Secretion of IFN-γ and, to a lesser extent, of IL-17 by CD4+ T cells plays a major role both in protection and immunopathology. Few Mtb Ags interacting with DCs affect priming, activation, and regulation of Ag-unrelated CD4+ T-cell learn more responses. Here we demonstrate that PstS1, a 38 kDa-lipoprotein of Mtb, promotes Ag-independent activation of memory T lymphocytes specific for Ag85B or Ag85A, two immunodominant

protective Ags of Mtb. PstS1 expands CD4+ and CD8+ memory T cells, amplifies secretion of IFN-γ and IL-22 and induces IL-17 production by effector memory cells in an Ag-unrelated manner in vitro and in vivo. These effects were mediated through the stimulation of DCs, particularly of the CD8α− subtype, which respond to PstS1 by undergoing phenotypic maturation and by secreting IL-6, IL-1β and, to a lower extent, IL-23. IL-6 secretion by PstS1-stimulated DCs was required for IFN-γ, and to a lesser extent for IL-22 responses by Ag85B-specific memory T cells. These results may open new perspectives for immunotherapeutic strategies

to control Th1/Th17 immune responses in Mtb infections Metformin price and in vaccinations against tuberculosis. Tuberculosis (TB) remains a global health problem due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), HIV-TB co-infection, and failure of the BCG vaccine to control adult pulmonary TB [1]. Protection from Mtb, both under Pyruvate dehydrogenase lipoamide kinase isozyme 1 natural conditions and following vaccination, is dependent, at least in part, on a robust Th1 response

through IFN-γ secretion by Ag-specific CD4+ T cells [2, 3] and, to a lesser extent, on Th17 responses [4, 5]. Both IFN-γ- and IL-17-induced inflammation need to be tightly controlled during Mtb infection in order to avoid important pathological consequences [6-10]. Hence, a deeper understanding of the immunological mechanisms modulating Ag-specific Th1 and Th17 responses during infection or vaccination is required. Although DC maturation and multiple signals required for optimal T-cell activation combine to promote specificity, Ag-independent activation of T lymphocytes can also occur upon infection. Proliferation and cytokine production by “bystander” CD4+ and CD8+ T cells was observed in mice with ongoing M. avium [11], Burkholeira pseudomallei [12], or Leishmania donovani [13] infection. In many cases, the bystander activation of T cells is mediated by pro-inflammatory cytokines released mainly by innate immune cells, including DCs. Several Mtb antigens induce DC activation, mostly in a TLR2-dependent manner, which may favor Th1 polarization of naïve T cells [14-18]. In contrast, the contribution of DC maturation mediated by Mtb antigens to the activation of unrelated Ag-specific memory T cells is unknown. PstS1 is a glycosylated lipoprotein component of the mycobacterial cell membrane that can be also secreted into the extracellular milieu [19].

This discovery transformed the management of two chronic relapsing conditions from maintenance symptomatic therapies, and in some cases surgery, to curative treatment with targeted antibiotics. The possibility

that infections by other organisms from the genus Helicobacter are implicated in the pathogenesis of other human diseases is a tantalizing one. The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), demonstrate many similarities to gastric and duodenal ulceration before the discovery of H. pylori, including unexplained onset in previously healthy hosts, a chronic relapsing disease course with no curative treatments, chronic gastrointestinal inflammation Ixazomib chemical structure and predisposition to malignant change. In this review, we shall consider the evidence supporting Helicobacter spp. as the pathogenic agents in IBD. We will discuss the relative incompatibility of H. pylori disease GSI-IX concentration and IBD, highlighted by the apparent protective effect of prior H. pylori infection on IBD disease risk. We shall review animal variants of IBD, which are both initiated by and associated with Helicobacter spp. infection. We will then review

the Helicobacter organisms associated with human gastrointestinal disease and the molecular evidence for Helicobacter organisms in human IBD. For the purpose of clarity, Helicobacter organisms associated primarily with gastritis or eltoprazine biliary disease are not covered within this article. More than 30 Helicobacter organisms have been described to date (see Fig. 1), but only H. pylori has been

proven to cause human disease. It is inconceivable that H. pylori is the only human pathogen within such a broad genus, and as described below, other candidates are already being investigated. IBD comprises two main conditions: CD and UC. The onset of both conditions occurs at all ages, but with a bimodal distribution with peaks in the late teenage/early adult years (particularly CD) and in late adulthood (particularly UC) (Koehoorn et al., 2006). CD is characterized by transmural inflammation of the gastrointestinal tract at any site from mouth to anus. The disease can affect the mucosa in continuity or include healthy areas between affected sites leading to so-called ‘skip lesions’. Such skip lesions are characteristic of CD and, in addition to the hallmark granuloma on biopsy, they are utilized in differentiating CD from UC. UC affects only the mucosal layer of the gastrointestinal tract and extends in continuity proximally from the rectum (Lennard-Jones, 1989). In UC, the colon is involved exclusively, although ‘backwash’ ileitis can be a feature of extensive disease. The aetiology of both conditions is poorly understood, but genetic, immunological and environmental factors all play a role.

Conclusions:  These results suggest that pulmonary edema in OZ following Temsirolimus ic50 orthopedic trauma is due to an elevated PGE2 and resultant increases in pulmonary permeability. “
“Please cite this paper as: Bruce AC and Peirce SM. Exogenous Thrombin Delivery Promotes Collateral Capillary

Arterialization and Tissue Reperfusion in the Murine Spinotrapezius Muscle Ischemia Model. Microcirculation 19: 143–154, 2012. Objective:  We examined the effects of exogenously delivered thrombin on cell recruitment in skeletal muscle and the formation of new collateral arterioles in the microvasculature in response to ligation-induced ischemia. Methods:  Thrombin or vehicle was locally applied to both

ligated and nonoperated Balb/c spinotrapezius muscles, which were harvested after three or seven days, imaged using confocal microscopy, and analyzed. Results:  Thrombin treatment resulted in accelerated arterialization of collateral capillaries and accelerated tissue reperfusion in ischemic muscles. Uninjured muscle treated with thrombin displayed increased vascular cell adhesion molecule 1 expression on arteriole and venule endothelium, increased expression of smooth muscle α-actin on capillary-sized vessels, increased infiltration by CD11b+ leukocytes, and mast cell infiltration and degranulation. Conclusions:  Exogenous delivery of thrombin enhances microvascular collateral development in response to ischemic

insult, and accelerates tissue reperfusion. Elicited responses from multiple cell types X-396 research buy probably contribute to these effects. “
“Microcirculation (2010) 17, 1–10. doi: 10.1111/j.1549-8719.2009.00013.x Objective:  Epoxyeicosatrienoic acids (EETs) are protective in both myocardial and brain ischemia, variously attributed to activation of KATP channels or blockade of adhesion molecule upregulation. In this study, we tested whether EETs would be protective in lung ischemia–reperfusion injury. Methods:  The filtration coefficient (Kf), a measure of endothelial permeability, and expression of the adhesion molecules vascular cell Tau-protein kinase adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) were measured after 45 minutes ischemia and 30 minutes reperfusion in isolated rat lungs. Results: Kf increased significantly after ischemia–reperfusion alone vs time controls, an effect dependent upon extracellular Ca2+ although not on the EET-regulated channel TRPV4. Inhibition of endogenous EET degradation or administration of exogenous 11,12- or 14,-15-EET at reperfusion significantly limited the permeability response to ischemia–reperfusion. The beneficial effect of 11,12-EET was not prevented by blockade of KATP channels nor by blockade of TRPV4.

Volkman et al. (2) sequenced high-quality draft genomes of three parasite laboratory clones (the reference sequenced as 3D7, HB3 and Dd2) isolated from different parts of

the world. Their work alone identified 26845 single-nucleotide polymorphisms (SNPs) at a frequency of one SNP every 780 bases between the three clones and an additional 37 039 insertion–deletions (indels) between 3D7 and HB3. They further extended their genotyping to 12 P. falciparum strains and 20 genomic regions from 54 worldwide P. falciparum isolates. Results were consistent with initial genetic diversity studies that RO4929097 solubility dmso were performed using whole-genome microarray analysis (5). All together, they identified more than 46937 SNPs (one every 446 bases in average) across the whole genome. High levels of SNPs were detected in genes involved in antigenic variation as well as genes involved in drug resistance. These data were further confirmed by the survey of approximately 60% PF-562271 purchase of P. falciparum predicted genes (3)

and a shotgun sequencing strategy of a Ghanaian clinical isolate (4). Taken together, these reports identified a high number of rare SNP variants and suggested that most SNPs have yet to be discovered. As a whole, these results underscore the importance of creating comprehensive maps of genetic diversity in P. falciparum field isolates. These SNPs are strongly suspected to be markers for various phenotypic traits such as virulence or resistance to drugs.

Recent advances in next-generation sequencing (NGS) technologies are enabling fast and affordable production of large amounts of genome sequence information. These technologies are already opening new perspectives of functional genomics in the field of primary, applied and clinical malaria research. After 30 years of dominance of first-generation ‘Sanger’ dideoxy sequencing, the past 5 years Atorvastatin have seen the explosion of NGS methods. Next-generation sequencing has transformed the field of whole-genome sequencing and analysis. Unlike Sanger sequencing, NGS avoids the need for bacterial cloning and therefore bypasses associated biases. For example, AT- or GC-rich regions are often toxic to bacteria and difficult to reliably read with cloning-based sequencing. This issue is of major importance in the case of the P. falciparum’s extremely AT-rich genome. The major leap forward from NGS is the ability to produce an enormous amount of data within small volumes; a tremendous number of DNA fragments, up to 2 billion short reads per instrument run, can be sequenced in parallel. Three main NGS platforms have been commercialized over the past 5 years: the Roche 454 (Roche Life Sciences, Branford, CT, USA), the Applied Biosystems SOLiD (Applied Biosystems , Carlsbad, CA, USA) and finally the Illumina® (formally known as Solexa) Genome Analyzer and Hi-Seq platforms.

We previously reported that a single nucleotide polymorphism (SNP), rs2268338, within the gene encoding ACCβ was associated with susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes. Although subsequent functional analyses suggested that increased expression of ACCβ in the kidney contributed to susceptibility to the disease, its pathological significance has not been fully elucidated yet. Methods: To know the role of ACCβ in the pathogenesis of diabetic

nephropathy, we examined the effect of ACCβ overexpression on podocyte injury using podocyte-specific ACCβ transgenic (TG) mice and ACCβ-overexpressing cultured murine podocytes. Results: TG mice showed normal renal manifestation under non-diabetic condition. However, 12 weeks after induction of diabetes Selleckchem Staurosporine by streptozotocin injection, the increase of urinary albumin excretion was exacerbated in TG mice, find more accompanied by a decrease in the expression of synaptopodin in podocytes,

compared to wild-type mice. In cultured murine podocytes infected with adenovirus vectors encoding ACCβ, the expression of synaptopodin and podocin decreased under high glucose condition, but not under normal glucose condition. Furthermore, overexpression of ACCβ under high glucose condition resulted in reorganization of stress fibers, increased production of cytokines such as MCP-1, IL-6, TNF-α and VEGF, and induction of apoptosis in the murine podocytes. AMP-activated protein kinase (AMPK) is the main kinase regulator of ACCβ, which inactivates ACCβ through the phosphorylation

of serine residues on ACCβ. The AMPK activation by 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) ameliorated ACCβ-induced decrease in the expression of synaptopodin and podocin, reorganization of stress fibers, increased production of cytokines, and induction of apoptosis under high glucose condition in the murine podocytes. Conclusion: From these observations, it is suggested that excess of ACCβ contributes to exacerbation of podocyte injury in diabetic nephropathy, and the regulation of AMPK/ACCβ pathway may be a new therapeutic strategy to prevent podocyte injury in patients with diabetic nephropathy. JHA JAY C1,2, GRAY STEPHEN P1, WINGLER KIRSTIN3, SZYNDRALEWIEZ not CEDRIC4, HEITZ FREDDY4, COOPER MARK E1,2, SCHMIDT HARALD HHW3, JANDELEIT-DAHM KARIN A1,2 1Diabetic complications division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; 2Department of medicine, Monash university, Melbourne, Australia; 3Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Netherlands; 4Genkyotex SA, Geneva, Switzerland Introduction: Chronic kidney disease is a major complication of diabetes. However, the underlying causes remain unclear.

Promoter regulation in the COX-2 promoter-flanking region (−95∼−90) containing the cis-acting elements C/EBP DNA binding activity in silico was predicted in the laboratory. Notably, the C/EBP-α-regulated protein COX-2 showed a similar result to that observed in IL-13-treated conditions. The COX-1 protein was considered a constitutive isoform, equally expressed in almost all tissues, which did not have any effects. In contrast, a previous report demonstrated that click here IL-13 downregulates PPAR-γ/HO-1

via ER stress-stimulated calpain activation. Further examining the regulatory role of C/EBP-β in the expression of protective PPAR-γ and HO-1 signaling, we found that IL-13 regulated LPS-induced protein expression in a dose-dependent manner (Supporting Information Fig. 1). The data showed that IL-13 markedly decreased the induction of C/EBP-β and PPAR-γ/HO-1 expression by activated microglia cells, indicating that IL-13 reciprocally Selleckchem Adriamycin regulated C/EBP-α and C/EBP-β in activated microglia. Calpain has been demonstrated to be involved in ER stress-induced activated microglia cell death [5]. Further investigating the possible mechanisms of IL-13 regulation of calpain in association with C/EBP-β, PPAR-γ, and HO-1, the results showed that IL-13 markedly enhanced calpain-II protein expression (Fig. 3A) and activity (Fig. 3B(i)) in primary

activated microglia, but markedly reduced the functional activity of calpain inhibitors ALLN, ALLM, and Z-Leu-Leu-CHO (Fig. 3B(ii)). In terms of the role of calpain-II in IL-13-induced C/EBP-β, PPAR-γ, and HO-1 downregulation, calpain-II was shown to interact with C/EBP-β and PPAR-γ but not HO-1 with co-immunoprecipitation and Western blot in activated microglia. Calpain-II was specifically associated with C/EBP-β and PPAR-γ in activated BV-2 microglia cells with the presence of IL-13-treated cells compared with the IgG control (Fig. 3C). There was no direct interaction Baf-A1 cost of HO-1 with calpain-II. To clarify if calpain cleaved C/EBP-β and PPAR-γ, C/EBP-β or PPAR-γ

were digested with recombinant calpain-II under various conditions in vitro cleavage assay. The incubation of C/EBP-β or PPAR-γ with recombinant m-calpain led to the complete digestion of C/EBP-β or PPAR-γ, as determined by Western blotting analysis (Fig. 3D). Moreover, the calpain inhibitor, Z-Leu-Leu-CHO, effectively reversed the IL-13-enhanced LPS-induced C/EBP-β downregulation, but not C/EBP-α and COX-2, in BV-2 microglia (Fig. 3E). These results indicated that calpain-II induction plays an important role in IL-13-triggered reduction of C/EBP-β and PPAR-γ in inflammation-activated microglia. Death of activated microglia could act as an endogenous mechanism for the resolution of brain inflammation [6]. Thus, the effect of knockdown of C/EBP-α expression was investigated to determine if C/EBP-α abolishes IL-13-enhanced apoptosis in activated microglia.

43 Whether this effect is directly mediated by CG is not clear, as reports show both an activation25 and inhibition26 of NF-κB in monocytes and endometrial stromal cells, respectively. Human CG also exhibits immunomodulatory functions by inducing suppressor T cells27 and has long been known to modulate both B- and T-cell response to mitogen stimulation.28–30 In addition, LH/CG receptors are present on maternal T lymphocytes23

providing for a direct mechanism whereby hCG could alter function of circulating immune cells. During normal pregnancy, there is an elevation of CD25+ CD4+ regulatory T cells (T-reg31), and hCG appears to recruit these cells to the fetal–maternal interface.16,32 Furthermore, CG induced bone marrow–derived, in vitro matured, dendritic cells toward a tolerogenic phenotype characterized by increased IL-10 and indolamine 2,3 dioxygenase production.33 The evidence that P4 shifts the cytokine profile toward Th2 is more compelling.15,34 This www.selleckchem.com/products/nu7441.html action is mediated, in part, through P4-induced production of immunosuppressive molecules including progesterone-induced blocking factor (PIBF115) and glycodelin A,35 among others. Progesterone-induced blocking factor stimulates Th2 cytokine production and can suppress NK cell activity in the uterus and systemically.36

As reviewed by this website Lea and Sandra,36 P4 induces a number of cytokines in peripheral T cells, including leukemia inhibitory factor, colony stimulating factor-1, IL-4 and IL-5. Together the uterine and systemic effects of P4 paint a fairly consistent picture of a Th2 bias and indirect suppression of uNK cells that promote immunologic recognition of pregnancy and tolerance. It is increasingly clear, however, that immunomodulation during pregnancy may be more complicated than the Th1–Th2 shift proposed by Wegmann,20,37–39 as evidence by marked activation (as opposed to suppression) of some components of the maternal immune system.40,41 For example, Abiraterone hCG treatment

of the baboon uterus upregulates superoxide dismutase 2 and complement component 3, to respond to oxidative stress and enhance phagocytosis, respectively.3,42 In addition, hCG binds to monocytes and increases their trafficking to the endometrium during early pregnancy and increases production of IL-8 via activation of NF-κB.43 From the standpoint of evolution, it would make sense to counter balance the immunosuppressive effects of pregnancy so as not to put the dam at greater risk of infection.44 Clearly, there is evidence that conceptus signals like hCG alter immune cell function in the uterus and peripherally.16,42 Although much work has focused on immunomodulatory mechanisms mediating fetal tolerance and maternal protection, circulating immune cells may play an active role in establishing and maintaining pregnancy.45 Using a luteal cell culture system, Hashii et al.46 showed that peripheral blood mononuclear cells (PBMC) from pregnant women increased P4, IL-4, and IL-10 production.

Limitations: This study was only a single-centre analysis of retrospective data and could be subject to selection bias. PLX4032 concentration Clinical

outcomes and quality of life in elderly patients on PD versus HD.  Harris et al.9 ran a prospective, cohort study of 174 new dialysis patients from four hospital-based renal units in London, specifically looking at an elderly cohort of 70 years and above and comparing modality outcomes. This ‘new’ patient cohort was compared with a prevalent patient cohort during the study period of 12 months. There were no significant differences in comorbidity between the PD and HD groups in new and prevalent patients. The results demonstrated no effect of modality on 12-month survival after controlling for potential confounding factors

such as patient comorbidity and included analysis of dialysis adequacy. Limitations: This was an observational cohort study of a single centre with small numbers that cannot be interpreted without considering BGJ398 price selection bias and generalizability. Thirty per cent of the dialysis population elected not to take part in the study, which could represent a participation bias and there was only a 12-month follow up. Although this study made adjustments for patient comorbid factors, the analysis did not examine specific diseases or their severity. Survival on haemodialysis and peritoneal dialysis over 12 years with emphasis on nutritional parameters.  Avram et al.2 performed a study enrolling 959 patients on HD and PD, commencing dialysis at a single centre in the United States from 1987 to 1999, to compare modality survival. This was Glutamate dehydrogenase a retrospective analysis of medical records. The cumulative survival over 12 years was

significantly higher in HD patients. This study demonstrated a 44% lower mortality risk for patients on HD compared with PD. Limitations: There were limited data on dialysis adequacy as PD adequacy was not routinely measured in the United States before 1992. A selection bias, once again, may have influenced the outcomes. There was no data adjustment for comorbid conditions other than diabetes and AIDS. Comparative mortality of haemodialysis and peritoneal dialysis patients in Canada.  Murphy et al.10 performed a prospective cohort study analysing mortality data from 822 consecutive patients commencing dialysis in 11 Canadian centres between March 1993 and November 1994. Extensive comorbidity data were collected prior to patient commencement. Average follow up was 24 months. The PD and HD patient groups differed considerably at baseline with respect to age, haemoglobin (Hb), albumin and comorbidity score (significantly higher in the HD group). Data were also obtained regarding acuity of onset of renal failure (majority in HD cohort) and severity of disease. When the mortality data for both groups were adjusted for comorbidity, survival for both groups was similar.

The cells in a volume of 50 μl were added to 96-well plates and stimulated in triplicates with heat-killed M. tuberculosis H37Rv, and cell wall (CW), and culture filtrate (CF) of M. tuberculosis [18], and purified proteins of PE35, PPE68, EsxA, EsxB and EsxV [13], at an optimal concentration of 5 μg/ml [19]. The cultures were pulsed on day 3 with 1 μCi 3H-Thymidine (Amersham Life Science, Amersham, UK), harvested 4 h later with a cell harvester and the amount of incorporated methyl-[3H] thymidine was determined using liquid scintillation counting [20]. The proliferation of spleen cells was considered positive with stimulation index (SI) > 5.0; which is defined

as: SI = average cpm in triplicate wells with antigen/average cpm in triplicate wells without antigen. Ethical approval.  Mice were immunized and handled according to established IACUC-approved protocols MG-132 solubility dmso at Kuwait University, Kuwait. DNA fragments suitable for cloning and expression of PE35, PPE68, EsxA, EsxB and EsxV genes in DNA vaccine vectors pUMVC6 and pUMVC7 AZD1208 were PCR amplified from genomic DNA of M. tuberculosis

using gene-specific primers suitable for cloning in each vector (Tables 1 and 2). The amplified DNA corresponding to the size of PE35, PPE68, EsxA, EsxB and EsxV genes were purified and ligated to pGEM-T Easy vector DNA yielding recombinant plasmids pGEM-T/PE35, pGEM-T/PPE68, pGEM-T/EsxA, pGEM-T/EsxB and pGEMT/EsxV, respectively. The analysis of DNA fragments released from the recombinant plasmids after digestion with EcoRI showed that the cloned DNA corresponded to the expected molecular size of PE35, PPE68, EsxA, EsxB of RD1 and EsxV of RD9 genes (data not shown). The Chlormezanone DNA corresponding to PE35, PPE68, EsxA, EsxB and EsxV genes from the recombinant plasmids pGEM-T/PE35, pGEM-T/PPE68, pGEM-T/EsxA,

pGEM-T/EsxB and pGEM-T/EsxV were released by restriction digestion with BamH I for pUMVC6 and BamH I and Xba I for pUMVC7, and ligated to appropriately digested pUMVC6 and pUMVC7 plasmid DNA to give rise to recombinant plasmids pUMVC6/PE35, pUMVC6/PPE68, pUMVC6/EsxA, pUMVC6/EsxB, pUMVC6/EsxV and pUMVC7/PE35, pUMVC7/PPE68, pUMVC7/EsxA, pUMVC7/EsxB and pUMVC7/EsxV, respectively. The identity of each cloned gene was confirmed by restriction digestion of recombinant plasmids with the restriction enzymes BamH I for pUMVC6; and BamH I and Xba I for pUMVC7, which released the cloned DNA corresponding to the size expected for each gene (data not shown). To study the immunogenicity of the RD1 PE35, PPE68, EsxA, EsxB and RD9 EsxV proteins in mice, studies were performed with the recombinant DNA vaccine constructs of pUMVC6 and pUMVC7 expressing the RD1 and RD9 proteins.

As shown in blood glucose reading (Fig. 7A) and tumor weight (Fig. 7B), anti-CTLA4 treatment effectively promoted the antitumor activity of the self-antigen-specific Teff cells by overcoming Treg cell-mediated suppression. Flow cytometry analysis Z-VAD-FMK supplier of the anti-CTLA4-treated and control animals demonstrated

that CTLA4 blockade had impacted both Teff and Treg cells in various lymphoid organs, resulting in a substantially skewed ratio of Treg:Teff cells (Fig. 7C–E). This dual effect of anti-CTLA4 antibody blockade was distinct from that by a subtle CTLA4 reduction (Fig. 5). Nonetheless, the results collectively establish a predominant role of CTLA4 in suppressing autoimmunity-mediated antitumor immunity at the tumor site. Evidence from previous studies with animal models has suggested that immune tolerance can preferentially distinguish healthy tissues from malignant cells expressing the same antigens [21-23]. Those results Maraviroc are consistent with the hypothesis of cancer immune surveillance. However, recent clinical trials of immunotherapies in general have not demonstrated a therapeutic effect against cancers in the absence of substantial off-target autoimmune toxicity [3-6]. Instead, observations from the clinical trials ostensibly highlighted

autoimmunity as a potential “double-edged sword” against tumors as well as healthy cells. Mechanistic studies with animal models are needed to dissect the autoimmune implications identified in the clinical setting. In a melanoma model, the efficacies of self-antigen-specific T cells in antitumor immunity have been well studied by using CD4- and CD8-restricted TCR-transgenic models [38, 39]. Perhaps due to the clonal nature of the antigen-specific T cells, those transgenic models did not develop spontaneous autoimmunity. Clomifene Our study, aided with a battery of well-characterized

models of autoimmunity, aimed to understand how T-cell clones with a potential of spontaneous autoimmunity function in tumor settings versus healthy tissues. Indeed, self-antigen-specific Teff cells could eradicate tumor cells. However, findings with the self-antigen-specific T cells also revealed a tumor microenvironment that is more tolerogenic than healthy tissues, that is, the tumor sites akin to an “immunoprivileged” environment that effectively inactivates autoimmune effectors. This is not merely because tumor cells might proliferate faster than healthy cells. Activated T cells can multiply at a rate on par with even a highly proliferative tumor cell. Indeed, as our study demonstrated, in the absence of Treg cells, Teff cells completely destroyed both tumor and healthy cells in the same animals. Tumor-mediated immunosuppression is a generally recognized obstacle for antitumor immunity. It has been debated whether and to what extent the suppression is systemic or limited to the site of tumor.