To do this, transient transfection assays were performed using either one of the two human CCL20 promoter-luciferase constructs: pCCL20 c/EBPmut, containing the full-length human CCL20 promoter bearing the mutated c/EBP site; and the pCCL20 NF-κBmut, containing the full-length CCL20 promoter bearing the mutated NF-κB site 14. As shown in Fig. check details 4, site-specific mutation of the single NF-κB responsive motif almost completely blocked the ability of IFI16 to trigger luciferase activity. In contrast,

mutation of the single C/EBP site only slightly decreased luciferase activity compared with the wild-type CCL20 promoter. In order to provide definitive evidence supporting the role of NF-κB as the mediator of CCL20 promoter activation by IFI16, HUVEC were transfected with the indicator plasmid 5× NF-κB luc 15, infected thereafter with AdVIFI16 or AdVLacZ and reporter gene activity subsequently measured 24 h later. As shown in Fig. 4, overexpression

of IFI16 significantly increased NF-κB transactivation of the reporter gene although at levels lower than those observed with the endogenous CCL20 promoter. Altogether, these results demonstrate that IFI16 interacts with NF-κB in order to trigger CCL20 promoter activity, in line with the results obtained from the ICAM-1 promoter analysis. However, NF-κB does not appear to be the only transactivator EPZ-6438 cost stimulated by IFI16 in order to trigger CCL20 promoter. The ligand–receptor pair CCL20-CCR6 is believed to be responsible for the chemoattraction of CD34-derived immature DC, Langerhans DC (L-DC), effector/memory T cells and B cells, and it plays a role at skin and mucosal surfaces under homeostatic and inflammatory conditions 16, 17. If this is the case, it is important to verify a functional link between the ability of IFI16 to trigger CCL4, CCL5 and CCL20 release by HUVEC

Bay 11-7085 and DC and B-lymphocyte chemoattraction. Using a transwell migration assay, we demonstrate that both L-DC and B cells migrate to a significantly greater degree in response to the supernatants from IFI16-infected HUVEC compared with the supernatants from LacZ-infected HUVEC (Fig. 5). This migration was significantly reduced by pre-incubation with the anti-CCL4, anti-CCL5 and anti-CCL20 mAb, but only when added to the supernatants from IFI16-infected HUVEC. In contrast, addition of an unrelated mAb of the same isotype, used as an internal control, did not influence cell migration (data not shown). These results confirm that the secretion of CCL4, CCL5 and CCL20 by IFI16-infected HUVEC is functional and important for inducing L-DC and B-cell migration into the mucosa and skin where these cells are particularly abundant.

Two primer sets, universal: F_338, R_518 [49] and A. muciniphila specific [50], were used in this assay. In order to ensure an optimal specificity with the A. muciniphila genome, the sequence of the forward primer was modified as follow: F-5′-ACWCCTACGGGWGGCAGCAG-3′. The reaction mixture (20 μL) composed of 1× SYBR green PCR Master Mix (Applied CP-690550 cell line Biosystems), 1 μL of each, either

A. muciniphila-specific primers or 16S rRNA universal primers at a final concentration of 0.25 μM, and 5 μL of template DNA adjusted to approximately equal concentration of 20 ng/μL. The PCR temperature profile was as follows: 95°C for 5 min, followed by 40 cycles of 95°C for 15 s, 60°C for 1 min. The fluorescence acquiring was set in the annealing/extension step. Subsequent to the amplification, a melting curve analysis was performed in order to distinguish putative nonspecific amplification. Serial tenfold dilutions of A. muciniphila pure culture (DSMZ 22959) genomic DNA was used to generate standard curves. A 2 cm part of ileum (starting from GW-572016 cell line caecum) was partitioned lengthwise, washed gently in ice-cold PBS and one half stored in tissue homogenate lysis buffer (Ampliqon, Skovlunde, Denmark) at −80°C after immediately frozen

in liquid nitrogen, while the other half was used for flow cytometry analysis. The intestines were homogenized by using a T25 Ultraturrax homeogenizer (IKA, Staufen, Germany) and subsequently centrifuged for 15 min at 10 000 G and 4°C. The supernatant was decanted and centrifugation Depsipeptide molecular weight was repeated twice, the last time in a 5 μm Ultrafree MC-centrifugal filter device (Millipore, Billerica, MA, USA). Samples were kept cold during all steps. Next, the supernatant was analyzed for levels of IFN-γ, TNF-α, IL-1α, IL-1β, IL-2, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12(p40), IL-15, and IL-17 by bead-based Milliplex xMAP Luminex technology (Millipore) in accordance with manufacturer’s instructions. Statistical

analysis was performed using GraphPad Prism version 5.02 (GraphPad Software, San Diego, CA, USA). Statistical significance was evaluated by the one-way ANOVA test with Tukey’s posttest when comparing three or more groups. Unpaired two-tailed t-test or Mann–Whitney test was used when comparing two groups. p values less than 0.05 were considered statistically significant. This work was supported by a grant from “Arkitekt Holger Hjortenberg og hustru Dagmar Hjortenbergs fond” and it was carried out as part of “Center for Applied Laboratory Animal Research” (www.calar.dk). The authors declare no financial or commercial conflict of interest. “
“In peripheral lymphocytes, the transcription factors (TFs) NF-κB, NFAT, and AP-1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes.

Most children may continue to have SDNS despite receiving cyclophosphamide. Additional alternative drugs may be needed. In the present study, the effects on SDNS of sequential treatment after cyclophosphamide usage were established. Methods:  Forty-six children with SDNS were enrolled in this retrospective uncontrolled study. In addition to prednisolone, patients were treated with cyclophosphamide as a first-line alternative drug. Children who still had SDNS despite cyclophosphamide therapy received chlorambucil, HDAC inhibitor levamisole or another course of cyclophosphamide. The treatment responses were recorded and the mean duration of follow up was 96 months.

Results:  Seventeen patients (37%) experienced no relapse after cyclophosphamide therapy. Twenty-five patients (54%) had varied responses. Only four patients showed no effect. Children who

still had SDNS despite cyclophosphamide therapy received second or more alternative drugs. Cyclophosphamide with or without chlorambucil resolved steroid-dependency in 33 of 46 (72%) children who either had complete remission or developed steroid-sensitive, rather than steroid-dependent, nephrotic syndrome. Conclusion:  With the exception of four patients who were lost to follow up and four who were refractory and needed other treatment, most children with SDNS could spare the steroid (complete remission or steroid sensitive nephrotic syndrome) after using one or more of these modulating agents. “
“In the Australian state of Victoria, the Renal Health Clinical Network (RHCN) of the Department of Health Victoria established a Renal Kinase Inhibitor Library Key Performance Indicator (KPI) Working Group in 2011. The group developed four KPIs related to chronic kidney disease (CKD) and

dialysis. A transplant working group of the 3-oxoacyl-(acyl-carrier-protein) reductase RHCN developed two additional KPIs. The aim was to develop clinical indicators to measure the performance of renal services in Victoria in order to drive service improvement. A data collection and bench-marking program was established, with data provided monthly to the Department using a purpose designed website portal. The KPI Working Group is responsible for analysing data each quarter and ensuring indicators remain accurate and relevant. Each indicator has clear definitions and targets and the KPIs assess (1) patient education, (2) timely creation of vascular access for haemodialysis, (3) the proportion of patients dialysing at home, (4) the incidence of dialysis-related peritonitis, (5) the incidence of pre-emptive renal transplantation, and (6) timely listing of patients for deceased donor transplantation. Most KPIs have demonstrated improved performance over time with limited gains notably in two: the proportion of patients dialysing at home (KPI 3) and timely listing of patients for transplantation (KPI 6). KPI implementation has now been established in Victoria for 2 years, providing recent performance data without additional funding.

, 2004). Our observation suggests that this effect becomes more evident when the basal levels of EpoR expression are low and ARA290 is applied in nanomolar concentrations. Based on these initial results,

we chose an incubation time of 6 h and 10 nM or 100 nM ARA290 as an appropriate condition to prestimulate cells in further experiments. Epo and its analogues have been described to enhance selleckchem proliferation in healthy tissue, tumors and cell lines (Kumar et al., 2005; Hardee et al., 2007). Such activity would clearly constitute a strong adverse effect for the usage of ARA290 in the urinary tract. In addition to its clinical relevance, pronounced differences in cell growth would also skew the results from in vitro assays. Therefore, we investigated the cell proliferation and viability of cells cultured in the presence of ARA290 for 24 h and performed an XTT assay. On applying the assay, see more we could not detect any significant difference in cell proliferation and viability between treated and control cells in concentrations used for further experiments (T24: 102.7±5.8% for 100 nM ARA290; 5637: 97.1±3.2% for 100 nM ARA290) nor at higher concentrations (for 1 μM ARA290, T24: 90.33±7.6%; 5637: 98.3±0.7%). No changes

were observed when cells were costimulated with inactivated bacteria (data not shown). The neutrophil-attractant chemokine IL-8 serves a crucial function during UTI in mediating the elimination O-methylated flavonoid of bacteria (Hedges et al., 1994; Agace, 1996). The treatment with recombinant Epo has repeatedly been demonstrated to reduce lipopolysaccharide-induced cytokine induction in leukocytes (Schultz et al., 2008; Strunk et al., 2008; Yazihan et al., 2008). To test whether ARA290 modulated this immune response, we costimulated bladder epithelial cell lines with E. coli NU14 and ARA290 in different concentrations. During the period corresponding to basal levels of EpoR expression, the additional presence of ARA290 enhanced IL-8 mRNA expression. At 3 h, an increase in the IL-8 mRNA levels was observed in T24 cells after costimulation with 100 nM ARA290, compared with

stimulation with bacteria alone (127% of 0 nM ARA290, P<0.05; Fig. 3a). This early proinflammatory effect was even stronger with 10 nM ARA290 (155% of 0 nM ARA290, P<0.05). Consequently, IL-8 protein levels were higher in cell culture supernatants 12 h after costimulation with 100 nM ARA290 (115% of 0 nM ARA290, Fig. 3b) or 10 nM ARA290 (125% of 0 nM ARA290, P<0.05). At later time points, when EpoR expression was upregulated, ARA290 costimulation did not further promote immune induction. In contrast, IL-8 levels were reduced on mRNA (61% of 0 nM ARA290, P<0.05; Fig. 3a) and protein levels (78% of 0 nM ARA290, P<0.05; Fig. 3b). This downregulation was also observed at 10 nM ARA290, even though not as pronounced (91% for mRNA and 81% of 0 nM ARA290 for protein, P<0.05).

Whether or

not this is due to an intrinsic defect in the immune system of DS individuals or mainly secondary to the various DS-associated characteristics needs to be investigated further. Chromosome 21 genes that may influence the immune response include SOD1 and RCAN1. AZD4547 Several components of the immune system are variably affected in DS subjects, from which the most consistently reported are defective neutrophil chemotaxis and low humoral immune responses, associated with infections being predominantly of the respiratory tract. Factors that may induce immunodeficiency have been postulated, such as zinc deficiency and accelerated immunosenescence, although their clinical significances have not been established. Common anatomical defects of DS disturb natural barriers and facilitate the infectious disease process and need be considered in the management of infections in these patients. We recommend investigation of DS children who present with increased frequency of infections for immunological and non-immunological factors that increase the risk of infection. In this evaluation, low specific antibody titres to routine childhood vaccines would suggest the need for additional booster immunization doses. The authors thank Dr Carla Davis and Dr Kathlyn

Ostermaier for critical review of this manuscript. The authors have nothing to disclose. “
“Macrophages altered by various Th2-associated and anti-inflammatory mediators – including click here IL-4 and IL-13 [inducing alternatively activated macrophages (AAMs)], IL-10 and TGF-β– were generically termed M2. However, markers that discriminate between AAMs and other M2 remain scarce. We previously described E-cadherin as a marker for AAMs, permitting

these macrophages to fuse upon IL-4 stimulation. To identify novel potential contributors to macrophage fusion, we assessed the effect of IL-4 on other adherens and tight junction–associated components. We observed an induction of claudin-1 (Cldn1), Cldn2 and Cldn11 genes by IL-4 in different mouse macrophage populations. Extending our findings to other stimuli revealed Cldn1 as a mainly TGF-β-induced gene and showed that Cldn11 is predominantly associated with IL-4-induced AAMs. Cldn2 is upregulated by diverse stimuli and is not associated with a specific macrophage Suplatast tosilate activation state in vitro. Interestingly, different claudin genes preferentially associate with M2 from distinct diseases. While Cldn11 is predominantly expressed in AAMs from helminth-infected mice, Cldn1 is the major macrophage claudin during chronic trypanosomiasis and Cldn2 dominates in tumour-associated macrophages. Overall, we identified Cldn1, Cldn2 and Cldn11 as genes that discriminate between diverse types of M2. Macrophages are very versatile innate immune cells that adopt various activation states depending on the environment.

Interestingly, the ability of Lcn2 to

induce neutrophil migration was not affected selleckchem by the binding of a bacterial siderophore, such as enterobactin, to the peptide. The physiological relevance of Lcn2 as a chemoattractant was confirmed by in vivo studies in mice. Consistently, i.p., i.v. injection, and intradermal administration of Lcn2 resulted in increased leukocyte migration, mobilization, or infiltration. In addition, we found that Lcn2 plays an important role for PMN migration because PMNs from Lcn2−/− mice had a significantly reduced adhesion capacity, which we could link to reduced expression of adhesion associated surface proteins and the chemokine receptor CXCR2 on these cells. Similar biological effects as observed herein for Lcn2 were previously reported for several myeloid-related proteins (MRPs), such as S100A9 Sorafenib mw (MRP14), S100A8 (MRP8), and S100A8/A9 [33-36]. These proteins have been reported to be, at least in part, expressed and stored in secondary granules such as Lcn2 and to act as chemotactic agents and modulators of neutrophil transmigration, which has been referred to stimulation of CD11b/CD18 integrin receptor expression [33]. Interestingly, MRPs can induce shedding

of CD62L and expression of CD11b on human PMNs [37]. Importantly, the expression of these adhesion molecules was significantly impaired on PMNs from Lcn2−/− mice as compared to Lcn2+/+ mice following an inflammatory stimulus. Moreover, the reduced expression of CXCR2 on PMNs of Lcn2−/− mice may negatively impact on the induction of chemotaxis by KC [38]. As we wanted to understand by which pathways Lcn2 exerts its chemoattractant activity, we analyzed the expression of the two previously described receptors of Lcn2, namely megalin and 24p3R [17]. We were able to show that primary PMNs express 24p3R but not megalin. Moreover, we found that the pharmacological blockage of Erk1/Erk2 signaling, a pathway that is induced

upon 24p3R/Lcn2 interaction [17], inhibited the Lcn2-inducible migration of neutrophils, whereas blocking of IL-8-inducible signaling cascades via DIC, PI3, and PKC did not affect Lcn2-dependent chemotaxis. We then employed Lcn2+/+ and Lcn2−/− mice to compare their PMN function. According to our previous results, the reduced in vitro migration of PMNs from Lcn2−/− SSR128129E as compared to Lcn2+/+ mice was not unexpected. Surprisingly, we observed, that the addition of rmKC or rmLcn2 could not ameliorate the diminished migration of Lcn2−/− PMNs. However, this could not be traced back to reduced expression of the Lcn2 receptor 24p3R, which was comparable on PMNs from Lcn2−/− and Lcn2+/+ mice. We could then demonstrate that the impaired PMN migration and mobilization in Lcn2−/− compared to Lcn2+/+ mice is also seen in vivo in the very early phase of host responses to bacterial infection. Such differences — although in different experimental approaches — have not been observed by Flo et al.

RA (all-trans retinoic acid, RA) is one of the key biologically active compounds of vitamin A, the other (11-cis retinal) is involved in vision. RA acts as a ligand for one of the members of the nuclear Omipalisib hormone receptor

superfamily, namely the RAR:RXR (RA receptor:retinoid X receptor) heterodimer [1]. In the absence of ligand, this receptor heterodimer binds to specific regulatory regions, termed response elements, of genes in the genome and represses their transcription. Upon ligand binding, the receptor heterodimer becomes activated and typically increases transcription [1, 3]. In addition, the ligand-bound receptor can also bind to other transcription factors (e.g. NF-κB, AP1) via protein–protein interactions without directly binding to DNA, and by doing so can interfere with (i.e. repress) the transcriptional activity of these factors. This

phenomenon is termed transrepression and is particularly important in the control of inflammation [1]. Therefore, the production and degradation of RA has to be very tightly regulated in order to coordinate its activating/inhibitory activities in the various cell types and tissues on which it acts. One of the functions of the RAR:RXR heterodimer is to turn on the degradation of RA by activating the expression of a p450 enzyme CYP26 [3], Selleck SP600125 thus forming a feedback loop to control RA actions. The cellular activities of RA are widespread. It regulates cell proliferation and differentiation in many cancer cell lines, keratinocytes as well as cells of the immune system such as myeloid cells (reviewed in [1, 4]). These activities were Y-27632 2HCl typically identified by using exogenous, often synthetic activators or antagonists of RAR [1]. However, there is validation of these somewhat “artificial systems” since it is also well established that endogenous retinoids

have immunomodulatory effects. For example, vitamin A deficiency increases childhood mortality and morbidity and increases an individual’s susceptibility to infectious diseases (reviewed in [5]). In addition, there have been a large number of studies on the role of RA and/or RAR in hematopoietic differentiation and function. Of note, RAR is known to be expressed in nearly all hematopoietic lineages and to have roles in early myeloid differentiation and granulopoiesis [6, 7]. RA has a dual effect on differentiation by either inducing maturation or cell death, depending on the cellular context. It also blocks erythroid differentiation by downregulating GATA-1 [8]. Importantly, there is evidence for both pro- and anti-inflammatory activities of RA in macrophages.

In the 12 studies[28, 31-33, 35, 37, 39, 41, 43-46] reporting the association of statin use and AKI requiring RRT, the incidence of AKI requiring RRT ranged from 0.049%[46] to 9%[28] (Table 1). The pooled incidence of AKI requiring RRT for all 12 studies was 0.94%. The pooled incidence of AKI requiring RRT among statin user and nonstatin user were 1.31% and 0.76%, respectively (Table 2). Two studies[34, 40] were not included in the calculation of the pooled incidence because the numbers of RRT events selleck inhibitor were not reported. For the same reason, we used the number of RRT events in the PSM cohort

instead of the source population in one study.[45] Among all the 24 studies, only three RCTs described adverse effects of statin therapy. One study[28] adopted a clinically significant elevation or serum creatinine kinase and alanine aminotransferase within the first five postoperative days as safety outcomes. The incidence of these adverse events was the same in the statin and the

placebo group in this study (10% vs. 10%). The other two RCTs[25, 27] merely reported no observed significant side-effects in the statin group, and the incidence was not specified. The 21 studies with use of statins and risk of postoperative AKI included a total of 106 586 cases and 869 889 controls (Table 1). When the results from all 21 studies[24-30, 32, 34-38, 40-47] were combined, the use of statins was associated with a significant Lonafarnib datasheet protective effect for perioperative PD-1/PD-L1 inhibitor review AKI (pooled OR 0.87, 95% CI 0.79–0.95, I2 = 58.8%) (Fig. 2A). If multiple effect sizes of different methodological quality were reported in the same study, only the one with the highest quality was included in this analysis of the 21 studies. In general, the propensity score matching (PSM) adjusted effect size was viewed as of the highest quality, the crude effect size of the lowest quality, and the multivariate adjusted effect size in between. In each study, the variables adjusted for in the multivariate

models and the variables used to calculate the propensity score, if available, were listed in the Appendix 1 (Table App2). To determine other sources of heterogeneity, we performed several sensitivity analyses (Table 3). First, we examined the impact of selection of studies of different methodological quality. We excluded RCTs from analysis, and the pooled summary effect estimate of the remaining 19 observational studies was still significant and was very similar (pooled OR, 0.87; 95% CI 0.79–0.96, I2 = 67.0%). We combined crude OR reported in 14 studies[29, 30, 32, 34, 35, 37, 38, 40-44, 46, 47] and an insignificant effect of statins on perioperative AKI was shown (pooled OR, 1.02; 95% CI 0.84–1.23, I2 = 90.6%). However, after pooling of the 13 studies[30, 34-38, 40-43, 45-47] with PSM or multivariate adjusted effect sizes, use of statins was associated with a significant protective effect (pooled OR, 0.

Mice were on C57BL/6J genetic background (at least 10 back-crosses) and WT C57BL/6J mice were used as control. For experiments, 7/11-week-old mice were kept in filtered-cages in a P2 animal facility. All animal experimental protocols complied with the French ethical and animal experiments regulations and were approved by the Ethics Committee for Animal Experimentation of CNRS Campus Orleans (N° CLE CCO 2011–028 to V.Q., UMR7355). Plasmodium berghei ANKA (PbA) 15cy1 line constitutively expressing GFP under EF1α-promoter control, was obtained from Dr. A. Waters [23]. Mice were infected intraperitoneally with selleck products 105 parasitized erythrocytes

as described [41]. Alternatively, mice were infected intravenously with 1000 motile sporozoites obtained from salivary gland homogenate of day-21-PbA-infected females Anopheles stephensi. Mice were observed daily and scored for ECM neurological signs, namely ataxia, paralysis, and coma. Parasitaemia was assessed with EGFP-PbA as described [41] and fluorescent cells analyzed by BD CANTO II flow cytometer. Data were acquired by using DIVA software (BD Bioscience, Rungis, France) and analyzed with FlowJO software (Treestar, Ashland, USA). Blood was drawn under Isofluorane anesthesia (CSP, Fontenay-sous-Bois,

France) into tubes containing Ethylenediaminetetraacetic Selleckchem Alectinib (EDTA), (Vacutainer; Becton, Grenoble, France) and hematological parameters determined using 5-part-differential-hematology see more analyzer MS9.5 (Melet Schloesing Laboratoires, France). Histological analysis was performed as described [41]. Briefly, mice were euthanized and perfused with intracardiac PBS/2 mM-EDTA. Organs were fixed in PBS/3.6%-formaldehyde for 72

h. Brain and lung microvascular obstruction was quantified on H&E stained sections, using a semiquantitative score with increasing severity of changes (0–5) by two independent observers, including a trained pathologist (B.R.). MRI and MRA measurements of cerebral vascular blood flow were performed using a horizontal 7 T/16 Bruker Biospec MR system (Bruker Biospin, Wissembourg, France), as described [8]. A homogeneous coil with inner diameter of 23 mm and length 55 mm was used to achieve uniform excitation and reception. A custom-built stereotaxic head holder was used to fix the animal into the birdcage coil (see below). The mice were anaesthetized with isoflurane (1.5%) and O2 (0.5 L/min) applied with a face mask allowing free breathing. Respiration was monitored using a balloon taped to the abdomen and connected to a pressure transducer (SA Instruments, Inc., Stony Brook, NY, USA). Body temperature was kept at 37 ± 0.5°C throughout the experiment, using warm water circulation. Brain lesions and global changes in tissue structure were accessed by T2 weighted (T2w) MR images using a MSME sequence, in both axial and sagittal planes, with the following parameters: RARE factor = 8, TR/TEeff.

The accumulation of MO and DC in the atheroma and the relative depletion in the circulation [24] could stimulate both T cell recruitment and activation and may facilitate the release of chemokines, cytokines and other inflammatory mediators which are involved in the development and RG7204 molecular weight progression of HIV-associated atherosclerosis. Targeting CCR5 by MVC could have a double therapeutic effect in HIV-associated atherosclosis:

blocking HIV entry into heart tissue via CCR5 and down-regulation of the accumulation of inflammatory cells in the atheroma. Moreover, the down-regulation of MCP-1-mediated chemotaxis induced by MVC could play a beneficial role in preventing the spread of HIV to the brain. It is also known that both subsets of circulating myeloid DC (mDC) and plasmacytoid DC (pDC) are defective in HIV infection, especially because of homing in lymphoid organ and tissue [25,26]. After exposure to virions and HIV-infected cells, mDC and pDC up-regulate both tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and activation and migration markers, such as CD83 and CCR7, and acquire a killer-cytotoxic activity [27,28]. These cells down-regulate CXCR4 and CCR5 and become less susceptible to HIV infection; however, they are more active as proinflammatory https://www.selleckchem.com/products/MG132.html cells by inducing apoptosis in infected

and uninfected CD4 T cells and by producing cytokines such as interferon (IFN)-α and TNF-α. Our experiments suggest that MCV could inhibit Sulfite dehydrogenase chemotaxis, especially on these activated DC which are usually present during HIV infection. The anti-chemotactic activity of CCR5 antagonist could have also potential therapeutic implications for

the management of inflammatory conditions other than HIV. The proposed mechanism of CCR5 antagonists in the treatment of rheumatoid arthritis involves inhibition of cell migration, a key pathway in the inflammatory process of the disease. In a mouse model of experimental autoimmune myocarditis (EAM) CCR5 was found to be important in the induction of the disease, and inhibition of CCR5 with monoclonal antibody reduced the severity of myocarditis significantly [29]. A critical issue associated with the block of cellular migration induced by CCR5 antagonist is a potential risk for treated patients of developing infectious complications. In effect, the reduced migratory capacity of MO and DC after pharmacological inhibition of CCR5 could impair the innate immune response against pathogens by blocking APC accumulation and activation at sites of microbial or antigenic challenge. Subjects homozygous for CCR5Δ32 who do not express CCR5 have a higher susceptibility to some infections, such as West Nile virus [30].