Abstract:
:Asthma is a common and complex inflammatory disease of the airways that remains incurable. Current forms of therapy are long term and may exhibit associated side-effect problems. Major participants in the development of an asthma phenotype include the triggering stimuli such as the allergens themselves, cells such as T cells, epithelial cells and mast cells that produce a variety of cytokines including IL-5, GM-CSF, IL-3, IL-4 and IL-13 and chemokines such as eotaxin. Significantly, the eosinophil, a specialized blood cell type, is invariably associated with this disease. The eosinophil has long been incriminated in the pathology of asthma due to its ability to release preformed and unique toxic substances as well as newly formed pro-inflammatory mediators. The regulation of eosinophil production and function is carried out by soluble peptides or factors. Of these IL-5, GM-CSF and IL-3 are of paramount importance as they control eosinophil functional activity and are the only known eosinophilopoietic factors. In addition they regulate the eosinophil life span by inhibiting apoptosis. While one therapeutic approach in asthma is directed at inhibiting single eosinophil products such as leukotrienes or single eosinophil regulators such as IL-5, we believe that the simultaneous inhibition of more than one component is preferable. This may be particularly important with eosinophil regulators in that not only IL-5, but also GM-CSF has been repeatedly implicated in clinical studies of asthma. The fact that GM-CSF is produced by many cells in the body and in copious amounts by lung epithelial cells highlights this need further. Our approach takes advantage of the fact that the IL-5 and GM-CSF receptors (as well as IL-3 receptors) utilize a shared subunit to bind, with high affinity, to these cytokines and the same common subunit mediates signal transduction culminating in all the biological activities mentioned. By generating the monoclonal antibody BION-1 to the cytokine binding region of the common subunit (betac) we have shown that the approach of inhibiting IL-5, GM-CSF and IL-3 binding and the resulting stimulation of eosinophil production and function with a single agent is feasible. Furthermore we have used BION-1 as a tool to crystallize and define the structure of the cytokine binding domain of betac. This knowledge and this approach may lead to the generation of novel therapeutics for the treatment of asthma.
journal_name
Immunol Cell Bioljournal_title
Immunology and cell biologyauthors
Ramshaw HS,Woodcock JM,Bagley CJ,McClure BJ,Hercus TR,Lopez AFdoi
10.1046/j.1440-1711.2001.00987.xsubject
Has Abstractpub_date
2001-04-01 00:00:00pages
154-9issue
2eissn
0818-9641issn
1440-1711pii
icb987journal_volume
79pub_type
杂志文章,评审abstract::We recently demonstrated that 17beta-estradiol (E2) enhances killing of Leishmania mexicana in macrophages from both male and female DBA/2 mouse by increasing nitric oxide (NO) production. Here, we analyzed the effect of E2 on leishmanicidal activity and cytokine production by bone marrow-derived macrophages (BMDMs) f...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.2008.39
更新日期:2008-08-01 00:00:00
abstract::Influx of Ca2+ via Ca2+ channels is the major step triggering exocytosis of pituitary somatotropes to release growth hormone (GH). Voltage-gated Ca2+ and K+ channels, the primary determinants of the influx of Ca2+, are regulated by GH-releasing hormone (GHRH) through G-protein-coupled intracellular signalling systems....
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1046/j.1440-1711.2000.00917.x
更新日期:2000-08-01 00:00:00
abstract::The present report provides the first extensive characterization of the OT-I TCR transgenic line, which produces MHC class I-restricted, ovalbumin-specific, CD8+ T cells (OT-I cells). These cells are shown to be positively selected in vivo in H-2b C57BL/6 mice and in bm5 mice, which express the Kbm5 mutant molecule. I...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1046/j.1440-1711.2000.00889.x
更新日期:2000-04-01 00:00:00
abstract::Plasma cells play a pivotal role in the immune system and are responsible for the synthesis and release of immunoglobulins. Numerous in vitro culture experiments on the yolk sac demonstrated the generation of mature cells of the myeloid and lymphoid lineages under appropriate culture conditions. However, there are no ...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1046/j.1440-1711.2003.t01-1-01178.x
更新日期:2003-10-01 00:00:00
abstract::Interleukin (IL)-9-producing CD4(+) T cells are a novel subset of T helper (Th) cells that develops independently of the Th1, Th2, Th17 and regulatory T-cell lineages. Similar to the murine model, transforming growth factor (TGF)-beta and IL-4 directed human naive CD4(+) T cells to produce IL-9. Whereas IL-4 suppresse...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.2010.53
更新日期:2010-08-01 00:00:00
abstract::Immunotherapy of tumours using T cells expanded in vitro has met with mixed clinical success suggesting that a greater understanding of tumour/T-cell interaction is required. We used a HPV16E7 oncoprotein-based mouse tumour model to study this further. In this study, we demonstrate that a HPV16E7 tumour passes through...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1111/j.0818-9641.2004.01273.x
更新日期:2004-10-01 00:00:00
abstract::Brucellosis remains a significant zoonotic threat worldwide. Humans and animals acquire infection via their oropharynx and upper respiratory tract following oral or aerosol exposure. After mucosal infection, brucellosis develops into a systemic disease. Mucosal vaccination could offer a viable alternative to conventio...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.2016.5
更新日期:2016-05-01 00:00:00
abstract::Hepatocyte growth factor (HGF) and its receptor c-Met signaling have been implicated in regulating various types of cells including epithelial cells. We have previously reported that c-Met is expressed by thymic epithelial cells (TECs), and that in vivo administration of hybrid cytokines containing IL-7 and the beta- ...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1111/imcb.1026
更新日期:2018-02-01 00:00:00
abstract::During an allergic inflammatory response in the airway, if a failure of the epithelial cell barrier occurs before the systemic immune response is triggered by allergens, more allergens can invade. Using a rat model of asthma, we previously found that mucosal mast cells, which localise to the epithelial layer of the ai...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.2010.90
更新日期:2011-02-01 00:00:00
abstract::Within the immune system multiple mechanisms balance the need for efficient pathogen recognition and destruction with the prevention of tissue damage by excessive, inappropriate or even self-targeting (auto)immune reactions. This immune homeostasis is a tightly regulated system which fails during tumor development, of...
journal_title:Immunology and cell biology
pub_type: 杂志文章,评审
doi:10.1111/imcb.12001
更新日期:2018-05-01 00:00:00
abstract::Mycobacterium tuberculosis uses numerous mechanisms to avoid elimination by the infected host. In this study, we investigated the possibility whether, similar to other pathogens, M. tuberculosis exploits natural CD4+ CD25+ T-regulatory cells (Treg) to suppress the effector function of responding host lymphocytes, thus...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1111/j.1440-1711.2006.01460.x
更新日期:2006-10-01 00:00:00
abstract::Peripheral tolerance mechanisms limit autoimmunity by constitutively eliminating self-reactive CD8+ T cells from the periphery in a process called deletion. Previous work has demonstrated that this deletion process is mediated by BIM-dependent apoptotic death due to transcriptional induction of the Bim gene. Currently...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.2016.53
更新日期:2016-10-01 00:00:00
abstract::Colorectal cancer (CRC) is one of the most prevalent cancers worldwide with rising mortality rates predicted in the coming decades. In light of this, there is a continued need for improvement in our understanding of CRC biology and the development of novel treatment options. Tumor-derived extracellular vesicles (tEVs)...
journal_title:Immunology and cell biology
pub_type: 杂志文章,评审
doi:10.1111/imcb.12038
更新日期:2018-03-25 00:00:00
abstract::PVG rats are resistant to actively induced experimental autoimmune encephalomyelitis (EAE) and this appears to be directly related to high and sustained systemic levels of reactive nitrogen intermediates(RNI) following sensitization for EAE when compared to the highly susceptible Lewis rat. An apparent cellular basis ...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1046/j.1440-1711.2002.01072.x
更新日期:2002-04-01 00:00:00
abstract::Several histone deacetylases (HDACs) are involved in the regulation of forkhead box protein P3 (FOXP3) expression and function by affecting features of FOXP3 protein stability. FOXP3, a forkhead family transcription factor specially expressed in regulatory T (Treg) cells, controls the expression of many key immune-reg...
journal_title:Immunology and cell biology
pub_type: 杂志文章,评审
doi:10.1038/icb.2011.101
更新日期:2012-01-01 00:00:00
abstract::See also: Outstanding Observation by Wirasinha et al., Short Communication by Barnes & Cyster. ...
journal_title:Immunology and cell biology
pub_type: 评论,杂志文章
doi:10.1111/imcb.12027
更新日期:2018-04-01 00:00:00
abstract::Genetic variants of interleukin 2 (IL-2) and its receptor are associated with murine and human susceptibility to Type 1 diabetes, yet the role of IL-2 in controlling pancreatic islet-reactive T cells is unknown. Here, we develop a model where IL-2 deficiency precipitates a breakdown of self-tolerance and progression t...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/sj.icb.7100049
更新日期:2007-06-01 00:00:00
abstract::Adjuvants are components that when added to subunit antigen (Ag) vaccines boost their immunogenicity and thus immune efficacy. However, there are few adjuvants that are approved for clinical use resulting in a critical need for the development of safe and effective adjuvants for use in both prophylactic and therapeuti...
journal_title:Immunology and cell biology
pub_type: 杂志文章,评审
doi:10.1038/icb.2009.21
更新日期:2009-07-01 00:00:00
abstract::Peyer's patches (PP) are important inductive sites for the mucosal immune response. It is well known that lymphocytes that migrate into PP are mainly of T-cell lineage from thymus-derived cells (i.e. alphabetaTCR(high) cells). In this study, we further characterized the properties of PP lymphocytes in mice using a mou...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1111/j.1440-1711.2005.01361.x
更新日期:2005-10-01 00:00:00
abstract::Many specific antiviral and antitumour immune responses have been attributed to the protective effects of antigen-specific CD8+ cytotoxic T lymphocytes (CTL). Recognition of virus infected or tumour cells by CTL requires presentation of at least one peptide epitope from a virus or tumour-specific antigen by the releva...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1046/j.1440-1711.2003.01130.x
更新日期:2003-02-01 00:00:00
abstract::The immune system has developed mechanisms to detect and initiate responses to a continual barrage of immunological challenges. Dendritic cells (DC), a heterogeneous population of leucocytes, play a major role as immunosurveillance agents. To accomplish this function, DC are equipped with highly efficient mechanisms t...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1111/j.1440-1711.2004.01216.x
更新日期:2004-02-01 00:00:00
abstract::γδ T cells producing interleukin-17A (γδT17) are thought to develop spontaneously in the thymus and to be maintained in the periphery. Previous studies suggested a role for T-helper 17 (Th17) cells in the maintenance of γδT17 via the expression of transforming growth factor-β1 (TGFβ1). However, we have previously foun...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.2016.94
更新日期:2017-03-01 00:00:00
abstract::The evolutionarily conserved catabolic process of autophagy involves the degradation of cytoplasmic components through lysosomal enzymes. Basal levels of autophagy maintain cellular homeostasis and under stress conditions high levels of autophagy are induced. It is often under such stress conditions that high levels o...
journal_title:Immunology and cell biology
pub_type: 杂志文章,评审
doi:10.1038/icb.2014.85
更新日期:2015-01-01 00:00:00
abstract::Adult Nematospiroides dubius excretory-secretory (ES) products were collected from worms cultured in vitro, radiolabelled and separated by sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE). The components were characterized and assessed for molecular weight (MW) after autoradiography and gel staining, for a...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.1989.16
更新日期:1989-04-01 00:00:00
abstract::Inappropriate activation of p34cdc2 kinase has been shown to occur during apoptosis induced by cytotoxic T-cell derived perforin and fragmentin. We analysed the effect of two inhibitors of p34cdc2 kinase on alloreactive Tc-cell-mediated lysis and DNA fragmentation of P815 and L1210 target cells. Olomoucine, a specific...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1046/j.1440-1711.2001.01008.x
更新日期:2001-06-01 00:00:00
abstract::Recombinant DNA techniques were used to clone, construct and express the bifunctional molecule FV/IL-2. The FV/IL-2 is a single-chain 37 kDa fusion protein expressed in Escherichia coli under control of the strong T7 bacteriophage promoter in the expression vector pT7-7-FV-IL-2. The fused gene fragment FV-IL-2 contain...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/icb.1994.42
更新日期:1994-08-01 00:00:00
abstract::Activins and inhibins are members of the transforming growth factor-β superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation...
journal_title:Immunology and cell biology
pub_type: 杂志文章,评审
doi:10.1038/icb.2011.32
更新日期:2012-02-01 00:00:00
abstract::Th-cell development has been suggested to include selective mechanisms in which certain cytokines select either Th1 or Th2 cells to proliferate and grow. The selective theory is based on the observation that Th2 cells secrete IL-4, a cytokine that promotes Th2 development, whereas Th1 cells secrete interferon-gamma (I...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/sj.icb.7100023
更新日期:2007-04-01 00:00:00
abstract::The identification of the genes that make up rearranged immunoglobulin genes is critical to many studies. For example, the enumeration of mutations in immunoglobulin genes is important for the prognosis of chronic lymphocytic leukemia, and this requires the accurate identification of the germline genes from which a pa...
journal_title:Immunology and cell biology
pub_type: 杂志文章
doi:10.1038/sj.icb.7100144
更新日期:2008-02-01 00:00:00
abstract::The molecular interactions between the T-cell receptor (TCR) and peptide-MHC (pMHC) have been elucidated in recent years. Nevertheless, the fact that binding of only slightly different ligands by a TCR, or ligation of the same pMHC at different developmental stages of the T cell, can have opposing consequences, contin...
journal_title:Immunology and cell biology
pub_type: 杂志文章,评审
doi:10.1046/j.1440-1711.2001.00994.x
更新日期:2001-04-01 00:00:00