38 μg mL−1, Super 1) cultures induced increased (P<0.01) candidacidal activity (23%) in macrophages compared with the candidacidal activity of macrophages treated with

control (PBMC without 3M-003) supernatants (Fig. 4). IFN-γ treatment of macrophages induced significantly (P<0.01) increased killing of C. albicans (37%) (Fig. 4). Similar results were obtained in another experiment where Super 1 and Super 3 (3 μM=1.14 μg mL−1), and IFN-γ at 1000 and 250 U mL−1, all increased (P<0.01) macrophage candidacidal activity compared with killing by control macrophages. When supernatants from PBMC+3M-003 Selleck PI3K Inhibitor Library (3 μM) cultures were incubated with monocytes, the candidacidal activity of monocytes was significantly (P<0.05) increased, to 20%, compared with monocyte killing of C. albicans by monocytes treated with control (PBMC without 3M-003) supernatants (Fig. 5). IFN-γ (250 U mL−1) treatment of monocytes also induced increased (P<0.05) learn more monocyte candidacidal activity (23%) (Fig. 5). In another experiment, supernatants from PBMC+3M-003 (3 μM, Super 3), but not Super 1 (1 μM), again increased (P<0.05) monocyte killing of C. albicans. IFN-γ (1000 U mL−1) treatment of monocytes also increased (P<0.01) the candidacidal activity of monocytes. Neutrophils were treated with supernatants from PBMC+3M-003 (1 and 3 μM, Super 1 and Super 3) cultures. Super 1 and Super 3 treatments significantly (P<0.01) increased neutrophil killing of C. albicans to

73% and 66% respectively, compared

with neutrophils treated with control supernatants (42%) (Fig. 6). Moreover, IFN-γ (250, 500, 1000 U mL−1) treatment of neutrophils significantly enhanced (P<0.01) the candidacidal activity of neutrophils to 68%, 73%, 88%, respectively, compared with control neutrophils (Fig. 6). In a second experiment, we found that supernatants from PBMC+3M-003 (3 μM) cultures or IFN-γ (250 U mL−1) treatment of neutrophils significantly (P<0.01) increased the candidacidal activity of neutrophils compared with killing of C. albicans by neutrophils treated with control (PBMC with no 3M-003) supernatants. The signaling pathway of imiquimod and related imidazoquinolines in a variety of immune and other cell types check through TLR-7 and TLR-8 is being defined. It involves MyD88, IRAK, TRAF6, nuclear factor-κB (NF-κB), and MAPK (Bottrel et al., 1999; Hurwitz et al., 2003; Akira & Takeda, 2004; Uematsu et al., 2005). By activation, in cells of the innate immune response (monocytes, macrophages, and dendritic cells) (Garland, 2003), of various downstream pathways, and not by direct action on T cells, these agents result in the induction of cytokines and chemokines, for example IFN-α, IFN-γ, G-CSF, GM-CSF, IL-1, MIP-1, MCP-1, TNF-α, IL-6, IL-8, IL-10, and IL-12 (Bottrel et al., 1999; Wagner et al., 1999; Dahl, 2002; Harandi et al., 2003; Gupta et al., 2004; Caron et al., 2005; Uematsu et al., 2005). This polarizes toward a T helper type 1 response.

We showed here that continuous presence of TGF-β was required following restimulation to maintain the inducible binding activity of the PcG protein Mel-18 at the Il17a promoter. In its absence, the binding of Mel-18 18 h following restimulation was comparable to that in resting cells. However, TGF-β

was not sufficient to induce the binding activity of Mel-18 at the Il17a promoter in the absence of TCR stimulation. Therefore, signaling pathways downstream to the TCR and polarizing cytokines synergize to induce and maintain, Selleck CB-839 respectively, the binding activity of Mel-18 at the Il17a promoter, and consequently to promote its expression. Eighteen hours following restimulation, the downregulation in the expression of the Th17 cytokines and transcription factors was IL-12-independent. IL-12 was more important for the upregulation of the expression of the Th1 key genes Tbx21 and Ifng. In accordance with that, IL-12 only modestly increased the detachment of Mel-18 from the Il17a promoter. It was previously shown that the differentiation of Mel-18-deficient CP-690550 research buy Th2 cells is impaired 73. Our recently published results demonstrated that PcG proteins positively regulate the expression

of the signature cytokine genes in Th1 and Th2 cells 74. The knockdown experiments here showed that Mel-18 positively regulates the expression of Il17a in restimulated Th17 cells. Considering that: (i) Mel-18 was associated with Il17a in correlation with gene expression and (ii) its binding was regulated synergistically by signaling pathways crucial for Il17a expression – our results support the idea that Mel-18 functions directly to increase Il17a expression, but indirect effects cannot be excluded. The binding activity of Ezh2 at the Il17a promoter was dependent on signaling pathways downstream to the Methane monooxygenase TCR, but in 18 h-restimulated Th17

cells the binding was TGF-β independent. Yet, knockdown of Ezh2 resulted in the downregulation of Il17a. Since Ezh2 is associated with Il17a promoter, a direct regulation of Il17a expression is suggested. However, as with Mel-18, it is also possible that Ezh2 indirectly regulates the expression of Il17a, for example by modulating the TCR signaling pathway; Ezh2 interacts with Vav 75 and is involved in actin polymerization 76. Ezh2 may also have a context-dependent functional role at the Il17a gene; it can function as transcriptional activator in the presence of Mel-18 but following its removal in the absence of TGF-β, Ezh2 may turn into a conventional PcG repressor. It was shown indeed that H3K27me3 is increased at the Il17a promoter in the presence of IL-12 and absence of TGF-β 42. However, this change requires a longer kinetics of 48 h, and therefore it was suggested by the authors that this is probably not the earliest event that initiates the repression of Il17a.

The resultant final diagnosis was enteric hyperoxaluria complicated by an acute irreversible oxalate nephropathy. Management

consisted of a low-oxalate diet and intensification selleck kinase inhibitor of pancreatic enzyme supplements to limit malabsorption. In addition, calcium carbonate and subsequently Sevelamer were added in order to reduce the enteric absorption of oxalate. Reduction in systemic oxalate load was attempted by the use of daily haemodiafiltration via a tunnelled internal jugular catheter and it is notable that he did not suffer any systemic manifestation of oxalate deposition such as heart block, arthropathy or neuropathy. The patient was managed as an outpatient and received tacrolimus, mycophenolate and steroids

and remained free of pulmonary rejection with Forced expiratory volume (FEV1) maintained above 3.0 L. The patient was distressed and angry at the need for regular haemodialysis and the impact it made on his life despite the renewed benefit of his lung transplantation. Options for renal transplantation were considered and his mother was assessed as a potential kidney donor. Ten months post lung transplant he underwent a renal transplant with Basiliximab and methylprednisolone induction with maintenance of standard tacrolimus RAD001 in vivo and mycophenolate dosing. There was immediate graft function and no complication. Calcium and Sevelamer supplementation were initially ceased, but were recommenced because of early hyperoxaluria with restoration of adequate glomerular

filtration and tubular flow. The patient was advised to maintain a urine output of 3 L a day (see Fig. 3). SPTLC1 Urinary oxalate excretion was monitored regularly in order to adjust pancreatic supplementation and oral oxalate binders. Initially very high levels may have reflected an elevated systemic burden and it is notable the urinary oxalate declined to the normal range after 3 months. A 2-week post-transplant renal biopsy showed no evidence of recurrent oxalate deposition. In the months following his renal transplant, intermittent episodes of diarrhoea related to antibiotics or mycophenolate use precipitated episodes of acute renal failure. However, these diarrhoeal episodes improved on switching mycophenolate to azathioprine. At 8 months post renal transplant he has a creatinine of 122 µmol/L with an eGFR of 60 mL/min per 1.73 m2. His lung function remains stable and he is gainfully employed as an electrician. Oxalate is a ubiquitous molecule found in the soil and taken up by plants and vegetables such as spinach, rhubarb and nuts. Concentrations in foods vary widely depending on the soil and water conditions they were grown in, making quantification in feeds difficult. Approximately2 20–40% of oxalate is obtained from the diet where it is absorbed in the colon.

However, CD62L is reported to be more strongly expressed on CD56bright NK cells 29, 37. A lower expression of the adhesion molecule CD62L could be substituted by the expression of other receptors. This can also be suggested for CCR7, which is expressed on human CD56bright NK cells but not CD56dim NK cells. CCR7 was not detected on any murine NK-cell population, illustrating the limits in comparability of murine and

human NK cells (23, 38 and data not shown). Utilization of certain markers for in vivo and in vitro studies is limited by expression stability. For instance, activation of human NK cells results in upregulation of CD56, which impairs the distinction of activated CD56dim NK cells from resting CD56bright NK cells 15, 39. We demonstrated downregulation of CXCR3 on CXCR3+ NK cells upon activation. find more Rapid ligand-induced internalization and degradation of CXCR3 as well as its de novo synthesis has been reported for both NK and T cells 40, 41. A physiological role of changes in CXCR3 expression DAPT chemical structure during maturation and trafficking of NK cells was suggested based on in vitro and in vivo data 41, 42. Notably, culture of sorted CXCR3− NK cells induced expression of this marker. The neCXCR3+ NK-cell population expressed CD27 at lower density than fresh CXCR3+ NK cells and therefore did not completely

correspond to resting CXCR3+ NK cells. Sorted human CD27+ NK cells lost CD27 expression upon stimulation with IL-15, and this new CD27− subset was highly cytotoxic 25. Importantly, CXCR3+ NK cells that downregulated CXCR3 expression in our experiments displayed stronger degranulation than sCXCR3+ NK cells. Plasmin Thus, the phenotype still correlated with the capacity to kill target cells. However, if and to what degree expression changes also occur in vivo has to be determined. CXCR3 downregulation can be assumed at least for tumor-infiltrating NK cells 28. Regarding the maturation level of the NK-cell subsets, analyses of CD11b expression revealed an immature phenotype of a fraction of CXCR3+ NK cells. Recent studies showed that KLRG1 is acquired by

developing NK cells, which are entirely CD27−43. CD27− NK cells never expressed CXCR3, supporting the suggestion that CXCR3− display a more mature NK-cell subset. However, as already discussed by Di Santo 44, “immature” NK cells may mediate effector functions different from those of their “mature” counterparts. CXCR3 is essential for recruitment of NK cells in response to infection, therefore it is very likely that CXCR3− and CXCR3+ NK-cell subsets fulfil different functional roles in the immune system. To clarify whether or not murine CXCR3− and CXCR3+ NK cells differ in their functional characteristics like human CD56dim and CD56bright NK cells, we determined proliferative capacity, cytolytic activity, degranulation and cytokine production of the NK-cell populations in response to physiological stimulation.

Treatment with ONO significantly recovered the levels of matrix Gla Protein and Fetuin-A suppressed by adenine-induced CKD, and suppressed the overexpression of RUNX2 in the VSMC of the thoracic aorta (immunohistochemistry). In addition, DHE expression, a marker of oxidative stress, BAY 57-1293 supplier was highly expressed in the VSMC of the thoracic aorta by adenine-induced CKD, and was significantly reduced by treatment with ONO. Conclusion: Taken together,

these results suggest the protective role of ONO on vascular calcification via regulating the factors involved in calcification and oxidative stress in the experimental CKD model. KATO SAWAKO1, MARUYAMA SHOICHI1, MAKINO HIROSHI2, WADA JUN2, UZU TAKASHI3, ARAKI HISAZUMI3, KOYA DAISUKE4, KANASAKI KEIZO4, NISHIYAMA AKIRA5, IMAI ENYU6, ANDO MASAHIKO7, MATSUO SEIICHI1 1Nagoya University Graduate School of Medicine; 2Okayama University

Graduate School of Medicine; 3Shiga University of Medical Science; 4Kanazawa Medical University; 5Kagawa University; 6Nakayama-temple Imai Clinic; 7Center for Advanced Medicine and clinical Research, Nagoya University Hospital Introduction: Several studies have demonstrated that spironolactone has anti-albuminuric function in diabetic nephropathy. But it has been still BMS-777607 unknown if spironolactone has an additional renoprotective effect. We therefore aimed to evaluate the changes of clinical biomarkers related to kidney as well as albuminuria to add spironolactone on conservative treatment with renin angiotensin system (RAS) blocking drugs. Methods: Forty-nine

Japanese patients with diabetic nephropathy and albuminuria (from 100 mg/gCr to 2000 mg/gCr) using RAS-blocking treatment were enrolled in prospective, randomized, open-labelled study. Patients were treated with additional spironolactone 25 mg once daily and matched control for 8 weeks. Results: Albuminuria ZD1839 was reduced by 33% (95%CI 22–54; P = 0.0002) during treatment with spironolactone. When adjusted by blood pressure and eGFR, treatment of spironolactone still showed significant effect on reduction of albuminuria (P < 0.004). There was a tendency to increase in serum aldosterone levels during the spironolactone treatment, but there was no additional impact on albuminuria by spironolactone treatment in patients with higher concentrations of aldosterone (P = 0.608). Spironolactone treatment induced significant decrease in urinary excretion of beta2-microglobulin, N-acetyl-beta-D-glucosaminidase and angiotensinogen by 2.3 ± 6.5 U/gCr, 1026.9 ± 3174.6 mg/gCr and 156.7 ± 466 mg/gCr compared to group C (P = 0.0304, 0.029 and 0.

edu.au Administrative Officer Ms Anna Golebiowski Email: [email protected] SCIENTIFIC PROGRAMME AND EDUCATION COMMITTEE A/Professor Kevan Polkinghorne (Chair) Dr Nicholas Cross A/Professor Glenda Gobe Dr Nicholas Gray Dr Sean Kennedy Dr Vincent Lee A/Professor Wai Lim A/Prof Dr Rangan A/Professor Sharon Ricardo Dr Matthew Roberts Dr Girish Talaulikar A/Professor Angela Webster LOCAL ORGANISING COMMITTEE Dr Matthew Roberts (Chair) A/Prof Eugenie Pedagogos Dr Trung Quach Dr Veena Roberts Prof Rowan Walker PROFESSIONAL CONFERENCE ORGANISER Arinex Pty Ltd 91–97 Islington Street Collingwood Victoria 3066 Australia

ABN 28 000 386 676 Website: http://www.arinex.com.au 2014 VISITING LECTURERS Associate Professor Angela Wang Associate Consultant Nephrologist, Queen Mary Hospital, Hong Kong Honorary Associate Professor, University of Hong Kong Visiting Professor find more of Nephrology at the Macau Institute of Applied Research in Medicine and Health, University of Science https://www.selleckchem.com/products/Metformin-hydrochloride(Glucophage).html and Technology Professor Robert Unwin Head

of the University College London Centre for Nephrology, Royal Free Campus Head of the Research Department for Internal Medicine, Division of Medicine, University College London Medical School Professor Rolf Stahl Chairman of the III. Medical Clinic of the University Hospital in Hamburg, Germany 2014 ANZSN SOCIETY SPONSORS Platinum Sponsors Amgen Australia Pty Ltd Fresenius Medical Care Australia Roche Products Pty Ltd Gold Sponsors Baxter Healthcare Pty Ltd/Gambro Pty Ltd Novartis Pharmaceuticals Cyclooxygenase (COX) Australia Pty Ltd Shire Australia Pty Ltd Silver Sponsor Sanofi Australia

and New Zealand Bronze Sponsor Servier Laboratories Australia Pty Ltd “
“We are very proud to inform all our readers that we are presenting the proceeding of the 17th Japanese Clinicopathological Conference of Renal Allograft Pathology, held on 20 July 2013 in Tokyo, Japan. A total of 154 clinicians (nephrologists, transplant surgeons) and pathologists attended the meeting and vigorously discussed a variety of issues related to kidney allograft disorders. Selected issues have been included as a supplement of Nephrology. The theme of the conference was ‘crosstalk between transplant pathologists and clinicians including transplantation surgeons and transplant nephrologists’. Three papers were presented for discussion for each of the following topics: T cell-mediated rejection or focal segmental glomerular sclerosis; antibody-mediated rejection; microvascular injury; BK virus nephropathy; and recurrent glomerular nephritis, such as IgA nephropathy or Henoch-Schönlein purpura nephritis. Nine other papers about interesting case reports were presented during the poster session. Finally, two very interesting cases from the poster session were also presented in live sessions using a high-resolution virtual slide system to ensure the audiences had access to thorough pathological information.

parvum and cultured with oocyst antigen demonstrated an increased induction of T cell proliferation and cytokine production (24,25).

In addition, NVP-AUY922 the observations pertaining to T cell responses to recombinant peptides have also been made elsewhere (26). Bonafonte et al. (6) showed specific proliferative responses in splenocytes and mesenteric lymph node (MLN) from infected BALB/c mice to a 23-kDa recombinant protein of C. parvum. Gomez Morales et al. (25) described proliferation of human PBMC with a 190-kDa recombinant antigen of C. parvum. Depending on the nature of the antigens that immune system encounters, CD4+ T helper (Th) cells may induce a cell-mediated immune response (Th1) or antibody-mediated response (Th2). These diverse Th responses are determined by the spectrum of cytokines produced by the T cells themselves and by the antigen-presenting cells. To study further the CD4+ T cell immune response to elucidate the possible mechanisms, we checked the production of Th1 cytokines (IFN-γ and IL-12) and Th2 cytokine (IL-4) induced by these antigens. We found that IFN-γ and IL-12 were induced

significantly after stimulation of the rCp15–23 antigen and that IL-4 could not be detected in all the cases. It is reported that IFN-γ is important for the expression of partially protective innate immunity against the parasite and in the T cell-dependent resolution of an infection (27–29). The development of a T cell-mediated control of infection has been correlated with the increased production of IFN-γ in spleen cells that were predominantly CD4+ (24,30). Moreover, it has been shown find more that intraepithelial lymphocytes of the gut, which are predominantly T cells, produce immunity against Cryptosporidium infection

via a mechanism involving IFN-γ production (31,32). Although interferon gamma expression is strongly associated with control of cryptosporidiosis, the involvement of IL-12 in protection against C. parvum was also observed (33). Strong expression of IL-12 mRNA in the intestines of neonatal BALB/c mice during C. parvum infection was allied to early control of infection (34). IL-12 is expressed while a Th1 response develops during a primary C. parvum infection and in mice plays an important part in inducing IFN-γ expression required for early parasite Fossariinae clearance. A previous study (35) suggested that the most effective Th response to control cryptosporidial infection might be a dynamic one in which there was a strong early Th1 response, but the later maturation of a more-balanced response with a Th2 component might facilitate parasite removal. Experimental studies have produced contrasting reports regarding the roles of the Th1 and Th2 cytokines. IL-4 is the main Th2 type cytokine. Investigations on the involvement of IL-4 in immunity against C. parvum infection have produced conflicting conclusions.

It is theoretically possible that the differences in the prevalence of nonneutral CDR-H3s observed in the mature, recirculating B-cell pool reflect the changes in the complement of VH in C57BL/6 B cells when compared to BALB/c B cells. However, in previous studies of BALB/c mice, we have shown that changes in the global repertoire of CDR-H3 due to changes in DH content had no effect on VH utilization [17, 19, 21]. Thus, this possibility seemed less likely in C57BL/6 see more mice.

One of the first, critical somatic, clonal selective steps in repertoire development depends on the interaction between the H chain and the surrogate light chain λ5 and VpreB [22, 23]. Successful passage through this checkpoint permits BGB324 clinical trial early pre-B fraction C cells to clonally expand and then transition to the late pre-B-cell fraction D stage at which light chain rearrangement occurs. Most of the selective influences that we had observed in developing BALB/c B lineage cells during this transition were also apparent in developing C57BL/6 B lineage cells. This included a decline in the use of VH81X, a decrease in the use of DH RF2 with a compensatory increase in the use of RF1, and a stabilization of average length and average charge

[8]. The latter two values in particular were indistinguishable between BALB/c fraction D and C57BL/6 fraction D (Fig. 4), suggesting that both mouse strains share similar preference for mechanistic regulation at the step where the interaction between the nascent heavy chain and the surrogate light chain components determine the efficiency Acyl CoA dehydrogenase of pre-BCR formation. For reasons unknown, BALB/c mice carrying the μMT mutation are leaky and can produce some B cells while C57BL/6 mice with

the same mutation are not leaky and do not produce B cells suggesting a different timing in the B-cell generation process [24]. Thus it is possible that differences in the timing of Dμ protein or pre-B-cell receptor expression between the two strains could have a downstream effect on repertoire development. A second selective step is the testing of the reactivity of the nascent IgM in fraction E. Failure at this step can lead to receptor editing, anergy, or cell death, reducing the likelihood of entry or survival of cells bearing “disfavored” IgM in the fraction F pool. Nussensweig et  al. have clearly demonstrated that this step selects against potentially pathogenic self-reactivity [25]. CDR-H3 sequences obtained from C57BL/6 fraction E cells showed a significant difference in the average hydrophobicity compared to BALB/c fraction E cells suggesting a difference in the intensity or consequences of self-antigen recognition at that stage between the two strains (Fig. 4B).

, 2007). These dosages can be achieved in the sputum by local administration by inhalation of, for example, colistin (Ratjen et al., 2006), tobramycin (Ratjen et al., 2009), aztreonam (Wainwright et al., 2011) and, in the future, fluoroquinolones (Geller et al., 2011). Combination antibiotics with compounds that

disrupt the biofilm structure is another therapeutic option suggested from in vitro studies. As DNA is an important part of the extracellular matrix of P. aeruginosa biofilms (Whitchurch et al., 2002), treatment with DNAase or alginate lyases might improve the penetration of antibiotics into the biofilm, improving the effect of the drugs, as suggested by in vitro studies (Yang et al., 2010). In addition, combination with macrolides, such as azitromycin, was introduced at the Copenhagen CF Centre in 2001 with good clinical effects (Hansen et al., 2005) as experienced in other CF centres PXD101 clinical trial (Saiman et al., 2003). The effect is considered to be multifactorial, also involving an antibiofilm effect, related to: (1) inhibition of

quorum sensing, as quorum sensing has been shown to be important for antibiotic tolerance to biofilms (Bjarnsholt et al., 2005); (2) the anti-inflammatory effect; and (3) alginate inhibition (Hansen et al., 2005). For treatment of heterogeneous CF P. aeruginosa populations, a combination of local therapy, such as inhalation devices for sinuses (Pari-sinus nebulizer) and for the conductive zones of the lungs (Heijerman et al., 2009) as well as systemic therapy to reach the respiratory zones of Talazoparib in vitro the lung is recommended (Doring et al., 2000; Hoiby et al., 2010). A pharmacogenetic tailored dosage will probably improve the efficacy of Neratinib clinical trial antimicrobials in the CF population. Fast metabolizers would require higher or more frequent antibiotic administrations to reach the PK/PD targets of efficacy and to avoid resistance development. In conclusion, biofilm formations can be prevented by early aggressive

antibiotic prophylaxis or therapy, and they can be treated by chronic suppressive therapy with combination therapy with pairs of antibiotics with synergistic activities on biofilms. “
“Complement receptors for C3-derived fragments (CR1–4) play critical roles in innate and adaptive immune responses. Of these receptors, CR3 and CR4 are important in binding and phagocytosis of complement-opsonized pathogens including parasites. The role of CR3 and CR4 in malaria or in cerebral malaria (CM) has received little attention and remains poorly understood in both human disease and rodent models of malaria. CR3 and CR4 are members of the β2-integrin family of adhesion molecules and are expressed on all leucocytes that participate in the development of CM, most importantly as it relates to parasite phagocytosis (monocytes/macrophages) and antigen processing and presentation (dendritic cells).

8,9 The T reg cells function to dampen immune responses through a variety of approaches, including contact-mediated inhibition, secretion of perforin and granzyme A/B, sequestration of key growth factors such as IL-2, and secretion of suppressive cytokines including TGF-β, IL-10 and IL-35.7 Interleukin-10 in particular plays an important role in immune homeostasis, both in mice10 and humans,11 suggesting that it has several non-redundant Pritelivir chemical structure roles in regulating inflammatory responses. Many cell types in addition to Foxp3+ cells12 can produce IL-10, most notably several lineages of CD4+ T cells,13 including Th1,14–16 Th214,17 and Th1718–20

cells, as well as various types of Treg cells.21 In a feed-forward mechanism, IL-10 can drive its own expression through the induction of an IL-10-producing Treg-cell population termed Tr1 cells.22,23 Conversely, IL-10 can also be induced independently of IL-10 signalling in both Foxp3+ and Foxp3− Treg-cell populations.24 Given its potent anti-inflammatory effects, various strategies are being explored to target IL-10 for therapeutic intervention.25 The intimate interplay between the critical factors in development

of Treg and Th17 cells, along with the dual reliance on TGF-β signalling for PD98059 cell line their differentiation,26 has led to conceptualization of a Treg–Th17 axis. From a therapeutics perspective, the identification of drugs that promote pro-inflammatory or anti-inflammatory responses by influencing differentiation along this axis has gained momentum as examples of T-cell plasticity continue to be characterized,27 in particular within the Treg-cell and Th17-cell populations.28 Moreover, several reports have characterized ‘hybrid’ T-cell populations where Foxp3 is expressed in various effector T-cell populations,29 and IL-10

can be produced by Th1, Th2 and Th17 cells.12 These results Orotidine 5′-phosphate decarboxylase suggest that it may be possible to treat disease by shifting the balance along the Treg–Th17 axis in situ during ongoing immune responses. For example, one mechanism to dampen inflammation would be to induce IL-10 expression within Th17 cells participating in pathological inflammation. To that end, targeting non-cytokine signalling pathways may be a viable option. For example, ATP,30 sphinogosine-1-phosphate31 and vitamin D32 can modulate Th17 development, whereas antigen-presenting cell (APC)-derived indolamine 2,3-dioxygenase33 and retinoic acid34 can promote Treg-cell populations, highlighting the importance of non-cytokine signalling pathways to this paradigm. Estrogen is a well-documented modulator of immune function in humans and mice, capable of increasing the expression of Foxp335 and IL-10.