3A). In addition, KLRG1 expression was increased in IFN-γ secreting P14 cells but decreased in cells producing

IL-2 after stimulation (Fig. 3B). Thus, KLRG1 was preferentially expressed by CD8+ T cells with a “late” differentiation phenotype. To determine whether KLRG1 played a causal role in CD8+ T-cell differentiation, expression of the T-cell differentiation markers used above was compared in P14 T cells from KLRG1 KO and WT mice at the acute and at the memory phase of the LCMV infection. Adoptively transferred P14 T cells from KLRG1 KO and WT mice proliferated to the same extent in recipient mice after LCMV infection and gave rise to similar numbers of memory T cells (Fig. 4, left). In addition, expression of CD5, CD27, CD62L and CD127 see more on effector and memory P14 T cells and their capacity to secrete IFN-γ and IL-2 after antigen stimulation did not differ between KO and WT cells (Fig. 4, right). Thus,

these data indicate that the differentiation pathways of P14 T cells after LCMV infection were not altered in Trametinib the absence of KLRG1. We and others have previously demonstrated that repetitively stimulated P14 memory T cells express high levels of KLRG1 and are impaired in their proliferation capacity after antigen stimulation 11, 29. In addition, recent data in the human system indicate that KLRG1 signaling induces defective Akt phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells 14. To determine whether KLRG1 is causally linked to impaired proliferation, P14 T cells from KLRG1 KO and WT mice were used in consecutive adoptive T-cell transfer experiment as outlined in Fig. 5A. Confirming previous findings 11, 29, “tertiary” P14 memory T cells from WT mice were mostly KLRG1+ and expanded only marginally after antigen stimulation in vivo when compared with naïve or primary AMP deaminase memory P14 cells (Fig. 5B and C). However, “tertiary” P14 memory T cells from KLRG1

KO mice also proliferated poorly, demonstrating that the impaired proliferative capacity of these cells was not due to KLRG1 expression. Infection of mice with MCMV leads to CD8+ T-cell memory inflation whereby the magnitude of the response to some epitopes (i.e. M38 or m139 in B6 mice) increases with time, whereas T-cell reactivity to other epitopes (i.e. M45 in B6 mice) contracts after the peak of the acute phase 30, 31. Interestingly, KLRG1 expression by M38- or m139-specific CD8+ T cells also increased in the course of the infection whereas the portion of KLRG1+ cells within the pool of M45-specific CD8+ T cells decreased (Fig. 6A). This observation prompted us to examine epitope-specific CD8+ T cells in MCMV-infected KLRG1 KO mice.

com/tox_tables.htm as mild, moderate, severe or life threatening. A “serious adverse event” was defined as one which, regardless of severity, resulted in either death, a life-threatening event, hospitalization or prolongation thereof, a persistent or significant disability, an important medical event or a congenital abnormality or birth defect. Blood was collected

for immunogenicity tests 7–14 days before MVA85A vaccination, and, for adolescents small molecule library screening on days 7, 14, 28, 56, 84, 168 and 364 after vaccination. To reduce blood collection volumes in children, blood was only collected from these participants on days 7, 28, 84 and 168 after vaccination. The ex vivo IFN-γ ELISpot assay was used as the primary immunological endpoint, and performed as previously described 25. Ag included recombinant Ag85A protein (provided by Tom Ottenhoff and Kees Franklin, 10 μg/mL), a single pool of peptides spanning the Ag85A protein (2 μg/mL each, Peptide Protein Research), live BCG (from the vaccine vial, strain SSI, Staten Serum Institute, 1.2×106 CFU/mL, prepared as previously

described 49) and M.tb PPD (Staten Serum Institute, 20 μg/mL). Peptide pools spanning the M.tb-specific Ag ESAT-6 and CFP-10 (15-mers, overlapping by 10; 10 μg/mL each, Peptide Protein Research) were also included for all participants. Medium alone served as negative control. Varidase (Streptokinase, 250 U/mL; Streptodornase, 62.5 U/mL, Lederle Laboratories) and PHA (Sigma-Aldrich, 10 μg/mL) served as positive controls.

For the children, only the Ag85A peptide pool, PPD, ESAT-6/CFP-10 and PHA were used. Plates, containing 3×105 PBMC per well, were incubated for 18 h at 37°C and developed according www.selleckchem.com/products/bgj398-nvp-bgj398.html to the manufacturer’s protocol (Mabtech). Assays were performed Vildagliptin in duplicate wells and the average (with background subtracted) was used for analysis. Whole blood intracellular cytokine staining was performed as previously described 25 at baseline in both age groups, and days 7, 28 and 168 post-vaccination in adolescents, or days 7, 84 and 168 post-vaccination in children. Briefly, 1 mL heparinized whole blood was incubated immediately after collection with Ag in the presence of anti-CD28 and anti-CD49d (BD Biosciences). After 7 h, Brefeldin A (Sigma-Aldrich) was added and samples were incubated for a further 5 h. BCG from the vaccine vial (1.2×106 CFU/mL), recombinant Ag85A protein (10 μg/mL, not used for children) and a single pool of Ag85A peptides (2 μg/mL per peptide) were used as Ag. No Ag (co-stimulant antibodies only) was used as negative control and Staphylococcal enterotoxin B (Sigma-Aldrich) as positive control. Erythrocytes were lysed and white cells fixed using FACSLysing Solution (BD Biosciences), before cryopreservation. Cells were thawed in batch, permeabilized with BD Perm/Wash buffer and stained with fluorescent antibodies. Antibodies for detecting cytokine responses by CD4+ and CD8+ T cells were as follows: CD3-Pacific Blue (UCTH1), CD8-PerCPCy5.

[84] Therefore, even with the QOL improvements associated with mesh repair in some studies, additional longitudinal studies are needed to further evaluate the selleckchem procedure related risks. In older women who do not wish to maintain vaginal coital function, colpocleisis has resulted in high anatomic success

rates[85] and may also include benefits such as shorter operating time, decreased blood loss and faster recovery. However, concern that women who undergo such an obliterative procedure may ultimately suffer from a negative body image, regret and dissatisfaction, may decrease willingness to colpocleisis as a surgical approach. However, in a multicenter prospective follow-up study, responses to PFDI and PFIQ revealed that 95% of 152 women (mean age 79.0 ± 5.6 years) who underwent colpocleisis were either “very satisfied” or “satisfied” with Gefitinib molecular weight the outcome of their surgery at the end of a 1-year follow-up.[86] Women reported improvements in lower urinary tract symptoms such as stress and urge UI; 98% indicated that their bodies looked the same

or better and 87% reported no change in sexual function with 10% reporting an improvement. These results suggest that colpocleisis is not associated with negative alterations in body image or sexual dissatisfaction, findings consistent with a study by Barber et al. in which women choosing to have obliterative surgery had similar improvements in QOL with no increase in depressive symptoms compared to those undergoing reconstructive surgery.[87] The prolapse repair success rate was equally high with 72% presenting at the 12-month evaluation with POP stage ± I. Complications related to the procedure itself were rare and medical in nature, occurring in the immediate postoperative period, most likely a reflection of the study groups’ older

age. In addition to evaluating surgical outcomes, QOL questionnaires may be helpful in identifying patients that may benefit from surgical repair. In a 16-month follow-up of patients who underwent vaginal and laparoscopic mesh repair for POP, a preoperative score of 20 on the PFIQ-7 was highly correlated with postsurgical improvement.[88] The use of validated QOL questionnaires in combination with a standardized staging system of POP has provided new tools for assessing treatment outcomes. Treatment efficacy and success is no longer solely determined by anatomic or other objective findings, but is also Urease based on improvements within a wide range of physical and emotional issues that directly impact the daily lives of women with POP. These instruments have also helped to better define the association between anatomic defects and a number of POP related symptoms, and have demonstrated potential for identifying candidates that may require intervention as well as discriminating among those most likely to benefit. Healthcare professionals who care for women with POP would likely find QOL questionnaires to be useful adjuncts in the diagnosis, treatment and management of their patients.

Survival levels of NSG–BLT mice were 51·1% (24 of 47 mice surviving) by 28 weeks post-implant compared to 86·7% (14 of 16 mice surviving) survival of irradiated-only control NSG mice that did not receive human tissues. We next evaluated if the number of CD34+ HSC injected influenced the incidence of xeno-GVHD in NSG–BLT mice, as indicated by the time of death. NSG mice that were irradiated and then implanted with human fetal thymic and liver tissues and injected with the indicated number of CD34+ HSC were monitored

for see more survival over 200 days (Supporting information, Fig. S8a). The data show that there is no correlation between the number of CD34+ HSC injected and the incidence of xeno-GVHD. In addition, we found no correlation between the percentages of CD3+ T cells in the peripheral blood of NSG–BLT mice at 12 weeks and incidence of xeno-GVHD (Supporting information, Fig. S8b). We also found no differences in the incidence of xeno-GVHD between NSG–BLT mice implanted with female and male tissues (Supporting information, Fig. S8c). The decrease in naive phenotype human CD4 and CD8 T cells in older NSG–BLT mice (Fig. 5) suggests that these T cells are being activated and mediating a xenogeneic GVHD. We hypothesized that the development of xeno-GVHD in NSG–BLT mice might result from a lack of negative selection against murine antigens in the human thymus or by a lack of peripheral regulation. Our previous studies showed that the xenogeneic

GVHD occurring after the injection of human selleck PBMC into NSG mice is mediated by T cell recognition of murine MHC (H2) classes I and II [55, 56]. To test if H2-reactive human T cells escape negative selection and contribute to the mortality of older NSG–BLT mice, NSG mice lacking the expression of murine MHC class I [NSG-(KbDb)null] or class II (NSG-Abo), were used to engraft fetal thymic and liver tissues. NSG-(KbDb)null

and NSG-Abo BLT mice did not have increased overall survival compared to standard NSG–BLT mice (Fig. 6a). Unexpectedly, the survival of engrafted NSG-(KbDb)null mice was reduced significantly compared to NSG–BLT mice (P < 0·001, Fig. 6a). Human cell chimerism Amylase (huCD45+ cells) was compared in the blood at 12, 16 and 20 weeks in NSG mice, NSG-(KbDb)null and NSG-Abo mice (Fig. 6b). Human CD45+ cell chimerism was comparable in the three NSG strains. Together, these data suggest that elimination of either murine class I or murine class II is not sufficient to overcome the mortality of older NSG–BLT mice. We next compared the engraftment and survival of NSG–BLT mice to BLT mice that were co-implanted under the renal capsule with 1 mm3 fragment of fetal mouse liver (fml) and human thymic tissue, in an attempt to enhance negative selection against murine antigens. Co-implant of fml did not increase the proportion of mouse cells (murine CD45+ staining) detected within human thymic organoid (Fig. 6c). Overall engraftment in the blood of both sets of mice was similar at 12 weeks after implant (Fig.

However, urbanization maintains exposure to the crowd infections that lack immunoregulatory roles, while accelerating loss of exposure to the natural environment. This effect is

most pronounced in individuals of low socioeconomic status (SES) Y27632 who lack rural second homes and rural holidays. Interestingly, large epidemiological studies indicate that the health benefits of living close to green spaces are most pronounced for individuals of low SES. Here we discuss the immunoregulatory role of the natural environment, and how this may interact with, and modulate, the proinflammatory effects of psychosocial stressors in low SES individuals. “
“Since their discovery as a distinct T helper (Th) cell lineage, Th17 cells have been extensively investigated both in mice and in humans. These studies have identified factors involved in their

differentiation and effector functions and have also revealed a high degree of flexibility that seems to be a characteristic of the Th17-cell lineage. In this review, we discuss recent studies addressing the heterogeneity of human Th17 cells, their differentiation requirements, their migratory capacities, and their role in defense against fungi and extracellular bacteria. Human T cells producing IL-17 were described as early as the late 1990s in the context of chronic inflammatory conditions www.selleckchem.com/screening/anti-infection-compound-library.html such as rheumatoid arthritis and airway inflammation [1, 2], but it was only in 2005 that they were recognized as a
age of effector T cells [3]. Three lines of evidence obtained in the mouse system supported this notion. First, pathogenic inflammatory T cells produced high levels of IL-17A, IL-17F, and TNF and were dependent on

IL-23 rather than IL-12 for their expansion [3]. Second, naïve CD4+ T cells acquired IL-17-, but not IFN-γ- or IL-4-producing capacity, when activated in vitro in the presence of TGF-β and IL-6 or IL-23 [4-6]. Third, overexpression of the orphan nuclear receptor RORγt was sufficient to PtdIns(3,4)P2 induce differentiation of Th17 cells, while deficiency of RORγt in T cells attenuated autoimmune disease due to lack of tissue-infiltrating Th17 cells [7]. From these groundbreaking studies, the field has progressed at an astonishing pace, taking advantage of new and powerful technologies that have become accessible in recent years. As in many other areas of immunology, discoveries from studies performed in both experimental animal models and in human systems have contributed to our current understanding of the Th17 system and the role these cells play in physiology and pathology. Here, we will review, in particular, studies that address the heterogeneity of human Th17 cells, their differentiation requirements, their migratory capacities, and their role in defense against pathogens. To perform their function, effector, and memory T cells have to migrate to specific tissue sites, which are marked by the presence of constitutive or inflammatory chemokines [8].

After challenging with 10 ng/mL LPS, the level and profile of SARM mRNA were examined at various time points by real-time PCR. In contrast to HEK293 cells which showed no change in SARM mRNA level, the U937 cells exhibited an eight-fold increase in SARM mRNA

after 1 h of LPS stimulation, followed by a repression at 6 h, and subsequently, returning to basal level after Selleck LY2157299 12 h (Fig. 5A). Western blot (Fig. 5B) showed apparent release of smaller fragments of SARM which merits further characterization in future studies. The upregulation of SARM mRNA at 1 h post LPS challenge suggests its role as a possible immunomodulator. This probably helps prevent immune over-reaction and restores homeostasis, which is crucial for the recovery phase following an acute infection. Our results also indicate that effective immune activation might be a prerequisite for SARM activation. Both our results and previous report buy Vismodegib 23 show that SARMΔN is more potent than the full-length SARM, suggesting a regulatory role of the N-terminal region. To identify the possible mechanism, we first performed a thorough

bioinformatic analysis of the SARM sequence and observed that SARM exhibits a unique domain architecture containing two N-terminal Armadillo Repeat Motif, two Sterile Alpha Motif and a C-terminal TIR domain (Supporting Information Fig. S1A), suggesting that SARM regulates TLR signaling via a mechanism different from other TLR adaptors. Sequence homology alignment of human SARM with that of other species showed that the N-terminal region is generally less conserved compared to the

other regions (Supporting Glutamate dehydrogenase Information Fig. S1B). Comparison of the five TLR-adaptor proteins revealed that both SARM and TRAM harbor a polybasic motif in the N-terminal region (Fig. 6A–C). The polybasic motif is known to be required for TRAM to associate with membranes 34. Notably, the polybasic motif is well-conserved in SARM homologues, from the nematode worm to human (Fig. 6D), indicating the significance of this motif for SARM function. Further analysis of the human SARM sequence revealed a GRR, located proximally downstream of the polybasic motif, spanning from amino acids 22 to 91 (Fig. 6B). Interestingly, unlike the polybasic motif, the GRR is unique to the human SARM. This recent acquisition of the GRR motif in the human SARM reflects its evolutionary divergence, suggesting that the humans have developed new regulatory mechanisms of action of SARM. A search for proteins with GRR showed that this motif is present in the NF-κB p105 and p100 35, 36. The GRR of NF-κB p105 functions as a processing signal for the maturation of the p50 subunit.

Samples were analysed using negative electrospray ionization (ESI). The ion spray voltage was set at −4500 V. The source temperature was SRT1720 set at 400°C. Nitrogen was used as the nebulizer and auxiliary gas and was set at 20, 50 and 50 arbitrary units for the curtain gas, the ion source gas 1 and the ion source gas 2, respectively. MS/MS spectra of

15-epi-LXA4 showed the same fragmentation pattern as the published [31] and commercial source (data not shown) spectra. Moreover, LC-MS/MS analysis confirmed 15-epi-LXA4 stability and no changes in height peak and area were observed during the time of the in-vitro assay conditions and using the 15-epi-LXA4 concentration reported to show biological activity (data not shown). The synthetic check details peptide WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met-NH2) was purchased from Tocris Bioscience (Bristol, UK). IL-8 was purchased from Peprotech (Rocky Hill, NJ, USA). Montelukast, MK-571, compound 43 and SCH527123 were synthesized at the Medicinal Chemistry Department in Almirall R&D Centre (Sant Feliu de Llobregat, Barcelona, Spain). Human Chinese

hamster ovary (CHO)-FPR2/ALX (ES-610-C) and human CHO-CysLT1 (ES-470-C) cell lines were purchased from Perkin Elmer (Waltham, MA, USA). Surface expression of the receptor FPR2/ALX was monitored by flow cytometry using a commercial monoclonal antibody against the receptor. Results clearly show high levels of receptor expression in FPR2/ALX-recombinant CHO cells compared to non-transfected CHO cells (increased 40-fold in mean expression). In addition, information on Bmax of recombinant cell lines by a radioligand saturation binding assay was provided by Perkin Elmer Grape seed extract and confirmed activity of both receptors in the recombinant cells. Ham’s F12 culture medium supplemented with 100 IU/ml penicillin and 400 μg/ml G418 was used to grow the cells. FPR2/ALX cell membrane preparation was performed from FPR2/ALX stable transfected CHO cells purchased from Perkin-Elmer. Adherent-growing CHO-h FPR2/ALX cells were washed in cold phosphate-buffered saline (PBS), harvested by scraping

and collected by centrifugation at 1500 g for 5 min. The cell pellet was washed twice with cold PBS and resuspended in homogenization buffer [15 mM Tris-HCl, pH 7·5, 2 mM MgCl2, 0·3 mM ethylenediamine teraacetic acid (EDTA), 1 mM ethylene glycol tetraacetic acid (EGTA)]. The cells were then lysed with an Ultraturrax homogenizer. Intact cells and nuclei were removed by centrifugation at 1000 g for 5 min. The cell membranes in the supernatant were then pelleted by centrifugation at 40 000 g for 25 min and resuspended in storage buffer (50 mM Tris-HCl pH 7·4, 0·5 mM EDTA, 10 mM MgCl2, 10% sucrose), aliquoted, quick-frozen in liquid N2 and stored at −80°C. Protein concentration in membrane preparations was determined using the DC Protein Assay kit (Bio-Rad, Hercules, CA, USA).

The preoperative evaluation included PD0332991 clinical trial history taking, physical examination, voiding diary, stress and 1-h

pad tests and a comprehensive urodynamic examination. Postoperative evaluation included a stress test, 1-h pad test, and uroflowmetry with postvoid residuals. Results: After 1 year of follow up, the rates of cure and satisfaction were 93.5 and 93.0%, respectively, in the Sparc group. The rates of cure and satisfaction were 95.2 and 85.7%, respectively, in the Monarc group. After 2 years of follow up, the rates of cure (93.5 vs 92.9%) and satisfaction (84.8 vs 83.3%) were similar between the two groups. No bladder injury occurred in the Monarc group. Bladder injury occurred in 6.5% (n = 3) of the patients in the Sparc group. Vaginal wall perforation occurred in 4.8% (n = 2) of the patients in the Monarc group (P >

0.05). Late complications included de novo urge symptoms (8.7 vs 11.9%) and voiding dysfunction (10.9 vs 9.5%). Conclusions: The transobturator Monarc procedure appears to be as efficient and safe as the retropubic Sparc procedure for the treatment of SUI. “
“To evaluate the effects of chronic hyperlipidemia on bladder function, we examined the functional and histological changes of the bladder in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits. Two age groups of WHHL-MI rabbits (6–12 months old, young WHHL-MI rabbits; and 20–24 months old, old WHHL-MI rabbits group) and the sex- and age-matched control rabbits were prepared. OSBPL9 Bladder functions were evaluated using frequency volume charts HM781-36B research buy and cystometrograms, and functional experiments using isolated bladder specimens. Histological studies of bladder were performed with HE staining and immunohistochemical staining

with mouse monoclonal S-100 protein antibodies and sheep polyclonal calcitonin gene-related peptide (CGRP) antibodies. In cystometrograms, it has been demonstrated that WHHL-MI rabbits showed significantly shorter micturition interval, smaller voided volume with non-voiding contractions compared to control. There was no significant difference in voiding pressure between young WHHL-MI and control rabbits. However, old WHHL-MI rabbits showed a lower voiding pressure than control rabbits. The functional experiments revealed that carbachol- and electrical field stimulation (EFS)-induced contractile responses of isolated bladder strips were significantly increased in young WHHL-MI rabbits than in control rabbits. However, in the bladder strips of old WHHL-MI rabbits, decreased responses to carbachol and EFS were observed. In WHHL-MI rabbits, bladder urothelium became thinner, smooth muscle area decreased and connective tissue area increased gradually with aging. A significant decrease in S-100 protein-positive neurons, and an increased number of CGRP-positive neurons were observed in both young and old WHHL-MI rabbits.

Current recommendations for supplementation range from 10–50 mg. These figures are based on older studies often with small numbers of patients. Suboptimal vitamin B6 status is common in the haemodialysis population. Advances in renal medicine and engineering of dialysis membranes may contribute to increased levels of deficiency. Vitamin B6 deficiency has been widely acknowledged in patients receiving haemodialysis.1–9 Numerous studies and reviews over previous decades have addressed this concern. The literature,

however, can often be contradictory and confusing. Wide variations exist in the use of vitamin supplementation in the management of kidney disease, and evidence-based recommendations are limited.10 While vitamin B12 and folate levels are routinely assessed in dialysis patients, vitamin B6 is not. The vitamin Opaganib B6 status of these patients can therefore only be inferred from biochemical parameters used in studies. This can present other issues, as technical differences in assay techniques used in studies further confuse the picture of the vitamin B6 status in the haemodialysis population.11 Many factors have been shown to lead to vitamin B6 deficiency in this patient group including: Decreased intake from the diet4,9 Since the first successful CHIR-99021 concentration haemodialysis with Kolff’s dialyser in 1945, numerous

advances have occurred with regards to the technology of dialysers and membranes.12 Clearance characteristics for larger molecules including uremic toxins has

improved; however, removal of important nutrients could be the inadvertent cost.2 Advances in renal medicine, including the introduction of resin-based phosphate binders and the use of erythropoiesis stimulating agents, have also been shown to affect vitamin B6 status as discussed in this paper. Low levels of B group Quisqualic acid vitamins have been shown to have negative effects on parameters including homocysteine levels and anaemia management.13–15 However, it is the original studies based on deficiency symptoms, which still remain the cornerstone for supplement recommendations today.4,7,9,16 This has led renal clinicians to question whether current supplement recommendations are adequate for patients receiving current dialysis. Since both improved technology and advances in renal medicine continue to change the dialysis process, this review has focused on the vitamin B6 status of haemodialysis patients specifically over the last decade. In addition, a previous review has compiled evidence of the vitamin B6 status of haemodialysis patients before the year 2000.11 This systematic review of studies of patients with chronic kidney disease (CKD) receiving maintenance haemodialysis was therefore undertaken with the following aims: 1 To determine the current level of vitamin B6 deficiency in the haemodialysis population; A search strategy was developed to identify appropriate studies.

Moreover, CD11c.DTR and CD11c.DOG mice have recently been reported to display neutrophilia and monocytosis upon DT injection. We discuss here some of the limitations that should be taken into consideration when interpreting results obtained with mouse models of DC ablation. Dendritic cells (DCs) are antigen-presenting

cells with roles in innate and adaptive immune responses. They comprise a heterogeneous group of cells and, therefore, are generally classified into subsets based on (i) select functional attributes, (ii) differences in levels of expression of certain cell-surface markers, and (iii) ontogenetic relationships [1-4]. Broadly speaking, DCs can be subdivided into two main groups: plasmacytoid DCs (pDCs), which utilize Toll-like receptors 7, 8, and 9 to respond rapidly find more to viruses by producing interferon-α; and conventional DCs (cDCs), which display an exquisite capacity Barasertib in vitro to initiate T-cell responses [1, 4]. cDCs in lymphoid tissues can be further divided into those normally resident at those sites (resident DCs) versus those that have immigrated from elsewhere (migrating DCs) [1-4]. The latter normally reside in nonlymphoid tissues but migrate to the draining lymph nodes via afferent lymphatics in the steady state and, prominently, during inflammation. Both resident and migrating cDCs can be further divided

into additional subsets. One such subset is the CD8α-expressing DC that resides in lymphoid organs and its CD103-expressing CD11b− counterpart in tissues, both of which are thought to possess a superior capacity to cross-present exogenous antigens to CD8+ T cells [1-4]. Langerhans cells (LCs) represent Montelukast Sodium another well-characterized population of DCs that resides in the skin and can migrate to skin-draining lymph nodes. LCs express high levels of the C-type lectin Langerin and, in contrast to cDCs and pDCs, are radioresistant and, therefore, remain of host origin in chimeric mice reconstituted with syngeneic bone marrow [5]. Our knowledge of DC biology has greatly benefited from the introduction of the CD11c.DTR mouse

model (Table 1) a decade ago [6]. This transgenic mouse strain expresses the diphtheria toxin receptor (DTR) under the control of a minimal CD11c promoter, which is active in both pDCs and cDCs. When CD11c.DTR mice are injected with diphtheria toxin (DT), cDCs and, to a lesser extent, pDCs are depleted, allowing for the study of DC-independent immune reactions; however, CD11c.DTR mice die after repeated DT injections, probably because of aberrant DTR expression on nonimmune cells, such as epithelial cells of the gut [7]. Therefore, experiments involving prolonged DC depletion require the use of radiation chimeras in which wild-type mice are reconstituted with CD11c.DTR bone marrow. As nonimmune cells in such chimeras remain of nontransgenic origin and, therefore, cannot express DTR, the deleterious effects of DT on mouse health are obviated.