This procedure yielded a T-cell population of ∼97% CD4+ T cells by FACS.

BALB/c LCs were plated in 96-well round bottom plates (104 cells/well), and exposed to VIP, PACAP, or medium alone for 2 h at 37°C. Cells were then washed four times with CM. Neuropeptide-treated or untreated LCs were co-cultured in each well with 2 × 105 CD4+ T cells from DO11.10 Tg mice (BALB/c background) in 200 μL of CM with varying concentrations of cOVA323–339. Forty-eight hours later cytokine content of supernatants was assessed. In some experiments 0.5 μg/mL of anti-IL-6 mAb or the isotype control was added to sets of wells when setting up the co-cultures Selleck BMS-354825 of LCs and T cells. Supernatant IL-17A, IFN-γ, IL-22, and IL-6 levels were determined with sandwich ELISA kits from R&D systems (IL-17A, IL-4 and IL-6), Antigenix America (Huntington Station, NY) (IL-22), and BD Biosciences (IFN-γ), following the manufacturer’s instructions. LCs were treated with 100 nM VIP, PACAP or medium alone for 2 h, washed four times, and then co-cultured

with CD4+ T cells from DO11.10 Tg mice in the presence of 10 μM OVA323–339 for 48 h. For the last 5 h of co-culture, cells were stimulated with 50 ng/mL phorbol myristate acetate (PMA) and 750 ng/mL ionomycin (Sigma-Aldrich St. Louis, MO). After 1 h, GolgiStop (BD Biosciences) was added to block cytokine secretion. LCs still bound to beads

were then removed by magnetic capture. INK 128 datasheet CD4+ T cells were surface stained for 20–30 min at 4°C with PerCP-Cy 5.5-labled anti-CD4 mAb (BD Biosciences) in PBS supplemented with 0.1% bovine serum albumin (BSA) and 0.1% sodium azide. CD4+ T cells were gated upon as shown in Supporting Information Fig. 1. After fixation and permeabilization with Cytofix/Cytoperm (BD Biosciences), cells were stained with fluorescein isothiocyanate (FITC) or Alexa Fluor 647-labeled Rebamipide anti-IFN-γ (clone XMG1.2; BD Biosciences), phycoerythrin (PE) or Alexa Fluor 647-lableled anti-IL-17A (clone TC11–18H10; BD Biosciences), anti-IL-4 (clone 11B11, BD Biosciences), and/or anti-IL22 (clone 1H8PWSR, eBioscience, San Diego, CA) monoclonal antibodies. Analysis was performed on a FACSCalibur (BD Biosciences). Data analysis was conducted using CellQuest Pro software (BD Biosciences). LCs were cultured in 100 nM VIP, PACAP or medium alone for 2 h, and then co-cultured with CD4+ T cells from DO11.10 Tg mice in the presence of 10 μM OVA323–339 for 24 h. Cultures were stimulated with PMA (50 ng/mL) and ionomycin (750 ng/mL) for 5 h, and LCs still bound to beads were removed by magnetic capture.

In one experimental outline of the Swiss Webster study the mice were fed on the same day and analysed on different days post-treatment. In the second experiment mice were fed on days 3, 7 and 14 prior to the analysis and mice were then all analysed on

the same day. Both experimental designs check details yielded results that were indistinguishable; therefore, data from both Swiss Webster experiments were combined. The experiment with 129/SvEv mice was staggered so that mice belonging to one experimental time-point group were analysed on two different days. Mice were killed by cervical dislocation prior to faecal slurry inoculation (axenic) and on days 3, 7, 14 and 28 post-inoculation. Colon, caecum and ileum were excised, cut longitudinally and half of each organ was prepared in paraffin with haematoxylin and eosin staining for light-microscopic examination as detailed previously [8]. The slides were reviewed in a blinded fashion and were assigned a histological score for intestinal inflammation ranging from 0 (no injury) to 10 (maximal injury). The histological inflammation scale represents the numerical sum of four scoring criteria: mucosal ulceration, epithelial hyperplasia, lamina propria mononuclear infiltration and lamina propria MK-2206 clinical trial neutrophilic infiltration [8]. To study epithelial barrier function a segment of colon was assayed in Ussing chambers,

as described previously [9]. In the chambers the flux of [3H]-labelled mannitol from the mucosal to the serosal side was monitored as an indicator for the permeability of the intestinal epithelial layer. Parts of colon, caecum and ileum were cultured for 24 h in 1 ml complete RPMI-1640 medium, as described previously [8]. Cytokine release in the supernatants was quantified using standard sandwich ID-8 enzyme-linked immunosorbent assay (ELISA) techniques. For the ELISA the following antibodies were used: anti-interferon (IFN)-γ (clone R4-6A2), anti-tumour necrosis factor (TNF)-α (clone G281-2626), anti-interleukin (IL)-17 (clone eBioTC11-18H10·1),

anti-IL-10 (clone JES5-2A5) and anti-IL-4 (clone 11B11) as capture antibodies and biotinylated anti-IFN-γ (clone XMG1·2), anti-TNF-α (clone MP6-XT3), anti-IL-17 (clone eBioTC11-8H4), anti-IL-10 (clone JES5-16E3) and anti-IL-4 (clone BVD6-24G2) as detection antibodies. All antibodies and recombinant cytokine standards were purchased from PharMingen Canada (Mississauga, Ontario, Canada) except for the anti-IL-17 monoclonal antibodies, which were obtained from eBiosciences (San Diego, CA, USA). All antibodies and standards were used at pre-titred concentrations to give optimal results. For the detection of IL-6 and granulocyte-colony stimulating factor (G-CSF) commercially available kits (R&D Systems, Minneapolis, MN, USA) were used. Spleens were removed from the killed mice, minced into a single-cell suspension in complete RPMI-1640 with 10% fetal calf serum (FCS) and depleted of red blood cells by osmotic shock.

One of the factors limiting progress in this area is the inherent complexity of the flora, but the advent of genomics-based approaches is rapidly plugging this technology gap and the increasing application of this technology will hopefully clarify the role of the flora to

a significant degree in the near future. More indirect human data are available from the relevant epidemiology literature concerning the role of microbial pathogens as opposed to commensal flora [28,29]. The original conceptualization of the hygiene hypothesis envisaged infection frequency as the key factor discriminating high-risk and low-risk populations, but it has become evident that qualitative aspects of https://www.selleckchem.com/products/BIBW2992.html infection(s) may be of equivalent or even greater importance. In particular, there is strong evidence linking enteric infections with reduced risk for allergic sensitization

Metformin in vivo [30], and similarly for mild–moderate respiratory infections (without wheeze/fever) which spread to the lower respiratory tract [31], whereas upper respiratory tract infections do not appear to play such a role [32]. In contrast to the above, one class of viral infections has been linked epidemiologically in multiple studies to risk for subsequent development of asthma in childhood, notably moderate–severe viral infections which spread to the lower respiratory tract and which are of sufficient

intensity to trigger wheeze and/or febrile responses [32–34]. These infections serve as independent risk factors for subsequent asthma development, but their asthma-promoting effects are much stronger against a background or respiratory allergy (reviewed in [35,36]). On the basis of these findings, we have proposed a ‘two-hit’ model for asthma aetiology in early childhood (Fig. 1) in which interactions between inflammatory pathways involved in host responses to aeroallergens and viruses infecting the airway epithelium synergize to perturb early postnatal lung growth and differentiation, resulting in later expression of the asthma phenotype [35,36]. These Cyclooxygenase (COX) interactions are most profound in children who are sensitized to aeroallergens early and who experience severe infections during the same period [32]. A key question remaining to be resolved fully relates to the nature of these interactions between the anti-viral and atopic pathways. We hypothesize that one important focus of these interactions is the network of airway mucosal dendritic cells (AMDC) first described in humans [37] and experimental animals [38,39] by our group, and which are now recognized generally to play an essential ‘gatekeeper’ role in control of immune responses in the respiratory tract to all classes of inhaled antigens and pathogens [40,41].

Polyclonal goat anti-human gal-1, gal-3 and gal-9 were from R&D Systems (Minneapolis, MN, USA). Secondary antibodies Alexa Fluor 647-conjugated donkey anti-goat (DAG), Alexa Fluor 568-conjugated goat anti-mouse (GAM) and Alexa Fluor 488-conjugated DAG were from Molecular Probes (Leiden, the Netherlands). Sputum cells from 15 asthma patients and 10 healthy donors were labelled with PO-anti-CD45, PE-anti-HLA-DR,

PB-anti-CD16 and APC-H7-anti-CD14. For galectin detection, cells were stained with goat polyclonal anti-gal-1, anti-gal-3 or anti-gal-9 followed by Alexa Fluor 647-DAG. Before antibody incubation, Fc-receptors were blocked with human gamma-globulin. Analyses MLN0128 clinical trial were performed with a fluorescence activated cell sorter (FACS)Canto II cytometer (Becton Dickinson, Franklin Lakes, NJ, USA). Galectin expression was analysed as mean fluorescence intensity (MFI). PBMC were islolated from 15 ml of venous peripheral blood from five healthy donors by density gradient. PBMC were seeded (5 × 105) onto 24-well plates and stimulated

with 100 ng/ml lipopolysaccharide (LPS); where indicated, 10 μg/ml human recombinant (h) gal-1 (Prepotech, London UK), gal-3 (ImmunoTools, Friesoythe, Germany) or gal-9 (R&D Systems) were added. After 24 h, cytokine expression was detected at mRNA and protein level using RT–PCR and cytometric bead array (BD Biosciences), respectively. Bead array data were acquired using FACSCanto II cytometer. In addition, Dabrafenib supplier IL-10

and IL-4 production were analysed in peripheral blood lymphocytes (PBLs) from four healthy donors. Briefly, PBMC were depleted of monocytes and PBLs (2 × 106) were seeded onto 24-well plates precoated or not with 0·5 μg/ml anti-CD3 and 1 μg/ml anti-CD28; where indicated, 10 μg/ml h gal-1, h gal-3 or h gal-9 were added. After else 24 h of incubation, culture supernatants were collected and quantified by cytometric bead array. RNA was isolated with Trizol RNA reagent (Invitrogen, Eugene, OR, USA) and RT–PCR was performed from 250 ng of RNA from 16 asthma patients and 11 healthy donors. In the case of PBMC, RNA was isolated from five healthy donors. mRNA levels of IL-5, IL-13, gal-1, gal-3 and gal-9 for sputum samples and IL-10, IL-12A, IL-12B, IL-1β and TNF-α for PBMC were determined in duplicate using Power SYBR Green PCR master mix from Applied Biosystems (Warrington, UK). Expression levels were normalized using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or beta-actin as controls. Primers sequences are shown in Supplementary Table S1. Cytospin preparations were fixed with 4% paraformaldehyde in PBS, permeabilized with 0·2% Triton X-100. After blocking of Fc-receptors with human gamma-globulin, cytospin preparations were labelled with anti-gal-1, anti-gal-3 or anti-gal-9. Next, Alexa Fluor 488-coupled DAG 1:100 was added. Preparations were blocked with goat serum and incubated with mouse anti-human CD45 followed by Alexa Fluor 568-coupled GAM.

[42] In other words, the ALT flap can be harvested as thinned skin, or a fasciocutaneous flap, myocutaneous flap, or chimeric flap to provide the necessary volume to restore a natural scalp contour. In 2004, Heller et al.[17] www.selleckchem.com/products/r428.html reported the use of ALT fasciocutaneous flaps to provide different tissue components for the repair of dura and scalp. The well-vascularized fascia components of ALT flaps were used to successfully to seal dural defects and overcome refractory infection in the area. This concept was applied successfully in three of our cases following extirpation of tumor involving

the scalp, bone and dura. Successful dural seal provided by the fascia component in these cases prevented cerebrospinal fluid leakage. With regards to donor-site morbidity, Boca et al.[20] concluded in his study that primary closure can be expected PLX3397 manufacturer when the maximum

width of the ALT flap was less than 16% of the thigh circumference, beyond which split-thickness skin grafts should be used to assist in closure. Donor site analysis showed that primary closure was preferred over skin graft wherever possible, as the latter would limit the range of motion at the hip and knee joint owing to adhesions between the skin graft and underlying muscle.[43] Cranioplasty is performed for both functional and aesthetic restoration of the cranial vault, the former being protection of intracranial contents and the latter for restoration of the natural head contour.[44] However, the decision for cranioplasty can only be made after stabilization of the patient

and the intracranial pathology.[45] Our experience with five patients in this series demonstrates this basic principle, where patients underwent cranioplasty for intracranial protection and restoration of calvarial contour after resolution of head injury. These patients underwent local flap coverage as the first line of treatment, as this represents Pyruvate dehydrogenase the best option for reconstruction of scalp defects. The ALT flap was used only when this option failed to achieve its goal. Our patients invariably express dissatisfaction to being socially handicapped, due to the unsightly appearances of exposed hardware or prosthesis after wound dehiscence or breakdown of the local scalp flap. Compared to local flaps, the free ALT flap proved competent in expedient coverage of these defects, had shorter recovery time and minimized damage to remnant scalp. Superficial temporal vessels are most commonly used as recipient vessels in free flap reconstruction of a scalp defect, not only because of their superficial location, but also its proximity to scalp defects. Scalp defects commonly occur in the anterior scalp, and in particular the frontal and temporal regions.[18] In our series, the superficial temporal vessels were used in seven out of nine patients.

E. H. holds a CIHR Doctoral MAPK inhibitor award, a MSFHR Junior Trainee Award, and a MSFHR/CIHR Transplant Trainee award; S. Q. C. holds a MSFHR Senior Graduate Studentship award and a CIHR/SRTC Strategic Training Program in Skin Research award. M. K. L. is a Canada Research Chair in Transplantation. Core support for flow cytometry sorting and lentiviral production provided by Lixin Xu and Rupinder Dhesi respectively, and was funded by the Immunity and Infection Research Centre MSFHR Research Unit. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers

are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. “
“Myeloid FcαRI, a receptor for immunoglobulin (Ig)A, mediates cell activation or inhibition depending on the type of ligand interaction, which can be either multivalent or monovalent.

Anti-inflammatory signalling is triggered by monomeric targeting using anti-FcαRI Fab or IgA ligand binding, which inhibits immune and non-immune-mediated renal inflammation. The participation of Toll-like receptors (TLRs) in kidney pathology in experimental models and various forms of human glomerular nephritis has been discussed. However, little is known about negative regulation of innate-immune activation. In the present study, we generated new transgenic mice that express FcαRIR209L/FcRγ chimeric protein and Torin 1 showed that the monovalent targeting of FcαRI exhibited inhibitory effects in an in vivo model of TLR-9 signalling-accelerated Reverse transcriptase nephritis. Mouse monoclonal anti-FcαRI MIP8a Fab improved urinary protein levels and reduced the number of macrophages and immunoglobulin deposition in the glomeruli. Monovalent targeting using MIP8a Fab attenuates the TLR-9 signalling pathway

and is associated with phosphorylation of extracellular signal-related protein kinases [extracellular signal-regulated kinase (ERK), P38, c-Jun N-terminal kinase (JNK)] and the activation of nuclear factor (NF)-κB. The inhibitory mechanism involves recruitment of tyrosine phosphatase Src homology 2 domain-containing phosphatase-1 (SHP-1) to FcαRI. Furthermore, cell transfer studies with macrophages pretreated with MIP8a Fab showed that blockade of FcαRI signalling in macrophages prevents the development of TLR-9 signalling-accelerated nephritis. These results suggest a role of anti-FcαRI Fab as a negative regulator in controlling the magnitude of the innate immune response and a new type of anti-inflammatory drug for treatment of kidney disease. Chronic inflammatory disease results from continuous injuries or errors in regulatory control mechanisms [1,2].

5b). These data suggest that demethylation of this CpG island of the Foxp3 promoter region correlates with Foxp3 expression. The methylation status of this region was evaluated in Foxp3− T cells that were activated for 72 hr in the presence of TGF-β alone, simvastatin alone, and the combination of TGF-β/simvastatin (Fig. 5c). After 72 hr, 48% and 42% of the CpGs of dimethylsulphoxide-treated or simvastatin-treated cells were methylated, respectively. However, this region in TGF-β-treated cells was less methylated (26%) than in dimethylsulphoxide-treated

or simvastatin-treated cells and the lowest level of methylation (16%) was observed in the cells treated with simvastatin/TGF-β. Seventy-two hours after activation, the extent of demethylation correlated well with the level of Foxp3 expression Cyclopamine detected by FACS analysis (bottom boxes in Fig. 5c). These results suggest that the synergistic action of simvastatin on TGF-β-mediated induction of Foxp3 may be mediated by co-operative control of methylation of the Foxp3 promoter. To directly examine the effects of simvastatin on TGF-β-mediated signal transduction, we measured phosphorylation of Smad3. Significant phosphorylation of

Smad3 was observed 24 hr after activation of cells cultured in the presence of Pritelivir manufacturer TGF-β, but not simvastatin alone, and the levels of Smad3 phosphorylation were not modulated when the cultures were stimulated with both TGF-β and simvastatin (Fig. 6a). In addition, the total amount of Smad4 was comparable in all treatment groups. The lack of an effect of selleck chemicals simvastatin on Smad3 phosphorylation is consistent with its late time of action and raised the possibility that simvastatin might block steps in the negative-feedback regulation of TGF-β signalling. Smad6 and Smad7 are the major inhibitory Smad proteins in the negative feedback regulation

of the TGF-β signalling pathway. In contrast to Smad3 phosphorylation, we could not detect Smad7 by Western blot analysis 24 hr after T-cell activation and only low levels of Smad6 were observed. The levels of Smad6/7 increased after 48 hr and were maximal at 72 hr after activation (Fig. 6b). Importantly, when combined with TGF-β, simvastatin markedly inhibited the induction of Smad6 at 48 and 72 hr, and completely blocked Smad7 induction at both 48 and 72 hr. Simvastatin alone also decreased levels of Smad6 and completely blocked Smad7 expression at 72 hr. As TGF-β has been reported to play an important role in Foxp3+ Treg homeostasis,16 we also examined the expression of Smad6/7 in nTregs that were activated under conditions similar to those used in our iTreg induction cultures. Foxp3− and Foxp3+ CD4+ T cells were FACS-sorted from Foxp3gfp mice and activated with anti-CD3/CD28 and IL-2 in the absence or presence of TGF-β for 72 hr (Fig. 6c).

0001) (Fig. 2C). The establishment of functional T-cell memory is vital for the success of an immunization protocol. To assess if functional CTL responses could be generated by a single immunization or if a prime boost regime Selleck Saracatinib were required, C57BL/6 mice were given single or multiple immunizations with TRP2/HepB human IgG1 DNA. No epitope-specific responses were detectable 20 days after a single immunization with TRP2/HepB human IgG1 DNA, but high-frequency responses were detectable after two immunizations (p=0.026) which increased further

with another immunization (p<0.0001) (Fig. 2D). The avidity of responses after two or three immunizations was analyzed. The responses induced in mice receiving two or three DNA immunizations were of high avidity (1.4×10−12 M and 1.8×10−12 M,

respectively). There is no significant difference in avidity between these two groups (p=0.89) (Fig. 2E). As both the frequency and avidity of the CTL response appear enhanced, the question “was avidity related to frequency?” arose. Over 80 mice were immunized with TRP2/HepB human IgG1 DNA and the frequency and avidity of responses measured. The avidity of the TRP2-specific responses ranged from 5×10−8 M to 5×10−13 M peptide. No significant correlation find more between avidity and frequency of TRP2 peptide-specific responses was identified, suggesting they are independent events (Fig. 3A). It is possible that xenogeneic human Fc influences the frequency and avidity of responses induced. Comparison of responses from immunization with human IgG1 or an equivalent murine IgG2a construct reveals similar frequency and avidity (Fig. 3B), suggesting that the xenogeneic human Fc was not influencing the response. Synthetic peptides have short half lives in vivo and are poor immunogens as they

have no ability to specifically target professional Ag presenting cells such as DC. Current therapies are showing DC pulsed with peptide induce an efficient immune response. TRP2/HepB human IgG1 DNA immunization was compared to DC pulsed with HepB/TRP-2 linked peptide. TRP2/HepB human IgG1 DNA demonstrated similar frequency responses compared to those also elicited by peptide-pulsed DC, both of which were superior to peptide immunization (p=0.0051 and p=0.0053) (Fig. 4A). Analysis of the avidity of responses reveals that the avidity in TRP2/HepB human IgG1 DNA immunized mice is 10-fold higher than with peptide-pulsed DC (p=0.01) (Fig. 4B). The TRP2 specific responses were analyzed for ability to kill the B16F10 melanoma cell line in vitro. Figure 4C shows that although responses from peptide and peptide-pulsed DC immunized mice demonstrate a good peptide-specific lysis, mice immunized with TRP2/HepB human IgG1 DNA showed better killing of the B16 melanoma cells (p=0.003). The enhancement of avidity could be related to direct presentation of the epitopes by the Ab–DNA vaccine and similar responses may be elicited by a DNA vaccine incorporating the native TRP2 Ag.

Administration of the STAT6-IP at the time of RSV challenge (Late Intervention) had no effect. Following RSV challenge, the STAT6-IP-treated mice in the Early Intervention group had lower airway eosinophils, increased lung IFN-γ levels, as well as increased IFN-γ-secreting Liproxstatin-1 CD4+ and CD8+ cells in the lungs. Our findings demonstrate the feasibility of targeting intracellular signaling pathways as a new way to modulate vaccine-induced responses. “
“There is strong evidence from animal models that placental and/or breast milk-mediated transfer of maternal allergen-specific

IgG prevents allergic immune responses in the progeny. Both human and animal data also point to IgA as having an important regulatory role. In contrast, little is known about maternal transfer of IgG and IgA specific for respiratory allergens in

humans. Dermatophagoides pteronyssinus (Der p) is an indoor allergen that is a major cause of asthma worldwide. We analysed maternal to child Der p-specific IgG and IgA transfer in a cohort of 77 paired maternal and child samples. We found Der p-specific IgG and its IgG1, IgG2 and IgG4 subclasses in all cord blood samples. Except PLX-4720 supplier for IgG1, cord levels were higher in newborns from atopic mothers (n = 29) compared to non-atopic mothers (n = 48). Der p-specific IgA was found in all colostrum samples and levels were independent of maternal atopic status. Notably, anti-Der p IgG was also found in colostrum and levels were higher in atopic mothers. We believe that our work is a critical first step in the identification of early factors that may impact asthma development and should guide the development of clinical studies that assess whether Der p-specific IgG and IgA protect children from allergy as demonstrated in animal models. Atopic asthma affects millions of children worldwide [1]. Pathogenesis of allergic disease results from complex interactions between Oxaprozin genetic

and environmental factors such as pollution, tobacco and microbial exposure including microbiota of the gastrointestinal tract. In most cases, symptoms of allergic asthma manifest in childhood, and the immunological changes leading to atopy can occur very early in life and even during gestation [2]. Thus, identifying early factors that predispose to asthma development may help to improve primary prevention. During pregnancy, mothers transfer to the foetus immunoglobulins (Ig) that recognize antigens to which she has been exposed [3]. IgG is the main Ig isotype transferred across the placental barrier [3–5], and its subclasses are ordered according to their relative serum levels: IgG1 > IgG2 > IgG3 > IgG4.

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 Ulixertinib 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 Adriamycin purchase 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 Inositol monophosphatase 1 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].