Our data show that T-cell development is not dependent on Akt HM phosphorylation. These findings are consistent with our previously proposed model in which mTORC2-dependent Akt HM phosphorylation is required to confer Akt specificity toward a limited subset of Akt substrates [[6]]. Our data also suggest that

Akt, when activated via phosphorylation of activation loop, plays a central role for DN–DP transition, most likely by controlling the survival of thymic T cells. Furthermore, our data suggest that phosphorylation of Akt at the activation loop may be sufficient to support TCR/CD3-mediated peripheral T-cell proliferation and survival. Since mTOR is an evolutionarily conserved regulator of cellular growth and metabolism, we investigated if Sin1 deletion may affect the size of resting peripheral T cells or activated T cells and proliferation. Venetoclax datasheet Sin1 deficiency had little effect on resting T-cell growth and activation induced blast cell growth. Furthermore, Sin1 deficiency did not impair antigen receptor/co-receptor-dependent T-cell proliferation in vitro. These results contrast with those reported Selleckchem Dabrafenib in mice bearing a T-cell-specific rictor deletion that show a modest defect in activation induced T-cell proliferation [[12, 21]]. It is possible that the differences in the in vitro T-cell stimulation conditions

between our assays may account for the difference in experimental results since we stimulated our T cells in the presence of plate-bound anti-CD3 antibody plus soluble anti-CD28 in the presence of exogenous IL-2. FoxO1 is an mTORC2-dependent Akt substrate that has been shown to play a key role in regulating T-cell development, homeostasis, and

effector cell differentiation [[16, 22]]. FoxO1 is required for proper expression of the genes that encode L-selectin (CD62L), interleukin 7 receptor alpha chain (CD127), and Foxp3 [[15, 16, 22]]. We have previously shown that Sin1 selleck chemicals deficiency results in decreased FoxO1 phosphorylation at the Akt target sites, leading to increased FoxO1 transcriptional activity [[6, 13]]. Consistently, we observed an increased proportion of Foxp3 expressing nTreg cells in the thymus and an increased expression of CD62L expression on naive peripheral CD4+ T cells in Sin1−/− chimeric mice. Surprisingly, Sin1 deficiency did not affect IL-7R expression on resting peripheral T cells. We have previously shown that in developing progenitor B cells, the mTORC2-Akt-FoxO1 signaling negatively regulates IL-7R expression [[13]]. IL-7R expression is suppressed in antigen activated T cells. It is possible that the loss of mTORC2 function has no effect on IL-7R expression in resting T cells because these cells normally have a very low level of Akt signaling.

Biologic dressings are simple, effective, and reliable tools for intermediate treatment of critical microsurgical wounds. Flap or replant viability was preserved in 100% of cases without compromising functional results. Biologic dressings can be used safely to treat microsurgical wounds with exposed critical structures. This use of a biologic dressing greatly simplifies the management of these types of wounds, avoiding the need for complex surgical intervention. © 2011 Wiley Periodicals, Inc. Microsurgery, 2012. “
“The purpose of this report was to retrospectively review the results of treatment of degloving injury of the finger by use of combined ipsilateral second dorsal nail-skin flap this website and contralateral

medial second toe flap. From 2010 to 2012, seven fingers in seven patients with complete

degloving injuries from the level of middle or distal phalanx were reconstructed with combined ipsilateral second dorsal nail-skin flap and contralateral medial second toe flap. The injured fingers included the index finger in four cases, and middle finger in three cases. The nerves of both the flaps were sutured to the bilateral common digital nerves. The donor site of second toe flap was covered with a full-thickness skin graft. All transferred flaps survived after surgery, and all postoperative courses were uneventful. During the follow-up period (mean of 15 months; ranging 6–20 months), the appearance of the reconstructed fingers was comparable Selleckchem Panobinostat with normal ones. The range of motion of the distal interphalangeal joint averaged 55 ± 5.8 degrees. The two point discrimination of the pulp ranged from 8 to > 15 mm (average, 11.3 mm). All the patients were able to walk without difficulty. The MHQ score averaged 59 ± 4.2 points and Maryland ID-8 foot rating score averaged 92 ± 4.2 points. The ipsilateral second toe dorsal nail-skin flap combined with contralateral medial second toe flap

may provide an alternative for the reconstruction of completely degloved fingers at the middle and the distal phalangeal level, with satisfactory functional and cosmetic results. © 2014 Wiley Periodicals, Inc. Microsurgery 34:540–546, 2014. “
“The question of how long a flap depends on its pedicle cannot be answered clearly from the available literature. To address this, we investigated the time to flap autonomization in the wound bed and the length of time to the point when flap necrosis is reduced to a clinically negligible level. The superficial epigastric flap was raised in 24 rats. After 3, 5, 7, or 10 days of wound healing, the pedicle was again exposed, ligated, and divided. Values of blood flow (flow), velocity (velocity), hemoglobin level (Hb), and oxygen saturation (SO2) were noninvasively measured using Laser spectrophotometry. The area of necrosis of the flap was 62.77 ± 1.71% after 3 days, 16.26 ± 0.86% after 5 days, 2.

Since thymic MDCs are not available from study participants we measured surface expression of TSLPR on peripheral blood CD11+ MDCs which were previously shown to induce ex BTK inhibitor datasheet vivo differentiation of Treg from CD4+CD8−CD25− naïve thymocytes following activation with TSLP 13. IL-7Rα surface expression levels on total CD4+ T cells and T-cell subsets were determined

by measuring the CD127-mean fluorescence intensity (MFI) using flow cytometric analysis (shown in Fig. 1). Highest surface expression levels of IL-7Rα were observed on Tconv with a memory phenotype, whereas IL-7Rα-MFIs on Tconv exhibiting either a naïve or a RTE phenotype were consistently ∼20% lower in both study cohorts. IL-7Rα-MFIs correlated highly between different Tconv subsets in all blood samples tested (Pearson’s correlation coefficient r2 ranged between 0.90 and 1.00 for all subsets, not depicted). Overall, IL-7Rα-MFIs of total Tconv and Tconv subsets were significantly

reduced in MS patients (n=56) versus age- and sex-matched control donors (n=33) (total Tconv: HC 309.2±45.7, MS 221.8±77.9; p<0.001; memory-Tconv: HC 353.1±52.7, MS 227.6±85.3; p<0.001; naïve Tconv: HC 284.5±39.9, MS 184.4±65.7; p<0.001; RTE-Tconv: HC 286.7±39.9, MS 191.0±67.0; p<0.001; Fig. 2A). Treg and Treg subsets invariably exhibited low surface expression levels of IL-7Rα in all samples analyzed (data not shown). CD25 expression of Tconv Epigenetics Compound Library research buy and Tconv subsets did not differ between pheromone both study cohorts (data not shown). In concordance with our previous findings, frequencies of Tconv and Treg exhibiting a naïve phenotype were clearly reduced in MS patients as compared to age- and sex-matched control

sonors, whereas memory cells were expanded (data not shown). In both study cohorts numbers of Tconv and Treg with a naïve or RTE phenotype strongly correlated with IL-7Rα surface expression levels on total Tconv and Tconv subsets. Highest correlations were observable, when frequencies of RTE-Tconv and RTE-Treg were plotted against IL-7Rα-MFIs on total Tconv (RTE-Tconv: HC: r2=0.112, MS: r2=0.184; RTE-Treg: HC: r2=0.173, MS: r2=0.341; shown for RTE-Treg in Fig. 2B). All correlations were statistically significant with p<0.05). IL-7Rα-MFIs and RTE-frequencies decreased with age in healthy donors (IL-7Rα-MFI on Tconv: r2=0.190, RTE-Tconv: r2=0.473, RTE-Treg: r2=0.393) but were both independent of age in MS patients. Total Treg and Tconv were immunomagnetically separated from peripheral blood samples of 15 patients and 15 age- and sex-matched control donors and suppressive activities of Treg were determined by in vitro proliferation assays. As expected, and previously shown 2, the mean Treg-mediated suppression of Tconv proliferation was significantly reduced in MS (HC: 59.1±21.9%, MS: 30.6±21.6%, p<0.

NewT should decrease injury of large arteries within the cortico-medullary junction. The two groups of patients had normal renal function and were similar in gender ratio and age range.

Biopsy tissue was processed, sectioned, routinely stained and examined by two pathologists. Scanned images of the biopsies with magnification 1x were obtained. Total area of the biopsy tissue and area of cortex were measured in mm2 using Image J image analysis program. Total number of glomeruli in each biopsy was recorded. Medical records were reviewed for post-biopsy bleeding complications, such as perinephric hematoma. Results: NewT had significantly higher percentage of cortical area than OldT (95.3% ± 3.53 vs. 85.0% ± 2.87, p = 0.026). NewT and OldT FK506 solubility dmso had similar median biopsy area (4.3 mm2 vs. 4.9 mm2, respectively). Total number of glomeruli per biopsy for NewT and OldT was 10 vs. 14, respectively (p = 0.087). Histology showed

no large arteries in any of the tissue specimens. The frequency of post-biopsy hematoma in NewT was 3.0% (n = 1) and in OldT was 4.2% (n = 2). Conclusion: Both renal biopsy techniques provided sufficient number of glomeruli for histopathologic examination and diagnosis of HSPN. Larger cortical area was in the biopsies obtained by new technique. Additional Venetoclax solubility dmso study is needed to evaluate whether the new technique can reduce post-biopsy bleeding complications in patients with HSPN and other renal diseases. ANUSORNVONGCHAI THITINUN1,2, CHIANG CHIH-KANG3, NANGAKU MASAOMI1, INAGI REIKO4 1Divisions of Nephrology Astemizole and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan; 2Division of Endocrinology, Renal Unit and Cell Biology, Lerdsin General Hospital, Bangkok, Thailand; 3Division of Nephrology, Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 4Divisions of CKD Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan Introduction: Recent studies revealed progressive renal damage by long-chain saturated fatty

acids via ER stress, however the effect of the fatty acids on EPO-producing cells has not been identified. Thus, we hypothesized that long-chain saturated fatty acid (palmitate) affects EPO production. Methods: In vitro, HepG2 was stimulated with palmitate-conjugated bovine serum albumin (palmitate-BSA) or fatty acid free BSA (control-BSA) in various doses and durations, and the change in hypoxia (CoCl2 or 1% O2)-induced EPO production. In vivo, 8-week-old C57BL/6J mice were intraperitoneally injected with palmitate-BSA or control-BSA for 5–11 days before induction of EPO production by CoCl2, chemical hypoxic inducer. Blood samples were measured for free fatty acid and EPO levels. The change in expression of ER stress-related transcription factors, EPO and HIF target genes were assessed by real-time qPCR.

MRPECs were treated with TGF-β1 (10 ng/ml) or recombinant human MMP-9 (rhMMP-9) (2 μg/ml) to induce EndoMT. EndoMT was assessed by morphological changes, immunofluorescence staining

and Western blot (WB) of endothelial (CD31 and VE-cadherin) and mesenchymal markers (α-SMA and vimentin). Notch signaling was examined by WB of Notch 1 and Notch intracellular domain (NICD). MMP-9 expression was examined by zymography. Interstitial fibrosis assessed by Trichrome stain, EndoMT Obeticholic Acid nmr and Notch signaling were examined in MMP-9 wildtype (WT) and knockout (KO) mice after unilateral ureteral obstruction (UUO). Results: TGF-β1 and rhMMP-9 induced EndoMT in MRPEC as evidenced by significant downregulation of VE-cadherin & CD31 and upregulation of α-SMA & vimentin. rhMMP-9 also induced EndoMT RO4929097 in MRPECs with upregulation of Notch signaling evidenced by an increase of Notch intracellular domain (NICD) accompanied by a decrease of Notch 1. Inhibition of MMP-9 or Notch signaling by their inhibitors demonstrated a dose-dependent response in preventing TGF-β1 or rhMMP-9-induced α-SMA and NICD in MRPECs. MMP-9 deficiency also led to a significant reduction in TGF-β1-induced NICD and α-SMA proteins in MRPECs of MMP-9 KO mice. MMP-9 KO mice with UUO showed a

significant reduction of interstitial fibrosis, α-SMA expression and fibroblasts originating via EndoMT. Conclusion: MMP-9-dependent Notch signaling plays an important role in kidney fibrosis through EndoMT of renal peritubular endothelial cells. JUTABHA PROMSUK1, WEMPE MICHAEL F2, ENDOU HITOSHI3, ANZAI NAOHIKO1 1Department of Pharmacology and Toxicology, Dokkyo Medical University, 3-mercaptopyruvate sulfurtransferase School of Medicine, Tochigi, Japan; 2Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Aurora, CO, USA; 3J-Pharma Co., Ltd., Yokohama, Japan Introduction: Diuretic drugs have high plasma protein binding and exhibit their diuretic effects from the luminal side of renal tubular cells; for example, they inhibit Na+-Cl− co-transporter located at the distal tubule and Na+-K+-2Cl− cotransporter located at the loop of Henle.

Consequently, the major route of diuretic drug secretion occurs via tubular pathways. Moreover, thiazides and loop diuretics usually induce hyperuricemia in patients. The interaction of diuretics with drug and urate transporters may help to explain these clinical observations. Organic Anion Transporters (OATs) OAT1 and OAT3, located at basolateral side of renal proximal tubule and renal apical drug exporter NPT4, which functions as a voltage-driven organic anion transporter, have been illustrated to transport various anionic drugs. The inhibition of organic anion transport by some diuretics was suggested, however there is no direct evidence to show whether various diuretics are substrates of these transporters and thus the goal of this study.

Furthermore, co-receptor usage of HIV-1 in tonsil cells correlated with inoculating virus tropism. Our combined cervix–tonsil organ culture could serve as an experimental model to study the earliest stages of HIV-1 transmission through cervicovaginal mucosa to its proximal lymph nodes. “
“Foxp3+ Treg cells are crucial for maintaining T-cell homeostasis, but their role in B-cell homeostasis remains unclear. Here, we

found that Foxp3 mutant scurfy mice had fewer B-lineage cells and progenitors, including common lymphoid progenitors and lymphoid-primed Selleckchem Nutlin-3a multipotent progenitors, but higher myeloid-lineage cell numbers in BM compared with WT littermates. Homeostasis within the HSC compartment was also compromised with apparent expansion of long- and short-term HSCs. This abnormality was due to the lack of Treg cells, but not to the Treg-cell extrinsic functions of Foxp3 or cell-autonomous defects. Among cytokines enriched in the BM of scurfy mice,

IFN-γ affected selleck screening library only B lymphopoiesis, but GM-CSF, TNF, and IL-6 collectively promoted granulopoiesis at the expense of B lymphopoiesis. Neutralization of these three cytokines reversed the hematopoietic defects on early B-cell progenitors in scurfy mice. Treg cells ensured B lymphopoiesis by reducing the production of these cytokines by effector T cells, but not by directly affecting B lymphopoiesis. These results suggest that Treg cells occupy an important niche in the BM to protect B-lineage progenitor cells from excessive exposure to a lymphopoiesis-regulating milieu. “
“Public health can be protected most effectively through vaccination programmes. However, while presently available vaccination techniques protects the individual by provoking immune

responses against exogenous antigens (ags), such as those associated with certain bacteria and viruses, they cannot protect against or treat mishaps caused Silibinin by endogenous ag. Recently, Barabas and colleagues have developed a new vaccination method, called modified vaccination technique (MVT), which allows the presentation of disease causing agents in such a way as to initiate and maintain desired immune response outcomes even in the context of mishaps associated with endogenous ag. For example, in an experimental autoimmune kidney disease, the MVT downregulated/terminated pathogenic immune responses that were causing morphological and functional changes of the kidney. The MVT promises, with appropriate case-specific modifications, both preventative and curative applications for ailments, such as endogenous ag initiated mishaps (i.e.

Whether vascular calcification can be prevented or reversed with strategies FDA-approved Drug Library cost aimed at maintaining phosphate homeostasis is as yet unknown. One recent study also determined an association between serum phosphate within the normal range and vascular and valvular calcification.21 This study of 439 young and middle-age participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with both normal renal function and CKD, and no known CVD, reported that after adjustment for eGFR, each 1 mg/dL increase in serum phosphate concentration was significantly associated with a 21%, 33%,

25% and 62% greater prevalence of coronary artery, thoracic, aortic valve and mitral valve calcification respectively. The CARDIA study, described earlier, also showed that phosphate levels within the reference range were significantly associated with coronary artery calcium levels in a young healthy adult population.19 Elevations in serum phosphate have been associated with structural changes and renal decline in animal models.68 In human observational studies, hyperphosphataemia is associated with progression of established CKD and the development of ESKD (end-stage AZD1208 mouse kidney

disease)23,69–71 and studies of renal transplant recipients describe an association between higher serum phosphate and renal allograft loss.27,28 Serum phosphate levels in the upper-normal range have also recently been reported to be associated with an increased risk of developing incident CKD and ESKD.6,24 One study involving 2269 participants from the Framingham Heart Study showed that those in the highest phosphate category had an increased risk of CKD with OR 2.14 (95% CI 1.07–4.28) Teicoplanin when compared with the reference group with serum phosphate 2.5–3.49 mg/dL.6 The same study also analysed 13 372 participants

from the Third National Health and Nutrition Examination Survey (NHANES III) and reported that phosphate ≥4 mg/dL was associated with an increased risk of incident ESKD (RR 1.90 (95% CI 1.03–3.53)). Zoccali et al. recently evaluated the relationship between baseline serum phosphate, disease progression and response to angiotensin-converting enzyme (ACE) inhibition in 331 patients with proteinuric CKD in the prospective Ramipril Efficacy In Nephropathy (REIN) trial.72 Phosphate levels in the highest two quartiles were significantly associated with faster progression to both ESKD and to a composite end-point of doubling of serum creatinine or ESKD compared with patients with phosphate levels below the median. Therefore, with higher serum phosphate levels the renoprotective effect of ramipril decreased, despite adjustment for potential confounders such as GFR and urinary protein. This suggests that phosphate may potentially modify the protective effect of the only real therapeutic class of agents used in CKD. FGF-23 is the most potent hormone regulating phosphate homeostasis.73 In health, FGF-23 is secreted by osteocytes and osteoblasts in response to dietary phosphate intake.

59 Hence, SOCS proteins do not simply regulate find more CD4+ T-cell commitment by inhibiting specific JAK/STAT responses, but rather, they adjust the balance between each lineage, suggesting that they might play an essential role in the regulation of CD4+ T-cell plasticity. It will be important to determine the relative expression of each SOCS in the context of human CD4+ T-cell polarization and ascertain whether these proteins might represent potential targets to medicate the growing allergy and autoimmune disease burden observed in recent decades. The authors

have no conflicts of interest to disclose. “
“The recognition by CD4+ T cells of peptides bound to class II MHC (MHCII) molecules expressed on the surface of antigen-presenting cells is a key step in Selleckchem Galunisertib the initiation of an adaptive immune response. Presentation of peptides is the outcome of an intracellular selection process occurring in dedicated endosomal compartments involving, among others, an MHCII-like molecule named HLA-DM (DM). The impact of DM on the epitope selection machinery has been known for more than 15 years. However, the mechanism by which DM skews the presented

repertoire in favour of kinetically stable complexes has remained elusive. Here, a review of the most recent observations in the field is presented, IKBKE pointing to the possibility that DM decides the survival of a peptide–MHCII complex (pMHCII) on the basis of its conformational flexibility, which is a function of the ‘tightness’ of interaction between the peptide and the MHCII at a specific region of the binding site. Class II MHC (MHCII) molecules are transmembrane heterodimeric proteins expressed on the surface of antigen-presenting cells, and they initiate or propagate immune responses by presenting antigenic peptides to CD4+ T lymphocytes.[1]

The MHCII molecules feature a high level of polymorphism, predominantly restricted to the peptide-binding site. This groove-shaped domain is the main structural characteristic of the MHCII and defines its function. Each individual expresses a small number of different MHCII molecules. Hence, each of these must be able to bind a large number of different peptides to ensure an immune response against many possible pathogens.[2] The MHCII-restricted presentation of peptides to CD4+ T cells can be considered the outcome of an intracellular selection process. MHCII molecules are transported from the endoplasmic reticulum through the Golgi to the MHCII compartment (MIIC) as complexes with the chaperone protein invariant chain (Ii).[3, 4] Ii stabilizes the nascent MHCII and prevents the binding of other endoplasmic reticulum-resident polypeptides.

Samples were analyzed by SDS-PAGE and autoradiography (Fig. 3A, upper panel) or subjected to western blotting with anti-Hrs Ab (Fig. 3A, lower panel). Active Syk was able to induce phosphorylation of Hrs, whose identity was confirmed by the anti-Hrs blot. AZD2281 order Hrs phosphorylation was undetectable in the absence of active Syk (data not shown). Next, we determine whether Hrs modifications induced in vivo require the presence of Syk. Lysates obtained from control or

Syk interfered cells were subjected to immunoprecipitation with anti-Hrs or isotype-matched control Abs. Probing of the immunoblot with anti-phosphotyrosine (pTyr) and anti-Ub Abs showed that Hrs phosphorylation and monoubiquitination are induced only in the presence of Syk (Fig. 3B and C). To further determine whether Hrs modifications require active Syk, we assessed the effect of piceatannol, a Syk-specific inhibitor [14], on the Ag-induced Hrs phosphorylation Ixazomib clinical trial and ubiquitination. After such pretreatment, a complete abrogation of inducible Hrs tyrosine phosphorylation was observed upon 5 min of Ag stimulation (Fig. 3D), and correlated with an impairment of Hrs ubiquitination

(Fig. 3E). The inhibitory effect of piceatannol on Syk kinase activity was validated by a marked reduction in antigen-induced tyrosine phosphorylation of whole others cell proteins and a complete abrogation of Syk autophosphorylation (Supporting Information

Fig. 4A). The requirement of active Syk in regulating Hrs phosphorylation and ubiquitination was also sopported by the employment of the Syk-negative variant of RBL-2H3 cells stably transfected with WT or a kinase inactive form of Syk (Supporting Information Fig. 4B and C). All together, these results demonstrate a critical role for Syk tyrosine kinase activity in controlling inducible Hrs posttranslational modifications in mast cells. In RBL-2H3 cells c-Cbl constitutively associates with Syk [30], and its ligase activity is rapidly induced upon receptor engagement [17]. To assess whether c-Cbl could act as the E3 Ub ligase for Hrs, we compared the level of Hrs monoubiquitination in cells transfected with non targeting siRNA (Ctrl-siRNA) or with c-Cbl-siRNA before and after FcεRI stimulation. We reproducibly obtained a protein level reduction of approximately 90% when compared with control cells (Fig. 4A, upper panel). c-Cbl-siRNA did not affect protein expression of Hrs, Syk, or FcεRI β and γ chains (Fig. 4A, middle and lower panels and data not shown). Lysates obtained from control or Cbl-interfered cells were immunoprecipitated with control or anti-Hrs Abs (Fig. 4B). c-Cbl knock-down abrogated inducible Hrs monoubiquitination, as demonstrated by anti-Ub and anti-Hrs immunoblot.

Based on this study, CD137 seems to be involved in priming and might play a role in limiting the early expansion of CD4+ T cells at the initial stage BYL719 supplier of immune response to protein antigen. In line with our observations, this study demonstrates that CD137−/− mice are not compromised in their capacity to elicit CD4+ T cell-mediated immune responses. Similar to our results, Lee et al. could not detect a difference with regard to the IgG1 response, suggesting that even in the absence of CD137 signalling, T cell-dependent humoral antibody responses to protein antigen develop normally [41]. However, in contrast to this study, we did not observe a

strong increase in Th2 cytokine levels in splenocyte cell cultures of CD137−/− OVA group compared with WT OVA. Whereas Lee et al. applied OVA subcutaneously only once to study initial T cell priming, we immunized WT and CD137−/− mice twice i.p. with OVA and aluminium hydroxide as adjuvant,

followed by six i.n. challenge periods. Therefore, the differences seen between these studies might be explained by the prolonged immunization protocol GW-572016 solubility dmso including OVA challenge periods to induce local recall response in our model. Whether CD137 plays a distinct role in priming versus recall responses in OVA-based models needs to be investigated further. It is possible that experimental models without the powerful effect Buspirone HCl of aluminium hydroxide as adjuvant could reveal minor changes between WT and CD137−/− mice that may be underestimated in our acute model based on OVA/Alum sensitization. Thus, testing of CD137−/− mice in another asthma protocol, i.e. with a weaker immunization protocol or with house dust mite as model allergen, could be a future perspective. Another possible explanation for the missing phenotype of CD137−/− mice with regard to asthma is that the missing CD137/CD137L co-stimulation might be compensated by other co-stimulatory signalling pathways, as we have shown previously for CD30 and CD134 (OX40) in a chronic asthma model [42]. CD30, another co-stimulatory

molecule of the TNFR superfamily, proved to be crucial for the development of asthma in an acute model [29] while, in contrast, we did not see differences between CD30−/− and WT mice in the chronic model [42]. We demonstrated that reduced expression of OX40 on T cells in the acute model and up-regulation in the chronic model indirectly supported a compensatory role of OX40 for CD30 signalling. Similarly, application of agonistic anti-OX40 mAb restored the asthma phenotype in CD30−/− mice in the acute model, whereas chronic airway inflammation was reduced in the presence of an inhibitory anti-OX40 ligand mAb. Therefore, it is possible that in CD137−/− mice the role of CD137 signalling is compensated likewise by other co-stimulatory pathways.