TLR signaling Kawai, T; Akira, S
Cell death and differentiation,
05/2006, Letnik:
13, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize ...specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-kappaB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.
Toll-like receptors and innate immunity Kumar, Himanshu; Kawai, Taro; Akira, Shizuo
Biochemical and biophysical research communications,
10/2009, Letnik:
388, Številka:
4
Journal Article
Recenzirano
Toll-like receptors (TLRs) are evolutionarily conserved innate receptors expressed in various immune and non-immune cells of the mammalian host. TLRs play a crucial role in defending against ...pathogenic microbial infection through the induction of inflammatory cytokines and type I interferons. Furthermore, TLRs also play roles in shaping pathogen-specific humoral and cellular adaptive immune responses. In this review, we describe the recent advances in pathogen recognition by TLRs and TLR signaling.
The mammalian innate immune system detects the presence of microbial infection through germ line-encoded pattern recognition receptors (PRRs). Toll-like receptors, retinoic acid-inducible gene-I-like ...receptors and nucleotide-binding oligomerization domain-like receptors serve as PRRs that recognize different but overlapping microbial components. They are expressed in different cellular compartments such as the cell surface, endosome, lysosome or cytoplasm and activate specific signaling pathways that lead to expression of genes that tailor immune responses to particular microbes. This review summarizes recent insights into pathogen sensing by these PRRs and their signaling pathways.
Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of ...anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM.
We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan–Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies.
In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group 6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03).
Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.
•Acral melanoma is a distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma.•We retrospectively examined advanced-stage acral melanoma patients treated with an anti-PD-1 antibody.•Anti-PD-1 antibodies have limited efficacy in Japanese acral melanoma patients.•Patients with nail apparatus melanoma had poorer response and survival than patients with palm and sole melanoma.
Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition ...receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response.
Summary
Induction of allograft tolerance has been considered the ultimate goal in organ transplantation. Although numerous protocols to induce allograft tolerance have been reported in mice, a ...chimerism‐based approach through donor haematopoietic stem cell transplantation has been the only approach to date that induced allograft tolerance reproducibly following kidney transplantation in man. Renal allograft tolerance has been achieved by induction of either transient mixed chimerism or persistent full donor chimerism. Although the risk of rejection may be low in tolerance achieved via durable full donor chimerism, the development of graft‐versus‐host disease (GVHD) has limited the wider clinical application of this approach. In contrast, tolerance induced by transient mixed chimerism has not been associated with GVHD, but the risk of allograft rejection is more difficult to predict after the disappearance of haematopoietic chimerism. Current efforts are directed towards the development of more clinically feasible and reliable approaches to induce more durable mixed chimerism in order to widen the clinical applicability of these treatment regimens.
Renal allograft tolerance has been achieved by induction of either transient mixed chimerism or persistent full donor chimerism. Current efforts are directed toward development of more clinically feasible and reliable approaches in order to widen the clinical applicability of these treatment regimens.
Aims
To confirm the stress‐relieving effects of heat‐inactivated, enteric‐colonizing Lactobacillus gasseri CP2305 (paraprobiotic CP2305) in medical students taking a cadaver dissection course.
...Methods and Results
Healthy students (21 males and 11 females) took paraprobiotic CP2305 daily for 5 weeks during a cadaver dissection course. The General Health Questionnaire and the Pittsburgh Sleep Quality Index were employed to assess stress‐related somatic symptoms and sleep quality respectively. The aggravation of stress‐associated somatic symptoms was observed in female students (P = 0·029). Sleep quality was improved in the paraprobiotic CP2305 group (P = 0·038), particularly in men (P = 0·004). Among men, paraprobiotic CP2305 shortened sleep latency (P = 0·035) and increased sleep duration (P = 0·048). Diarrhoea‐like symptoms were also effectively controlled with CP2305 (P = 0·005) in men. Thus, we observed sex‐related differences in the effects of paraprobiotic CP2305. In addition, CP2305 affected the growth of faecal Bacteroides vulgatus and Dorea longicatena, which are involved in intestinal inflammation.
Conclusions
CP2305 is a potential paraprobiotic that regulates stress responses, and its beneficial effects may depend on specific cell component(s).
Significance and Impact of the Study
This study characterizes the effects of a stress‐relieving para‐psychobiotic in humans.
We report here the long‐term results of HLA‐mismatched kidney transplantation without maintenance immunosuppression (IS) in 10 subjects following combined kidney and bone marrow transplantation. All ...subjects were treated with nonmyeloablative conditioning and an 8‐ to 14‐month course of calcineurin inhibitor with or without rituximab. All 10 subjects developed transient chimerism, and in seven of these, IS was successfully discontinued for 4 or more years. Currently, four subjects remain IS free for periods of 4.5–11.4 years, while three required reinstitution of IS after 5–8 years due to recurrence of original disease or chronic antibody‐mediated rejection. Of the 10 renal allografts, three failed due to thrombotic microangiopathy or rejection. When compared with 21 immunologically similar living donor kidney recipients treated with conventional IS, the long‐term IS‐free survivors developed significantly fewer posttransplant complications. Although most recipients treated with none or two doses of rituximab developed donor‐specific antibody (DSA), no DSA was detected in recipients treated with four doses of rituximab. Although further revisions of the current conditioning regimen are planned in order to improve consistency of the results, this study shows that long‐term stable kidney allograft survival without maintenance IS can be achieved following transient mixed chimerism induction.
The authors evaluate the long‐term results of HLA‐mismatched kidney transplantation without maintenance immunosuppression in 10 subjects following combined kidney and bone marrow transplantation in comparison with 21 immunologically similar living donor kidney recipients who were treated with conventional immunosuppression.
There is a need to identify new biomarkers of radiation exposure for not only systemic total-body irradiation (TBI) but also to characterize partial-body irradiation and organ specific radiation ...injury. In the current study, we sought to develop novel biodosimetry models of radiation exposure using TBI and organ specific partial-body irradiation to only the brain, lung or gut using a multivariate proteomics approach. Subset panels of significantly altered proteins were selected to build predictive models of radiation exposure in a variety of sample cohort configurations relevant to practical field application of biodosimetry diagnostics during future radiological or nuclear event scenarios. Female C57BL/6 mice, 8-15 weeks old, received a single total-body or partial-body dose of 2 or 8 Gy TBI or 2 or 8 Gy to only the lung or gut, or 2, 8 or 16 Gy to only the brain using a Pantak X-ray source. Plasma was collected by cardiac puncture at days 1, 3 and 7 postirradiation for total-body exposures and only the lung and brain exposures, and at days 3, 7 and 14 postirradiation for gut exposures. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (P < 0.01) in expression after irradiation were used to build predictive models of radiation exposure using different sample cohorts. Model 1 compared controls vs. all pooled irradiated samples, which included TBI and all organ specific partial irradiation. Model 2 compared controls vs. TBI vs. partial irradiation (with all organ specific partial exposure pooled within the partial-irradiated group), and model 3 compared controls vs. each individual organ specific partial-body exposure separately (brain, gut and lung). Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay for all samples. Each model algorithm built using a unique sample cohort was validated with a training set of samples and tested with a separate new sample series. Overall predictive accuracies of 89%, 78% and 55% resulted for models 1-3, respectively, representing novel predictive panels of radiation responsive proteomic biomarkers. Though relatively high overall predictive accuracies were achieved for models 1 and 2, all three models showed limited accuracy at differentiating between the controls and partial-irradiated body samples. In our study we were able to identify novel panels of radiation responsive proteins useful for predicting radiation exposure and to create predictive models of partial-body exposure including organ specific radiation exposures. This proof-of-concept study also illustrates the inherent physiological limitations of distinguishing between small-body exposures and the unirradiated using proteomic biomarkers of radiation exposure. As use of biodosimetry diagnostics in future mass casualty settings will be complicated by the heterogeneity of partial-body exposure received in the field, further work remains in adapting these diagnostic tools for practical use.
A large number of urban surface energy balance models now exist with different assumptions about the important features of the surface and exchange processes that need to be incorporated. To date, no ...comparison of these models has been conducted; in contrast, models for natural surfaces have been compared extensively as part of the Project for Intercomparison of Land-surface Parameterization Schemes. Here, the methods and first results from an extensive international comparison of 33 models are presented. The aim of the comparison overall is to understand the complexity required to model energy and water exchanges in urban areas. The degree of complexity included in the models is outlined and impacts on model performance are discussed. During the comparison there have been significant developments in the models with resulting improvements in performance (root-mean-square error falling by up to two-thirds). Evaluation is based on a dataset containing net all-wave radiation, sensible heat, and latent heat flux observations for an industrial area in Vancouver, British Columbia, Canada. The aim of the comparison is twofold: to identify those modeling approaches that minimize the errors in the simulated fluxes of the urban energy balance and to determine the degree of model complexity required for accurate simulations. There is evidence that some classes of models perform better for individual fluxes but no model performs best or worst for all fluxes. In general, the simpler models perform as well as the more complex models based on all statistical measures. Generally the schemes have best overall capability to model net all-wave radiation and least capability to model latent heat flux.
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