Novartis Foundation Symposium最新文献

{"title":"HSP27: an anti-inflammatory and immunomodulatory stress protein acting to dampen immune function.","authors":"Carol L Miller-Graziano,&nbsp;Asit De,&nbsp;Krzysztof Laudanski,&nbsp;Tara Herrmann,&nbsp;Sanjukta Bandyopadhyay","doi":"10.1002/9780470754030.ch15","DOIUrl":"https://doi.org/10.1002/9780470754030.ch15","url":null,"abstract":"<p><p>The effects of HSP27 on human monocytes (MO) are predominantly antiinflammatory through preferential interleukin (IL)10 induction and by alteration of MO to immature dendritic cells (iDCs) or MO to macrophage (Mac) differentiation. Initial HSP27 inclusion in IL4+GM-CSF MO to iDC induction cultures allows Mac differentiation (CD14++, CD16+), decreases iDC (CD1a+) differentiation, and depresses DC induction of allogeneic T lymphocyte proliferation (MLR). HSP27 increased MO IL10 and M-CSF production but subsequent increased Mac differentiation isn't responsible for depressed MO to iDC differentiation and function. Mac function after IL10 induced MO to Mac differentiation is also altered by HSP27 inclusion so that Mac phagocytic activity and scavenger receptor expression (CD163) are depressed. HSP27, in addition to immature DCs, doesn't increase Mac differentiation but instead generates inhibitory DCs, which depress rather than stimulate T cell proliferation even during anti CD3+CD28 induction. Upon maturation, these HSP27-altered inhibitory DCs have increased production of the T cell and DC suppressive mediator, thrombospondin 1. HSP27's anti-inflammatory and immunodepressive effects include deranging MO differentiation to both Mac and DCs, altering their receptor expression, and inducing production of inhibitory mediators such as thrombospondin-1 as well as IL10. These data suggest HSP27 belongs to a new group of 'anti-danger signals'.</p>","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"291 ","pages":"196-208; discussion 208-11, 221-4"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/9780470754030.ch15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27517649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD8 and cytotoxic T cells in type 1 diabetes.","authors":"Mark Peakman","doi":"10.1002/9780470697405.ch9","DOIUrl":"https://doi.org/10.1002/9780470697405.ch9","url":null,"abstract":"<p><p>The intra-islet cellular infiltrate found at post mortem in patients with new-onset Type 1 diabetes mellitus (T1DM) comprises both CD4+ and CD8+ cells, yet very few studies have investigated CD8 T cell responses to islet autoantigens. We therefore examined the response of peripheral blood CD8 T cells from new-onset T1DM patients and control subjects possessing HLA-A*0201 genes to potential CD8 T cell epitopes contained in a panel of peptides derived from proinsulin, glutamic acid decarboxylase, islet-specific glucose-6-phosphatase catalytic subunit-related protein and islet amyloid polypeptide, each putatively presented by the HLA class I molecule, HLA-A2.1 (A*0201) using a variety of techniques including in vitro culture with peptide, enzyme-linked immunospot (ELISPOT) assay and HLA tetramers. We find CD8 T cells present using these techniques, some of which have cytotoxic activity. The demonstration that rare islet autoreactive CD8 T cells are detectable in blood should promote mechanistic studies on these cells, as well as advancing T cell assay development.</p>","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"292 ","pages":"113-9; discussion 119-29, 202-3"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/9780470697405.ch9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27974152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune markers of disease and therapeutic intervention in type 1 diabetes.","authors":"Bart O Roep","doi":"10.1002/9780470697405.ch15","DOIUrl":"https://doi.org/10.1002/9780470697405.ch15","url":null,"abstract":"<p><p>Type 1 diabetes results from a T cell-mediated autoimmune destruction of the insulin-producing pancreatic beta cells in subjects with a genetic predisposition to this disease. Therapies directed against T cells have been shown to halt the disease process and prevent recurrent beta cell destruction after islet transplantation. Less is known about the mechanisms by which T cell-targeted therapies modify disease, how the immune system may suppress autoreactivity, and whether (or which) autoantigen(s) are critically involved in disease modulation. Autoreactive T cells have proven to be valuable tools to study pathogenic or diabetes-related processes. Measuring T cell autoreactivity has also provided critical information to determine the fate of islet allografts transplanted to type 1 diabetic patients. Unfortunately, cellular autoimmunity is a difficult study subject, and most activities were aiming at defining disease-associated T cell responses. A perhaps even more important goal will be to define and measure changes in T cell autoimmunity that are associated with disease intervention following immunotherapy, as autoantibodies do not qualify for this purpose. Recently, we have identified immune markers that associate with remission after initiation of insulin therapy ('honeymoon'), and disease suppression with antibody therapy (ATG, daclizumab, anti-CD3) or islet autoantigen. The challenge for the future is to determine which immune factors associate with tolerance to beta cell antigens, and to define what measures T cells can provide to suppress autoreactivity.</p>","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"292 ","pages":"159-71; discussion 171-3, 202-3"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/9780470697405.ch15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27974154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic pathology in type 1 diabetes in human.","authors":"Alan K Foulis","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>In type 1 autoimmune diabetes there is a selective destruction of insulin-secreting beta cells. Around the time of clinical presentation, insulitis, a chronic inflammatory infiltrate of the islets affecting primarily insulin containing islets, is present in the majority of cases. The inflammatory infiltrate consists primarily of T lymphocytes; CD8 cells outnumber CD4 cells, there are fewer B lymphocytes and macrophages are relatively scarce. beta cell death may involve the Fas apoptotic pathway since they have been shown to express Fas, infiltrating T lymphocytes express Fas-L and apoptotic beta cells have been described. Hyperexpression of class I MHC by all the endocrine cells in many insulin-containing islets is a well recognized phenomenon, characteristic of the disease. It has been argued that this is an earlier event than insulitis within a given islet and appears to be due to secretion of interferon alpha by beta cells within that islet. A recent study has found evidence of Coxsackie virus infection in beta cells in three out of six pancreases of patients with recent-onset type 1 diabetes. Coxsackie viruses are known to induce interferon alpha secretion by beta cells and this could initiate the sequence of events that culminates in their autoimmune destruction.</p>","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"292 ","pages":"2-13; discussion 13-8, 122-9, 202-3"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27974203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism.","authors":"Jinbo Fan,&nbsp;Pamela Sklar","doi":"10.1002/9780470751251.ch5","DOIUrl":"https://doi.org/10.1002/9780470751251.ch5","url":null,"abstract":"<p><p>Bipolar disorder is a chronic severe mood disorder that has been consistently demonstrated to have a strong inherited component. Traditional approaches to gene discovery have produced conflicting results regarding the association between genes and bipolar disorder. Numerous genes have been proposed as associated with bipolar disorder. This paper will focus on one of these, brain-derived neurotrophic factor (BDNF). BDNF is an interesting candidate gene for bipolar disorder because of its important role in the neurodevelopment of the CNS. Previous genetic work has identified a potential association between a Val66Met polymorphism in the BDNF gene and bipolar disorder. Meta-analysis based on all original published association studies between the Val66Met polymorphism and bipolar disorder up to May 2007 shows modest but statistically significant evidence for the association between the Val66Met polymorphism and bipolar disorder (random-effects pooled odds ratio [OR] = 1.13, 95% Confidence Interval [CI] = 1.04-1.23, Z = 2.85, P = 0.004) from 14 studies consisting of 4248 cases, 7080 control subjects and 858 nuclear families. Further large-scale studies are warranted to elucidate the relevant BDNF gene variation(s) that act as risk factors for bipolar disorder susceptibility.</p>","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"289 ","pages":"60-72; discussion 72-3, 87-93"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27456023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining optimal immunotherapies for type 1 diabetes. Introduction.","authors":"Matthias von Herrath","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"292 ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27974202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and therapeutic control of diabetogenic CD8+ T cells.","authors":"Pere Santamaria","doi":"10.1002/9780470697405.ch12","DOIUrl":"https://doi.org/10.1002/9780470697405.ch12","url":null,"abstract":"<p><p>CD8+ T cells are important contributors to the initiation and progression of type 1 diabetes (T1D). A very significant fraction of islet-associated CD8 T cells in NOD mice recognize epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), a non-essential endoplasmic reticulum-resident protein of unclear function. IGRP is also a target of CD8 T cell responses in human T1D patients. In NOD mice, most IGRP-reactive CD8 T cells target the IGRP(206-214) epitope and are diabetogenic. We have shown that the pathogenic activity of this T cell subset is controlled by genetic elements associated with diabetes susceptibility and resistance. One of these elements (Il2) has been recently implicated in susceptibility to several human autoimmune disorders, including TID. In mice, Il2 polymorphisms control a negative feedback mechanism initiated by activated, IL2-producing autoreactive T cells in the pancreatic lymph nodes that increases the regulatory activity of CD4+CD25+ T cells. Not all IGRP-reactive CD8 T cell clones are pathogenic, however, and we have evidence that some of these clonotypes are actually anti-diabetogenic. We had previously shown that administration of altered peptide ligands (APL) targeting IGRP(206-214)-reactive CD8 T cells resulted in diabetes protection only at doses that did not delete low-avidity clones, suggesting a protective role for these clonotypes. I discuss evidence showing that transgenic expression of a low-avidity IGRP(206-214)-reactive T cell receptor (TCR) efficiently prevents the development of insulitis and diabetes in NOD (non-obese diabetic) mice and that these cells do so by killing autoantigen-loaded antigen presenting cells in the pancreas-draining lymph nodes. These results illustrate a novel mechanism for regulation of immune responses to self-antigens and expose a new target for therapeutic intervention. Here I briefly summarize work done by us and others indicating that a prevalent subset of autoreactive CD8 T-cells in the NOD mouse are major (albeit likely dispensable) players in the pathogenesis of spontaneous autoimmune diabetes in the NOD mouse; that these T cells are targets of genetic elements affording autoimmune disease susceptibility and resistance; that they can either be diabetogenic or anti-diabetogenic according to their avidity for peptide/MHC; and that they can serve as useful targets for therapeutic intervention.</p>","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"292 ","pages":"130-6; discussion 136-45, 202-3"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/9780470697405.ch12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27978953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-environment interactions in environmental lung diseases.","authors":"S. Kleeberger, Hye-Youn Cho","doi":"10.1002/9780470696781.CH13","DOIUrl":"https://doi.org/10.1002/9780470696781.CH13","url":null,"abstract":"Lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) have complex etiologies. It is generally agreed that genetic background has an important role in susceptibility to these diseases, and the genetic contribution to disease phenotypes varies between populations. Linkage analyses have identified some predisposing genes. However, genetic background cannot account for all of the inter-individual variation in disease susceptibility. Interaction between genetic background and exposures to environmental stimuli, and understanding of the mechanisms through which environmental exposure interact with susceptibility genes, is critical to disease prevention. Use of animal models, particularly inbred mice, has provided important insight to understand human disease etiologies because genetic background and environmental exposures can be controlled. We have utilized a positional cloning approach in inbred mice to identify candidate susceptibility genes for oxidant-induced lung injury. Subsequent investigations with cell models identified functional polymorphisms in human homologues that confer enhanced risk of lung injury in humans. This 'bench to bedside' approach may provide an understanding of gene-environment interactions in complex lung diseases is essential to the development of new strategies for lung disease prevention and treatment.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"15 4","pages":"168-78; discussion 178-83"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50673940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What can we learn from the disrupted in schizophrenia 1 interactome: lessons for target identification and disease biology?","authors":"Luiz M Camargo,&nbsp;Qi Wang,&nbsp;Nicholas J Brandon","doi":"10.1002/9780470751251.ch17","DOIUrl":"https://doi.org/10.1002/9780470751251.ch17","url":null,"abstract":"<p><p>Emerging genetic and biological data strongly supports Disrupted in Schizophrenia 1 (DISC1) as a schizophrenia risk gene of great significance for not only understanding the underlying causes of schizophrenia and related disorders but potentially to open up new avenues of treatment. DISC1 appeared to be a very enigmatic protein upon the initial disclosure of its protein sequence. Though it contained some well-characterized protein domains, they did not reveal anything about possible function. Recently, the identification of its binding partners has revealed an incredible diversity of potential cellular and physiological functions. In an attempt to capture this information we set out to generate a comprehensive network of protein-protein interactions (PPIs) around DISC1. This was achieved by utilizing iterative yeast-two hybrid screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and has provided a molecular framework to explore the function of DISC1. Interrogation of the interactome has shown DISC1 to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Furthermore, potential novel therapeutic targets have also emerged as we have characterized in detail the interactions with the phosphodiesterase PDE4B in collaboration with the Porteous and Houslay labs, and with Ndel1-EOPA with Hayashi and colleagues. Many components of the interactome are themselves now being shown to be schizophrenia risk genes, or to interact with other risk genes, emphasising the power of protein interaction studies for revealing the underlying biology of a disease.</p>","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"289 ","pages":"208-16; discussion 216-21, 238-40"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27458051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The biology of extracellular molecular chaperones. Chair's introduction.","authors":"Péter Csermely","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"291 ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27517239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}