Other studies show that balneotherapy with Dead Sea salt solution soaks in combination with NB-UVB therapy is superior to NB-UVB therapy alone [24, 25], which could be attributed to increased photosensitivity of the skin to UV radiation [26, 27]. We do not think that explains the results in our study for two reasons. As mentioned above, there are studies showing GPCR Compound Library ic50 that bathing in the geothermal seawater without NB-UVB treatment has a beneficial clinical effect [1, 2]. In

addition, the cumulative dose of NB-UVB therapy in this current study was only 10 treatment sessions for patients bathing in geothermal seawater combined with NB-UVB therapy compared with 24 sessions for patients treated with NB-UVB therapy alone. However, the agents responsible for learn more these beneficial effects of bathing in saline or thermal water have not been fully elucidated but most likely involve chemical [26, 28, 29], thermal [30], mechanical [2] and immunomodulatory effects [28, 31]. Furthermore, studies have shown that bathing in salt solutions has been associated with increased photosensitivity of the skin to UV radiation [26, 27]. Even though balneotherapy

and spa therapy are widely used, the immune modulatory mechanisms are only partly understood. Few studies have shown immunomodulatory effects on epidermal Langerhans cells, inhibition of Th1 differentiation and cytokine production from keratinocytes [28, 31]. One recent study from Korea [32] showed that thermal spring water

suppressed the expression of pro-inflammatory cytokines in human keratinocytes ‘in vitro’ as well as the differentiation of mouse CD4+ T cells into Th1, Th2 and Th17 cells. CCR4 has been found to be abundantly expressed on circulating T cells with a skin-homing CLA+ phenotype [33] in normal subjects as well as in patients with psoriasis [34], which is consistent with our results. In contrast, CCR10 and CD103 are weakly expressed in the peripheral blood of normal subjects and nearly undetected in normal skin [35, 36]. In addition, CCR10 is expressed by a minority (approximately 30%) of circulating CLA+ T cells [37]. However, both CCR10 and CD103 Sitaxentan have been found in the inflamed psoriatic lesions [35, 36]. Their involvement in the immunopathogenesis of psoriasis is further suggested by our findings demonstrating the increased proportion of circulating skin-homing CLA+ T cells co-expressing the tissue retention integrin CD103 and/or the chemokine receptors CCR4 and CCR10. More importantly, they had a positive correlation with the clinical improvements observed in the study, thus implicating the role of directing CCR4+/CCR10+ and CD103+ subset of skin-homing T cells (CLA+) into psoriasis plaques during the active stage of the disease. CLA+, CD103+ T cells, various adhesion molecules as well as activation markers did not change significantly during or after both treatment protocols.

BrdU staining was performed with the APC BrdU Flow Kit (BD Biosciences) according to manufacturer’s protocol. Flow cytometric analysis was performed on an LSR II cytometer (BD Bioscience) equipped with the BD FACSDiva software. Post acquisition analyses were conducted using the FlowJo software (Treestar). Total RNA was isolated using the RNeasy Mini Kit (Qiagen) from 6×105 FACS-sorted GFP+ Treg cells, purity >95%, from either 2 WT or 2 OT-II donors per experiment. cDNA templates were synthesized

using SuperScript® II reverse transcriptase (Invitrogen) according to manufacturer’s recommendation. To MAPK Inhibitor Library ic50 generate template libraries of rearranged TCR CDR3 regions from Treg-cell cDNA for the Genome Sequencer selleck chemical FLX System (454 sequencing, Roche), we used primers spanning the variable region between constant Cα and V elements of the Vα8 family (comprising TRAV12-1*01, TRAV12-1*03, TRAV12-1*04, TRAV12-1*05, TRAV12D-2*01, TRAV12D-2*02, TRAV12D-2*03, TRAV12D-2*04, TRAV12D-2*05, TRAV12D-3*01, TRAV12D-3*02, and TRAV12D-3*03). (For primers and PCR conditions please see Supporting Information Table 1.) Forward and reverse primers contained at their 5′ ends the universal adapter sequences and a multiplex identifier (MID) respectively. Amplicons were purified by agarose gel electrophoresis and QIAquick Gel Extraction Kit

(Qiagen), and quantified by Quant-iT™ dsDNA HS Assay Kit (Invitrogen). Single PCR amplicon molecules were immobilized onto DNA Capture Beads within an oil–water emulsion to enable clonal amplification in a second PCR process with universal primers. The emulsion was then disrupted and isolated beads were loaded onto PicoTiterPlates. Sequencing reactions were performed by ultra-deep 454 pyrosequencing on the Genome Sequencer FLX system (Roche Applied Cepharanthine Sciences). Productive rearrangements and CDR3α regions were defined by comparing nucleotide sequences to the reference sequences from IMGT®, the international ImMunoGeneTics information system®

(http://www.imgt.org) 33. Rearrangements were analyzed and CDR3α regions were defined using IMGT/HighV-QUEST 57. For transfers of purified cell populations, suspensions from pooled spleens and lymph nodes (inguinal, brachial, axillary, submandibular, and mesenteric) were enriched by magnetic beads (CD4+ T Cell Isolation Kit, MiltenyiBiotec) and subsequently sorted into Foxp3+ and Foxp3− cells by FACS. 4×106 or 2×106 of either Foxp3+ or Foxp3− sorted cells, 1×107 unpurified pLN or mLN cell suspensions, or 1.1×107 enriched CD4+ cells from Foxp3.LuciDTR-4 donors were resuspended in 150 μL PBS and injected into the lateral tail vein of indicated recipient mice. After 9 wk, mice were sacrificed and pLN, mLN, spleen, and the small intestine were taken to recover and analyze transferred Treg cells identified by congenic markers and GFP reporter fluorescence. Mice were imaged 5 min after i.p. injection of 4.

Proteinuria, anti-dsDNA autoantibodies and immune complex deposits could not be detected in young (2 months old) mice. CD74 acts as a mediator of B-cell proliferation and survival by initiating a signalling cascade following

MIF binding.17,19 We therefore determined the CD74 mRNA levels in B cells from 8-month-old SLE-afflicted mice with established disease (defined as 100%) in comparison with its levels in B cells from 2-month-old young, healthy control mice. As shown in Fig. 1(a), click here CD74 mRNA levels were significantly elevated in the B cells of SLE-afflicted mice compared with its levels in the cells of young mice. The levels of CD74 in B cells of mice with SLE were further determined at the protein level by Western blotting. The results of a representative blot of CD74 from three experiments performed are presented in Fig. 1(b). CD74 protein levels were elevated in B cells derived from SLE-afflicted mice compared with those of young healthy controls. CD44 was found to be essential for the MIF-induced signalling cascade.22,23 It was of interest to determine whether the expression of CD44 required for the CD74-induced cascade19 is also up-regulated in the SLE-diseased mice and whether their ligand, MIF, is similarly affected. Furthermore, the ability of hCDR1 to immunomodulate the latter molecules was studied. To this end, RNA was extracted from purified spleen-derived B cells of mice

from vehicle, hCDR1 or control peptide-treated Selleck BYL719 Branched chain aminotransferase mice, obtained at the end of the experiments, and was examined by real-time reverse transcription-PCR. Figure 2 presents the percentage gene expression of MIF and its receptor complex components (CD74 and CD44) in the three treatment groups. The figure shows that treatment with hCDR1 significantly down-regulated the expression levels of

the studied molecules, whereas treatment with the control peptide either did not affect their expression or slightly up-regulated the expression (in the case of MIF). Western blot analysis, shown in Fig. 3(a), confirmed that, in agreement with the mRNA expression levels, treatment with hCDR1 resulted in reduced expression of CD74 protein in B lymphocytes, compared with the expression of the latter in vehicle and control peptide-treated mice. We also examined the cell surface expression of the receptor complex components CD74 and CD44 on B cells from spleens of BWF1 mice that were treated with hCDR1 or vehicle only, using flow cytometry. As shown in Fig. 3(b), B cells derived from hCDR1-treated mice expressed lower cell surface levels of CD74 (13·8%) and CD44 (30·4%) compared with B cells from the vehicle-treated mice (23·8% and 39%, respectively). Figure 3(c) shows the significant down-regulation in the mean percentage change, determined in three individual experiments, of surface expression of CD74 and CD44 in B cells from SLE-afflicted mice following hCDR1 treatment compared with vehicle-treated mice.

Membrane-type-1 matrix metalloproteinase (MT1-MMP) belongs to a group of six membrane-bound MMPs and it is expressed on endothelium, myeloid cells and lymphocytes. It is thus an ectoenzyme cleaving cell-surface adhesion molecules. Shedding of

adhesion molecule CD44 by MT1-MMP renders the cells more motile 3. Cleavage of ICAM-1, on the other hand, is thought to regulate the transmigration process. In addition to adhesion molecules, MT1-MMP also cleaves and thus inactivates chemokines such as CCL7 and CXCL12 64. Overall, the sheddases importantly contribute to the extravasation process by trimming both adhesion molecules and chemokines. Most likely they also degrade extracellular matrix molecules facilitating leukocyte movement within selleck the tissues. Manipulation of purinergic signaling provides a possibility to temper inflammation without interfering with the classical chemokine and cytokine this website signals 39. The beneficial role of adenosine, a powerful inhibitor of inflammation and vascular

leakage, has been demonstrated in clinical settings by infusing it in ischemia-reperfusion injuries; however, due to the short half-life (<10 s) its clinical use is not feasible. Therefore, the generation of endogenous adenosine through the induction of CD73 provides an attractive alternative. IFN-β induces CD73 expression and enzymatic activity on endothelial cells but not on leukocytes or cancer cells and IFN-β has protective effects in animal models of acute BCKDHA lung inflammation 46. Promising results have also very recently been reported in clinical trials of acute lung injury and acute respiratory distress syndrome, in which IFN-β significantly decreased the mortality (http://www.faronpharmaceuticals.com). IFN-β therapy also increases

levels of endothelial CD73 and soluble CD73 in the serum in multiple sclerosis patients, and these parameters associate with the clinical response 65. Thus, it may be envisioned that IFN-β-induced, CD73-mediated adenosine production contributes to the improved vascular barrier function and reduced leukocyte infiltration in several organs. Moreover, recent studies have demonstrated that TGF-β induces expression of CD73 on leukocytes, possibly providing an additional therapeutic approach to up-regulate CD73 for anti-inflammatory purposes from the leukocyte side as well 66. Statins also increase the expression and enzymatic activity of CD73; however, they act by inhibiting the endocytosis of CD73 without increasing protein synthesis. Therefore, statins may be beneficial only for short-term applications such ischemia-reperfusion injuries or for cardiac pre-conditioning. Clinical trials with statins targeting CD73 independently of their cholesterol-lowering effects have been recently completed (http://clinicaltrials.gov/).

Our model makes use of selective in-vivo expression of individual MHC II alleles on a C57BL/6 (IAb IEneg) background, which reconstitute IEdb expression and thereby allow presentation of moth cytochrome c (MCC) to the 5C.C7 TCR. Using host mice transgenic for the MHC II IE alpha chain, we have restricted expression Ipatasertib manufacturer of IE to radioresistant LCs, while maintaining normal T cell homeostasis

via expression of IAb on all host and donor-derived DCs. We have demonstrated that LCs, as the sole antigen-presenting subset in this model, induce deletion of CD4+ T cells even when highly activated by exposure to multiple TLR and inflammasome-mediated signals. Thus our results indicate that LCs are precommitted to the induction of immunological tolerance. LCs can also inhibit the immune response driven by radiosensitive, immunogenic DC subsets. The use of this model has thus allowed the first direct investigation of the in-vivo function of EGFR inhibitor review LCs, in contrast to the essentially indirect ablation studies in which the function of multiple DC subsets is assessed in the presence or absence of LCs [8]. While chimeric models are useful for assessing the function of LCs, restricting

functional presentation capacity to defined DC subsets in tissues such as gut and lung remains a challenge. The development of further transgenic and knock-in models that will allow functional analysis of individual DC subsets in mice possessing the full complement of MHC-expressing DCs

remains a high priority. The goal of DC subset biology, in the context of T cell responses, is to understand how DCs control the many classes of immune responses that are generated in vivo. Defining the individual functions of DC subsets should allow us to develop a more complete understanding of the mechanisms controlling T cell-mediated immunity and tolerance, maximizing the therapeutic potential of targeting DC subsets for future translation into the clinic. The recent demonstration that mouse and human DC subsets are related much PIK3C2G more closely than previously believed underlines the importance of studying DC biology in the mouse using physiological models. The limitations in the models currently available to study DC subset control of T cell responses (summarized in Table 2) highlight the importance of careful interpretation of the results from these models. The improvement and combination of current models should allow for a clearer picture of DC biology. The authors have no competing interests. “
“Conditional ligands have enabled the high-throughput production of human leukocyte antigen (HLA) libraries that present defined peptides. Immunomonitoring platforms typically concentrate on restriction elements associated with European ancestry, and such tools are scarce for Asian HLA variants.

6B). On the contrary, IKKε-Δ647 exerted FDA-approved Drug Library concentration a prominent dominant-negative effect on NF-κB induction mediated by overexpression of IKKε-wt when expressed in equal amounts, but not when IKKε-wt

was expressed at a five or tenfold excess (Fig. 6C). When quantifying IFN-β in the supernatants of these cells, we observed that the release of IFN-β induced by overexpression of IKKε-wt was reduced when any of the isoforms was cotransfected (Fig. 5B). Infection with VSV activates the TBK1/IKKε complex and, thereby, type I IFN release. On the other side, VSV replication is very efficiently blocked by type I IFN 1. Therefore, we measured virus spread as an indicator for IFN release. HEK293T cells transiently transfected with IKKε-wt, the different variants, or various combinations thereof were infected with VSV-GFP. GFP-positive cells were harvested 12.5 h after infection, fixed, and quantified by flow cytometry. As shown in Fig. 7, overexpression of IKKε-wt decreased infection rates of HEK293T cells in comparison to vector-transfected cells, and this inhibition was abrogated when IKKε-sv1 or IKKε-Δ647 were coexpressed. IKKε forms homodimers to exert some of its biological functions independently of TBK1 10. To investigate whether the IKKε splice variants interact with IKKε-wt to produce dysfunctional heterodimers explaining the observed dominant-negative effects, we coexpressed untagged

IKKε-wt with FLAG-tagged IKKε splice variants in HEK293T cells and performed IP with the anti-FLAG mAb. Coprecipitating IKKε-wt was visualized using an anti-IKKε mAb, recognizing the C-terminus of the protein. As shown in Fig. 8, IKKε-wt coprecipitated see more with all FLAG-tagged splice variants. FLAG-IKKε-sv1 partially contains the epitope recognized by the anti-IKKε mAb and is therefore detected in the anti-IKKε blot of the FLAG-IP as well (Fig. 8). Thus, heterodimer formation with IKKε-wt could explain the observed dominant-negative effects of the splice variants. Activation of IRF3-dependent type I IFN

expression by IKKε requires dimerization Teicoplanin with TBK1 and interaction with at least one of the scaffold proteins NAP1, TANK, and SINTBAD 7–9. To investigate the molecular mechanism causing the lack of IRF3 activation by the truncated IKKε isoforms, we performed co-IP experiments using lysates from transiently transfected HEK293T cells. First, interaction of the FLAG-tagged IKKε isoforms with TBK1 was investigated. As shown in Fig. 9A, IP of TBK1 indicated that IKKε-wt only interacts with TBK1. However, precipitating the IKKε proteins with the anti-FLAG Ab revealed coprecipitation of TBK1 with all isoforms although at a lower intensity with IKKε-Δ647 (Fig. 9A). From these data, we concluded that the lack of IRF3 activation by truncated IKKε is not due to its inability to bind to TBK1. Next, we tested the scaffold proteins NAP1, TANK, and SINTBAD for coprecipitation with the FLAG-tagged IKKε isoforms.

Over the years, this polysaccharide has been referred to as a PS/A by this research group. Later, Christensen et al. (1990) described a slime-associated antigen (SAA) isolated from the same strain and having a similar function. SAA was claimed to be different from PS/A. However, Baldassari et al. (1996) suggested that SAA and a hexosamine-containing polysaccharide intercellular adhesin (PIA) of S. epidermidis strains RP62A and 1457, check details described at that time by Mack et al. (1994), could be the same antigenic molecule. Mack et al. (1996) were the first to elucidate the chemical structure of PNAG (called, according to its biological properties, PIA). Using a combination

of analytical methods and nuclear magnetic resonance (NMR), PIA was identified as a linear β(1,6)-linked N-acetylglucosaminoglycan containing c. 130 N-acetylglucosamine (GlcNAc) residues, partially substituted with O-succinyl groups, partially de-N-acetylated and apparently phosphorylated (Mack et al., 1996). The genes encoding PNAG biosynthesis are

organized in the icaADBC (intercellular adhesion) operon, which consists of four ORFs (Heilmann et al., 1996; Gerke et al., 1998) with a transcriptional repressor gene, icaR, located upstream and transcribed in the opposite orientation (Conlon et al., 2002). The ica locus was later found in a number of S. aureus strains, and its presence was related to the ability to form a biofilm in vitro (Cramton et al., 1999). A recombinant ROCK inhibitor strain of Staphylococcus carnosus (pCN27), containing icaABC of S. epidermidis RP62A, unlike the parent S. carnosus strain, which is biofilm-negative, was adherent to glass and revealed the ability to form intercellular aggregates as well as to produce PNAG (Heilmann et al., 1996). McKenney et al. (1998) subsequently demonstrated that the recombinant S. carnosus (pCN27) antigen was identical to PS/A and ‘chemically related’, but distinct from PIA in molecular size, solubility, and substitution of the majority of the amino groups of the glucosamine residues with succinate. This polymer,

named poly-N-succinyl-β-(1,6)-glucosamine (PNSG), was suggested as a potential vaccine candidate against staphylococcal infections (McKenney et al., 1999, 2000). However, Aspartate subsequent studies carried out by the same group showed that the presence of the N-succinyl substitution was an analytical artefact (Joyce et al., 2003). These authors used a ‘PS/A overproducing strain’S. aureus MN8m, and the corresponding polysaccharide was named SAE (S. aureus exopolysaccharide). Detailed NMR studies, in combination with the chemical modifications, allowed a complete assignment of NMR spectra of SAE. According to Joyce et al. (2003), the main differences between SAE and PIA were phosphorylation (absence of a phosphate substitution in SAE) and molecular mass [>300 kDa for SAE and ∼30 kDa for PIA (Mack et al.

, 2009). With respect to the IFN-γ induction profile, a profound differentiation could be made between strong IFN-γ inducers (strains B1836, B2261, the mixture of B2261 and B633, B633 alone and CBI 118) and poor IFN-γ inducers (B1697 and B223). This differentiation has been observed for other strains (Miettinen et al., 1998; Ongol et al., 2008; Vissers

et al., 2010), and was already detectable on day 1, being the most prominent on day 8. Activation of Th1 cells (rather than CD8+ T-cells and natural killer cells) is possibly responsible for this observation. Even though IL-12 production was low, IFN-γ induction and IL-12 production correlated on all tested days, as IL-12 and IFN-γ act synergistically. The differential cytokine Rapamycin molecular weight activity profiles were also observed when comparing the IFN-γ/IL-13 ratio in the unstimulated day 8 cultures with strains B1697 and B223 having a 5 ± 3 and 30 ± 0 ratio, respectively, Selleckchem XAV939 strain CBI 118

having a 188 ± 58 ratio and for all other strains, this ratio was between 250 and 355. This lower IFN-γ/IL-13 ratio for strains B1697 and B223 is mainly due to the lower IFN-γ induction and subsequent lower IL-13-inhibiting capacity. The percentage nonviable cells of αCD3/αCD28-stimulated cultures was in general higher than 50%, which is probably mainly caused by activation-induced cell death (AICD). AICD in T lymphocytes is the process Ixazomib mw by which cells undergo apoptosis in a controlled manner after activation through the T-cell receptor by, for example, CD3 monoclonal antibodies (Green et al., 2003). Furthermore, often the trypan blue exclusion technique is used to analyze cell death, in which early apoptotic cells will not be visualized and cell death numbers are, therefore, lower compared with the use of an Annexin V/PI staining and flow cytometric analysis. The polyclonal αCD3/αCD28 stimulus is widely used to provide all T cells with the required activation signals, with an optimum in proliferation and cytokine induction at days 3–5 (Jeurink et al., 2008). This could

explain why no difference was observed in IFN-γ induction between the control and the tested strains, as the effect of the strains is generally much weaker than the stimulus applied. However, the bacteria do have an effect on modulating this polyclonal stimulation with respect to some of the tested cytokines and proliferation, which strengthens the evidence that the bacteria can induce strong immunomodulating activities in vitro. The inhibition of IL-13 induction provoked by all tested strains was also observed for other strains in hPBMC cultures stimulated polyclonally using the lectin phytohemagglutinin (Niers et al., 2005) or the superantigen Staphylococcus enterotoxin A (Pochard et al., 2002; Ghadimi et al., 2008).

In addition, we investigated whether the effect exerted by these antigens in the modulation of the angiogenesis factors was direct or through other inflammatory mediators, such as nitric oxide. iNOS is known to regulate VEGF expression, and thereby angiogenesis (33–35). As alveolar macrophages release nitric oxide in response to helminthic antigens (21), may be inhibition of iNOS

could be decreased VEGF production. We confirmed the ICG-001 manufacturer relationship between the production of nitric oxide and the angiogenesis factors by using inhibitors of the ONSi (l-NAME and l-canavanine), which inhibited the expression of angiogenesis factors. In summary, this study demonstrated that angiogenesis factors Gefitinib cost play a role in the primary infection by S. venezuelensis as the inhibition by endostatin produced a decrease in the number of larvae and females. Direct mechanisms with diminution of angiogenesis factors and indirect mechanisms with decrease of the number of eosinophils could be related to the protection from the parasitic infection. Angiogenic factors are induced by somatic antigens of third stage larvae of S. venezuelensis. A positive relationship between angiogenesis factors

and nitric oxide has been observed using nitric oxide synthase inhibitors. This work was supported by the projects of Junta Castilla y León SA116A08. Shariati F fellowship, acknowledges financial support from Ministry of science of IR Iran. “
“Bacterial biofilms are imaged by various kinds of microscopy including confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). One Metformin purchase limitation of CLSM is its restricted magnification, which is resolved by the use of SEM that provides high-magnification spatial images of how the single bacteria are located and interact within the biofilm. However, conventional SEM is limited by the requirement of dehydration of the samples during preparation.

As biofilms consist mainly of water, the specimen dehydration might alter its morphology. High magnification yet authentic images are important to understand the physiology of biofilms. We compared conventional SEM, Focused Ion Beam (FIB)-SEM and CLSM with SEM techniques [cryo-SEM and environmental-SEM (ESEM)] that do not require dehydration. In the case of cryo-SEM, the biofilm is not dehydrated but kept frozen to obtain high-magnification images closer to the native state of the sample. Using the ESEM technique, no preparation is needed. Applying these methods to biofilms of Pseudomonas aeruginosa showed us that the dehydration of biofilms substantially influences its appearance and that a more authentic biofilm image emerges when combining all methods. Bacteria are found in at least two distinct states – either as planktonic or sessile cells.

Indeed, as shown in Fig. 6B similar Foxp3 staining could be observed

in the lamina propria of TNBS-treated mice that received PI when compared to TNBS-treated mice that received saline suggesting that Foxp3+ T cells are normally present in the lamina propria of PI-treated mice. Our data demonstrate that the phospholipid PI inhibits T-cell proliferation and Ku-0059436 manufacturer differentiation but does not affect Treg differentiation. In vitro experiments established that PI strongly inhibited PMA-stimulated T-cell activation. Moreover, T cells stimulated with plate-bound anti-CD3 and soluble anti-CD28 antibodies were also effectively inhibited by PI. The latter experiments excluded that PI acted through interference with processes such as transmembrane diffusion of PMA. Inhibition was dose dependent and did not involve anergy, apoptosis or deletion as reflected by the fact that suppression PD0332991 research buy was reversible when PI was removed (Supporting Information Fig. 3). Moreover, suppression was not restricted to a specific subset of T cells as both CD4+ and CD8+ T-cell activation was inhibited. In contrast, PI did not affect T-cell proliferation indirectly by inhibiting antigen-presenting DCs, as loading of DCs in the presence of PI before co-incubation did not

inhibit T-cell activation. These data strongly implicate an effect of PI on the intracellular pathways that are associated with T-cell activation. By determining phosphorylation activity of various intracellular checkpoints of T-cell activation we established that PI exerted its effects on the PKC–MAPK pathway. As we found decreased ERK1/2, P38 and JNK phosphorylation upon PI treatment, we hypothesize that PI targets OSBPL9 one of the common inositol lipid pathways that precedes these downstream routes. Recently, it was established that inositol lipid signaling is regulated through cellular expression of a class of PI-transfer proteins PI-TPα and PI-TPβ 11. Modulation of this signaling has been associated with changes in cellular proliferation. In particular, overexpression of PI-TPα in fibroblasts induces an increased growth rate, whereas the growth rate of PI-TPβ overexpressing cells

is decreased 12, 13. Future studies into the specific regulation of expression of such transfer proteins may lead to the development of novel PI-based immunosuppressants. The inhibition of signal transduction in T cells cultured with PI led to reduced IL-2 mRNA expression and low levels of IL-2 protein release, which abrogated T-cell proliferation. In consequence, PI inhibited inflammatory CD4+ Th cell proliferation and cytokine release. Crucially, Foxp3+ Treg differentiation was not aborted by addition of PI, which is a pivotal characteristic for a potential immunosuppressant. As such, the immunosuppressive effects of PI share more similarity with the inhibitor rapamycin, which preserves Foxp3+ T cells while inhibiting inflammatory responses than with cyclosporine, which suppresses both inflammatory and Tregs 14, 15.