1B) with no significant difference in spinal cord pathology (Fig. 1C). Disruption of BBB permeability is another parameter used to assess the neuroinflammatory response in EAE and susceptibility to disease. At day 10 (d10) postimmunization, we found that B6 and H3H4RKO mice had increased BBB permeability during the acute early phase of the disease compared with that of H1H2RKO mice (Fig. 1D).

These results indicate that the combined effect of disrupting H1R and H2R signaling is antipathogenic in EAE, whereas the combined effect of disrupting selleck chemicals llc H3R and H4R signaling is propathogenic. HA and HRs have been shown to be important in regulating hematopoiesis [[39-41]]. We examined the frequency of different cell types in the primary and secondary lymphoid tissues of naïve B6, H1H2RKO, and H3H4RKO mice. There was no significant difference in the total number of cells in the thymus, lymph node, or spleen among the three strains (Fig. 2A). buy 5-Fluoracil We also analyzed the frequency of CD4+, CD8+, Foxp3+

Treg, B cell (CD19+), CD11b+, CD11b+Gr1+, NKT (CD1d tetramer+), and NK (NKp46+) cells in primary and secondary lymphoid tissues and found no significant differences in the frequency of these cell types (Fig. 2B, C, D, and E), with the only exception being the lymph node B-cell frequency, which was significantly decreased in H3H4RKO compared with H1H2RKO mice (Fig. 2C). These results strongly suggest that the differences in EAE susceptibility observed between H1H2RKO and H3H4RKO mice are not due to differences in the frequency of immune cells in the primary and secondary lymphoid tissues. Although the exact pathogenic mechanisms underlying MS and EAE are not known, it is thought to be highly dependent on CD4+ T cells capable of producing IFN-γ and/or IL-17 [[2]]. HA and HRs play a role in T-cell polarization, proliferation, and cytokine production [[4]]. Therefore,

to elucidate the immune mechanisms associated with differential EAE susceptibility observed in B6, H1H2RKO, and H3H4RKO mice, we compared their MOG35–55-specific T-cell responses on d10 post immunization. In ex vivo proliferation assays, Phenylethanolamine N-methyltransferase splenocytes and draining lymph node (DLN) cells from all three strains responded equivalently in a dose-dependent fashion to MOG35–55 (Fig. 3A). Splenic and DLN cells from H1H2RKO mice restimulated ex vivo with MOG35–55 produced significantly less IFN-γ (Fig. 3B) and IL-17 (Fig. 3C) compared with restimulated cells from H3H4RKO mice. In addition, H3H4RKO mice produced significantly more IFN-γ and IL-17 compared with B6 mice. IL-4 was undetectable among the three strains. These results suggest that the differences in EAE susceptibility observed in H3H4RKO mice can, in part, be attributed to increased encephalitogenic Th1 and Th17 effector T-cell responses. Previously, we showed that H1R regulates IFN-γ and IL-4 production by activated CD4+ T cells and Th1/Th2 effector T-cell responses [[31]].

DJ Nikolic-Paterson has acted as a consultant for Johnson & Johnson. 143 NEW MODELS FOR THE PREDICTION OF EARLY AND LATE RENAL EVENTS IN TYPE 2 DIABETES M Jardine, J Hata, V Perkovic, T Ninomiya, H Arima, M Woodward, S Zoungas, A Cass, A Patel, M Marre, J Chalmers On Behalf of the Advance Collaborative Group J Chalmers has received research grants from Servier, administered through the University of Sydney, for the ADVANCE trial. J Chalmers, S Zoungas, M Woodward, A Patel and M Marre have received honoraria from Servier for speaking at scientific

meetings. 144 PATTERNS OF PROGRESSION IN CHRONIC KIDNEY DISEASE (POPE) STUDY: Dabrafenib clinical trial BASELINE DATA C Nelson, RG Fassett, N Boudville, E Pedagogos, H Healy, G Mangos, H Moody, G Kirkland, T Kay, P Champion De Crespigny, D Hoffman, D Waugh Audit4 is proprietary software owned and developed by Software for Specialists. Roche Products Pty Ltd supports the customization of Audit4 by nephrologists as a quality use of medicines project in Nephrology. 186 THE EFFECT OF DIALYSIS MODALITY ON THE SURVIVAL OF END-STAGE RENAL DISEASE PATIENTS WITH CHRONIC HEPATITIS C INFECTION – A MULTI-CENTRE REGISTRY

STUDY B Bose, SP McDonald, CM Hawley, FG Brown, SV Badve, KJ Wiggins, KM Bannister, Selleckchem Torin 1 N Boudville, P Clayton, DW Johnson Professor David Johnson is a consultant for Baxter Healthcare Pty Ltd and has previously received research funds from this company. He has also received speakers’ honoraria and research grants from Fresenius Medical Care and is a recipient of a Queensland Health Research Fellowship. Dr Kym Bannister is a consultant for Carbohydrate Baxter Healthcare Pty Ltd. Dr Fiona Brown is a consultant for Baxter and Fresenius and has received travel grants from Amgen and Roche. Dr Stephen McDonald has received speaking honoraria from AMGEN Australia, Fresenius Australia and Solvay Pharmaceuticals and travel grants from AMGEN

Australia, Genzyme Australia and Jansen-Cilag. The remaining authors have no competing financial interests to declare. “
“A PRAGMATIC TRIAL OF A POLYPILL-BASED STRATEGY TO IMPROVE ADHERENCE TO INDICATED PREVENTIVE TREATMENTS AMONG PEOPLE AT HIGH CARDIOVASCULAR DISEASE RISK A Cass, A Patel, A Rodgers The polypill formulations used in this study have been developed and provided free of charge by Dr Reddy’s Laboratories, Hyderabad, India. A RANDOMISED, CONTROLLED TRIAL OF EXIT SITE APPLICATION OF MEDIHONEY FOR THE PREVENTION OF CATHETER-ASSOCIATED INFECTIONS IN PD PATIENTS – HONEYPOT STUDY D Johnson, S Badve, E Pascoe, E Beller, A Cass, C Clark, J de Zoysa, S McTaggart, N Isbel, A Morrish DJ is a consultant for Baxter Healthcare Pty Ltd and has previously received research funds from this company. He has also received speakers’ honoraria and research grants from Fresenius Medical Care.

In the control group absolute lymphoblast output peaked at day 10 with 3·25 ± 0·8 × 108 cells/h, significantly higher than the pre-challenge output of around 0·5 × 108 cells/h. In both groups, the lymphoblast output had returned to pre-challenge levels

by the end of the experiment. A CD4+ blast cell response was observed in both the control and previously infected groups of lambs, with a repeated measures model showing strong evidence of a difference in the pattern of responses over time between the two groups (P < 0·001). In the control group, the CD4+ blast cell response peaked at day 10 at 1·58 ± 0·19 × 107 cells/h (Figure 4a), HKI-272 purchase and in the previously infected group peaked at day 3 at 0·9 ± 0·24 × 107 cells/h (Figure 4b). A CD8+ blast cell response was observed in the controls but not in the previously infected group (Figure 4c, d). No significant changes were observed in the gamma-delta T cell receptor positive blast cell response of either group of lambs (Figure 4e, f), the increase in mean output observed on day 12 in the controls being caused by a single outlier animal. Prior

to challenge, three of the previously infected lambs had elevated levels of γ/δ TCR+ blast cells (Figure 4f), however these had subsided by day 1. The CD25+ blast cell response was similar to CD4, with strong evidence of a difference in pattern selleckchem of response between the two groups (P < 0·001). Naïve lambs showed

an increase in CD25+ blast cells from day 5, peaking at day 10 at 1·76 ± 0·3 × 107 cells/h (Figure 4g). In the previously infected group the response occurred sooner, peaking on day 3 at 1·30 ± 0·3 × 107 cells/h (Figure 4h). In the naïve group a CD21+ blast cell response was observed which peaked on day 10 at 0·76 ± 0·1 × 107 cells/h (Figure 5a), significantly (P < 0·05) higher than the pre-challenge output of 0·16 ± 0·1 × 107 cells/h. The same response occurred more quickly in the previously infected lambs peaking on day 5 at 0·73 ± 0·2 × 107 cells/h (Figure 5b). The repeated measures model showed inconclusive evidence (P = 0·068) of a difference in the pattern of responses between the two groups, due in part to relatively high estimated standard errors. IgA+ Aspartate blast cell output was increased 10 and 12 days after the naïve lambs were infected, peaking at 0·51 ± 0·1 × 107 cells/h (Figure 5c), and in the previously infected group peaked on day 3 at 0·23 ± 0·1 × 107 cells/h (Figure 5d). This led to strong evidence of a difference in pattern of response over time between the two groups (P < 0·001). Before challenge mean total IgA concentrations in the efferent gastric lymph of control and previously infected lambs were similar, at 0·53 ± 0·2 and 0·34 ± 0·04 mg/mL respectively (Figure 6a, b).

In addition, our technique allows direct ex vivo visualisation without any need for further processing of the tissues, in contrast to immunohistochemistry

and MPO analysis. Histology is labour-intensive and tedious, while MPO assays can be problematic and do not distinguish between neutrophils and macrophages. In conclusion, this study presents a robust model to track neutrophil recruitment which can be used to complement other available BI 6727 molecular weight methods traditionally used for tracking neutrophils. In addition to experimental models of IBD, this versatile technique will be useful for monitoring neutrophil trafficking during inflammatory responses in a range of disease settings and constitutes a novel approach for the assessment of potential therapeutics that aim to reduce neutrophil infiltration. Thus, it can be used as an informative and specific tool for both the pharmaceutical industry and the basic research community. We thank

Grainne Hurley for her excellent technical assistance. see more The authors are supported in part by Science Foundation Ireland and by a research grant from GlaxoSmithKline. None of the co-authors have any conflict of interest to declare in connection to the paper. The work described has not been published or submitted elsewhere. S.M. and G.M. are employees of GlaxoSmithKline. “
“B1 B cells represent a unique subset of B lymphocytes distinct from conventional B2 B cells, and are important in the production of natural antibodies. A potential human homologue of murine B1 cells was defined recently as a CD20+CD27+CD43+ cell. Common variable immunodeficiency (CVID) is a group of heterogeneous conditions linked by symptomatic primary antibody failure. In this preliminary report, we examined the potential clinical utility of introducing CD20+CD27+CD43+ B1 cell immunophenotyping as a routine assay in a diagnostic clinical laboratory. Using a whole blood assay, putative B1 B cells in healthy controls and in CVID patients were measured. Peripheral blood from 33 healthy donors and 16 CVID

patients were stained with relevant monoclonal antibodies and underwent flow cytometric evaluation. We established a rapid, Calpain whole blood flow cytometric assay to investigate putative human B1 B cells. Examination of CD20+CD27+CD43+ cells is complicated by CD3+CD27+CD43hi T cell contamination, even when using stringent CD20 gating. These can be excluded by gating on CD27+CD43lo–int B cells. Although proportions of CD20+CD27–CD43lo–int cells within B cells in CVID patients were decreased by 50% compared to controls (P < 0·01), this was not significant when measured as a percentage of all CD27+ B cells (P = 0·78). Immunophenotypic overlap of this subset with other innate-like B cells described recently in humans is limited. We have shown that putative B1 B cell immunophenotyping can be performed rapidly and reliably using whole blood. CD20+CD27+CD43lo–int cells may represent a distinct B1 cell subset within CD27+ B cells.

5 μg. Ag85A DNA vaccine was injected intramuscularly at a dosage of 100 μg. IFN-γ ELISPOT assay.  ELISPOT assay for IFN-γ was performed with ELISPOT assay kit (BD PharMingen, San Diego, CA, USA) as instructed by the manufacture. Briefly, plates were coated with the capture anti-IFN-γ monoclonal antibody (mAb) overnight at 4 °C and then blocked with complete media for 2 h at room temperature. The mice were sacrificed 2 weeks after the

final immunization. The splenocytes of five mice from each group were isolated, plated in duplicate (4 × 105 cells/well) and cultured at 37 °C for 48 h with recombinant Ag85A protein (at the final concentration of 5 μg/ml) or phytohemagglutinin (PHA) as a positive control (at the final concentration of 10 μg/ml). The plates were washed with deionized water and PBST, incubated for 2 h at room temperature after the addition of biotinylated anti-IFN-γ mAb, and then incubated for 1 h with Streptavidin-HRP. The 3-amino-9-ethylcarbazole Selleckchem ABT 888 (AEC) substrate was then added for signal development. Spots were enumerated with CTL-ImmunoSpot® S5 Micro Analyzer (Cellular Technology, Cleveland, OH, USA). Cytokine production in vitro.  Mice were

sacrificed 2 weeks after the final immunization. The splenocytes of five mice from each group were isolated, plated (4 × 105 cells/well) and cultured with Ag85A protein (5 μg/ml) or PHA (10 μg/ml) for 72 h. The concentrations of IFN-γ and interleukin (IL-4) in the culture supernatants were measured using enzyme-linked immunosorbent assay (ELISA) kit (NeoBioscience Technology Company, Shenzhen, China) following the manufacturer’s procedures. Mouse model Peptide 17 manufacturer with MDR-TB.  Seventy female BALB/c mice 6–8 weeks of age were infected intravenously with 220,000 CFU of M. tuberculosis HB361, which was resistant to RFP, isoniazid (INH) and streptomycin, but sensitive to PZA. Treatment of mouse model.  The 70 female BALB/c mice infected with MDR-TB HB361 were randomly divided into seven groups and treated as follows: Fossariinae (1) plasmid vector pVAX1 treatment

as negative control (2) RFP (Red Flag Pharmacy, Shenyang, China) treatment as negative control (3) PZA (Jing Hua Pharmacy, Chengdu, China) treatment as positive control (4) M. vaccae vaccine treatment as positive control (5) Ag85A DNA (prepared by Shanghai H&G Biotechnology Company, Shanghai, China [16]) treatment (6) RFP combined with Ag85A DNA treatment and (7) PZA combined with Ag85A DNA treatment. The mice were treated on the third day after infection. Both RFP (0.4 mg) and PZA (0.6 mg) were orally administered every day for 2 months. M. vaccae vaccine was injected intramuscularly at a dosage of 0.0075 μg for five times at 2-week intervals. Ag85A DNA vaccine was injected intramuscularly at a dosage of 100 μg for five times at 2-week intervals. Bacterial counts.  Mice were sacrificed 4 weeks after the last injection of vaccines. The lungs and spleens of the mice were taken and homogenized in saline.

5% of the patients. Econazole, clotrimazole and ketoconazole were notably active against A. flavus. Aspergillus keratitis is a significant problem in patients with ocular lesions in South-Indian States, warranting early diagnosis and initiation of specific antifungal therapy to improve outcome. “
“Onychomycosis is a common superficial fungal infection, which usually caused by dermatophytes, yeast and non-dermatophytic moulds. Recently, we isolated a Rhodotorula minuta isolate from a 15-year-old immunocompetent

girl student in Hangzhou (China) that was identified using microscopy, culture morphology, find protocol histological diagnosis, API 20C AUX Yeast Identification Kit and sequencing of the Internal Transcribed Spacer region. In vitro, antifungal susceptibility tests showed that this Palbociclib yeast isolate was susceptible to low concentrations of amphotericin B, itraconazole, voriconazole and 5-flvoriconaz but that it appeared to be dose-dependent susceptible to fluconazole(MIC = 16 μg/ml). Furthermore, the effective result of therapy with itraconazole against R. minuta was consistent with that of susceptibility

tests. “
“Endogenous endophthalmitis caused by filamentous fungi has been infrequently described and its prognosis in immunocompromised patients is largely unknown. Patients were identified through a single-centre database containing patients with endophthalmitis. Cases published since 2002 were reviewed. Clinical and treatment features as well as outcomes were analysed. Six patients were identified from the database. Underlying conditions were haematological malignancies (HM) and/or allogeneic haematopoietic

stem cell transplantation (HSCT). Three patients underwent vitrectomy. None of the patients survived and the median time from first evidence of endophthalmitis until death was 33 days. The median time from first evidence of an invasive fungal infection to endophthalmitis was only 5 days. Fifty-six patients were identified from the literature. The majority of these patients underwent vitrectomy (27) or enucleation (10) and received intraocular antifungal therapy (28). Only 13 (23%) of 56 patients experienced an improved vision. The survival rate was L-NAME HCl 52% in all 56 patients but was significantly less in patients with HM or post-HSCT when compared with all others (26% vs. 70%, respectively; P = 0.003). Endogenous endophthalmitis caused by filamentous fungi is frequently associated with a permanent decrease or loss of vision. This type of fungal infection carries a particular poor prognosis in patients with profound immunosuppression, requiring improved treatment strategies. “
“Clinical Paracoccidioides spp. isolates from patients with paracoccidioidomycosis (PCM) in Mato Grosso, Brazil exhibit different patterns of serologic reactivity.

This is important as the concentration of complement proteins in serum is very high. Therefore, to inhibit complement activity in totality, either a set of inhibitory proteins or a multicomplement-binding protein could fulfil such a requirement. The complement proteins usually act on the surface of target pathogens. However, blocking of complement activation in blood-sucking H. contortus is all the more important as antibodies formed against the internal proteins of the parasite during infection

[42] in combination with complement proteins (acquired during blood meal) would damage the internal tissues with serious consequences for the parasite. Identification of H.c-C3BP should facilitate development of new therapeutics considering a key role of this protein in immune modulation. We thank Director, IVRI, Selleckchem Ibrutinib for providing the necessary facilities, Prof. Anil K Jaiswal, University of Maryland, USA, for mass spectrometry. This work was supported by a grant from the Department of Biotechnology, Government of India, to PJ. “
“Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)-α production,

and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (Treg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration selleck of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN-α secretion potently (−64%) but TLR-9-induced IFN-α secretion only slightly (−20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar

efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN-γ and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced Org 27569 up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4+forkhead box protein 3 (FoxP3)+ regulatory T cells, but did not affect the generation of suppressive CD8+CD38+lymphocyte activation gene (LAG)-3+ Treg. In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4+ T cell proliferation and induce CD4+FoxP3+ regulatory T cell generation. Plasmacytoid dendritic cells (PDC) have important functions in innate and adaptive immunity. They are unique in rapidly producing massive amounts of type I interferon upon recognition of viral nucleotides or self-DNA-protein complexes by their Toll-like receptors (TLR).

As observed with human samples, Ag-driven immune responses were notably enhanced in mice immunized with ovalbumin Ag, with increases in cell proliferation, and IFN-γ in cell culture supernatants following blockade in vitro (Fig. 5A, n = 4). Similar enhancements were observed when splenocytes from transgenic OT-II mice, which express the mouse CD4+ T-cell receptor specific for chicken ovalbumin 323–339, were incubated

with ovalbumin Ag in the presence of increasing amounts of anti-sCTLA-4 mAb (Fig. 5B). The examples shown here are typical of several experiments using a range of immunogens, all of which demonstrate that selective AZD1208 mw blockade of sCTLA-4 in vitro, enhances Ag-specific immune responses. We have also found that blockade of sCTLA-4 in vivo, in which mice were immunized under cover of 100 μg/mouse of anti-sCTLA-4 Ab, enhances Ag-specific immune responses (Fig. 5C and Supporting Information Fig. 4). Thus, we were able to address functional blockade of sCTLA-4 using the JMW-3B3 anti-sCTLA-4 mTOR inhibitor mAb in murine models of disease. Finally, given the promise of pan-specific anti-CTLA-4 Ab blockade in the treatment of tumors, including melanoma [30, 31, 34], we investigated whether selective blockade of sCTLA-4 also protected against metastatic melanoma spread in vivo. Mice were infused with

B16F10 melanoma cells and coadministered with anti-sCTLA-4 Ab JMW-3B3, pan-specific anti-CTLA-4 Ab, IgG1 isotype control, or left untreated (Fig. 5D). When mice were sacrificed and examined for metastatic melanoma in the lungs, blockade with either anti-sCTLA-4 or pan-specific anti-CTLA-4 Ab significantly reduced the mean number of metastatic foci

by 44 or 50%, respectively, Phosphoglycerate kinase compared with that with the IgG1 isotype control (p < 0.0001, Mann–Whitney U test). Thus, in this model, inhibition of tumor spread mediated by pan-specific anti-CTLA-4 mAb could be recapitulated by selective blockade of sCTLA-4. This study identifies a potentially important role for the alternatively spliced and secretable CTLA-4 isoform, sCTLA-4, as a contributor to immune regulation. We demonstrate that sCTLA-4 can be produced and has suppressive functions during human T-cell responses in vitro, that the Treg-cell population is a prominent source, and that specific blockade of the isoform can manipulate murine disease in vivo. The general relevance of CTLA-4 to regulatory activity is well recognized from previous work demonstrating both cell intrinsic and extrinsic inhibitory effects on T-cell responses [35, 36]. The sCTLA-4 isoform, in contrast, has received little attention, with interest largely arising because a single nucleotide polymorphism in the 3′ untranslated region of CTLA-4, which reduces sCTLA-4 expression, has been identified as a susceptibility factor for several autoimmune diseases [23, 24].

Comparative microarray analysis revealed an additional set of genes that were significantly upregulated in E10.5 TLR2+ CD11b+ macrophages. This analysis, together with our genetic, microscopic, and

biochemical evidence, showed that embryonic phagocytes express protein machinery that is essential for the recycling of cellular iron and that this expression can be regulated by TLR engagement in a MyD88-dependent manner, leading to typical inflammatory M1 responses. These results characterize BMS-354825 cell line the utility of TLRs as suitable markers for early embryonic phagocytes as well as molecular triggers of cellular responses, the latter being demonstrated by the involvement of TLRs in an inflammation-mediated regulation of embryonic homeostasis via iron metabolism. “
“Synthetic oligonucleotides

(ODN) expressing CpG motifs mimic the ability of bacterial DNA to trigger the innate immune system via TLR9. Plasmacytoid dendritic cells (pDCs) make a critical contribution to the ensuing immune response. This work examines the induction INK 128 research buy of antiviral (IFN-β) and pro-inflammatory (IL-6) cytokines by CpG-stimulated human pDCs and the human CAL-1 pDC cell line. Results show that interferon regulatory factor-5 (IRF-5) and NF-κB p50 are key co-regulators of IFN-β and IL-6 expression following TLR9-mediated activation of human pDCs. The nuclear accumulation of IRF-1 was also observed, but this was a late event that was dependant on type 1 IFN and unrelated to the initiation of gene expression. IRF-8 was identified as a novel negative regulator of gene activation in CpG-stimulated pDCs. As variants of IRF-5 and IRF-8 were recently found to correlate with susceptibility to certain autoimmune diseases, these findings are relevant to our understanding of the pharmacologic effects of “K” ODN and the role of TLR9 ligation under physiologic,

pathologic, and therapeutic conditions. Cells of the immune system utilize TLR to sense ligands uniquely expressed by pathogenic microorganisms. Human plasmacytoid dendritic cells (pDCs) use TLR9 to detect Rebamipide the unmethylated CpG motifs present at high frequency in bacterial DNA [1-3]. Synthetic oligonucleotides (ODN) encoding unmethylated CpG motifs mimic the effect of bacterial DNA and trigger pDC activation. Several structurally distinct classes of CpG ODN have been described. Those of the “K” class (also referred to as “B” class) are characterized by their ability to stimulate human pDCs to secrete pro-inflammatory cytokines such as IL-6 and TNF-α. Clinical trials of “K” ODN show promise for the treatment of cancer, allergy, and infectious disease [4, 5]. Identifying the signaling pathways triggered when human pDCs are stimulated by “K” ODN is, thus, of clinical relevance. pDCs are a major source of type I IFNs and various pro-inflammatory cytokines [6, 7].

These GSK1120212 molecular weight cells produce T-helper type 1 (Th-1) cytokines [interferon (IFN)-γ, interleukin (IL)-2, IL-12] important for the activation of antimycobacterial activities of macrophages (Sable et al., 2007). However, some unconventional T cells (CD4CD8 αβ T-cells, γδ cells, NK 1.1) have also been implicated in protective immunity to tuberculosis through the recognition of nonprotein mycobacterial antigens including glycolipids (mycolic acids, phosphatidylinositol mannosides, lipoarabinomannan, etc.) and their presentation to a variety of CD1-restricted lymphocytes. These cells also activate antigen-presenting cells (APCs), boost the expression of major histocompatibility complexes (MHCs) and

costimulatory molecules

and amplify IL-12, learn more IL-18 and IFN-γ production (Doherty & Andersen, 2005). Recently, the importance of CD8+ cytotoxic T-lymphocyte (CTL) responses to the generation of an effective vaccine against tuberculosis has also been recognized. Accumulating evidence indicates that the MHC-I pathway is critical to achieve protection (Orme, 2006). Studies with endogenous proteins, such as heat shock protein 65 (HSP65), have shown the superiority of these antigens to stimulate CTLs, which are able to either kill infected macrophages unable to eliminate the bacilli or kill the mycobacteria in the extracellular space directly (Lima et al., 2004). On the other hand, the role of Th-2 cytokines, such as IL-4, IL-5, IL-10 and IL-13, in protective immunity against Uroporphyrinogen III synthase Mtb remains unclear. It has been suggested that generation of a Th-2 response is associated with a greater risk of progression from Mtb infection to active disease by seriously undermining the efficacy of a Th-1 response to mycobacterial antigens (Doherty & Andersen, 2005). Some authors have also observed a relationship between the presence

of concomitant parasite infections and exposure to environmental mycobacteria, with a systemic bias towards Th-2 responses that reduces the efficacy of BCG (Rook et al., 2001). In this context, effective tuberculosis vaccine design is based on generating the cellular responses required to kill the bacteria and prevent establishment of infection (against infection and pulmonary disease) or to avoid reactivation or progression toward clinical tuberculosis in the case of latent patients. In the first case, the general strategy involves a prophylactic vaccine able to induce protective immunity, measured in terms of lymphocyte subsets expanded after immunization. In the second case, the strategy focuses on utilizing a postexposure vaccine to eliminate or contain latent tuberculosis and prevent reactivation (Sadoff & Hone, 2005; Sable et al., 2007). Concerns regarding the use of postexposure vaccines and their adverse influences result from the fact that the infected lung has already undergone inflammation, tissue damage and remodelling responses (Orme, 2006).