuli, such as LPS, through direct inhibition of the Janus tyrosine kinase (JAK) and consequent inhibition of signal transducer and activator of transcription factors (STAT), as a ‘classical’ negative feedback loop. In addition, the C-terminal SOCS box domain interacts with components of the ubiquitin ligase system and mediates proteasomal degradation of associated proteins, including key elements of other pro-inflammatory pathways, such as the nuclear

factor-κB and Jun N-terminal kinase pathways. Experimental evidence suggests that miR-155 plays a pro-inflammatory role and may be implicated in chronic inflammatory processes, such as those Y-27632 2HCl contributing to cancer and to certain neurodegenerative diseases. Given the similarities between microglia and other cells of the immune system, such as macrophages and dendritic cells, where miR-155 has been found to be up-regulated upon activation,20 in this work we investigated the contribution of miRNA-155 to microglia activation and microglia-mediated immune responses. To our knowledge, this is the first study providing evidence that miR-155 has a strong pro-inflammatory role during microglia activation and is required for SOCS-1 post-transcriptional regulation and progression of the immune response in these cells. Moreover, our results suggest that miR-155 inhibition induces neuronal protection from microglia-induced damage, and miR-155 may therefore constitute an interesting and promising target for the control of neuronal inflammation.

05% Tween-20 plus 10% goat serum and incubated for 1 h at 37°C. Plates were then washed and incubated with HRP-conjugated anti-human IgG (Sigma, USA) at 1:3000 dilution. A substrate solution containing

OPD (0.5 mg/mL) in sodium citrate buffer, pH 5.0, and 0.03% H2O2 was used to develop the colorimetric reaction. Reactions were then stopped with 2 M see more H2SO4 and the A492 was measured in an ELISA reader (Spectramax, Molecular Devices). Blood from active TB patients (n=11) or PPD-negative (n=6) healthy BCG-vaccinated subjects were collected and PBMC were obtained through Ficoll gradient as previously described 50. PBMC (5×106 cells/mL) were exposed to purified sMTL-13 (10 μg/mL) for 48 h and IFN-γ was measured in culture supernatants by a cytometric bead assay (Bencton, Dickinson and Company, USA) following the manufacturer’s instructions. Non-parametric Mann−Whitney test, Kruskall−Wallis with Dunn’s multiple Ivacaftor mw comparison tests or Friedman test were used to the significance of differences between groups. Values of p<0.05 were considered statistically significant. The ROC curve was used for analysis of the accuracy values: area under the ROC curve, sensitivity, and specificity, obtained by using MedCalc Statistical (Version 5.00.020,

Brussels, Belgium). The authors thank Mr. Jorge Tolentino and Dr. Bruno Bezerril (Fiocruz/BA) for technical support and Prof. Mario Steindel for critical reading of this manuscript. They also thank Marcos L’Hotellier and the staff of the DRD-CPHC/JF

for helping with the TB patients. They are indebted to Drs. Luciana Leite and Ivan Nascimento (I. Butantan) as well as Profa. Maria Luiza Bazzo (UFSC) for providing the M. bovis BCG CFP and non-tuberculous mycobacteria strains, respectively. L.N. received CAPES/CNPq fellowship. A.B. received funding from CNPq (472477/2007-2 and 565496/2008-5), CAPES (210/2007), FAPESC (04524/2008-1) and WHO/TDR (2008-8734-0). C.D.S., B.S.C., H.C.T., S.C.O., M.B.N., and A.B. are CNPq investigators. Conflict of interest: The authors declare no financial or commercial conflict of interest. “
“Division of Immunoregulation, National Unoprostone Institute for Medical Research, London, UK Administration of peptides i.n. induces peripheral tolerance in Tg4 myelin basic protein-specific TCR-Tg mice. This is characterized by the generation of anergic, IL-10-secreting CD4+ T cells with regulatory function (IL-10 Treg). Myelin basic protein Ac1–9 peptide analogs, displaying a hierarchy of affinities for H-2 Au (Ac1–9[4K]<<[4A]<[4Y]), were used to investigate the mechanisms of tolerance induction, focusing on IL-10 Treg generation. Repeated i.n. administration of the highest affinity peptide, Ac1–9[4Y], provided complete protection against EAE, while i.n. Ac1–9[4A] and Ac1–9[4K] treatment resulted in only partial protection. Ac1–9[4Y] was also the most potent stimulus for IL-10 Treg generation. Although i.n.