Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes
人类 1 型糖尿病中胰腺 CD8 T 细胞的特异性、表型和功能
基本信息
- 批准号:10061526
- 负责人:
- 金额:$ 45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-05-02 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAntigensAntiviral AgentsAreaAttentionAutoantigensAutoimmune DiseasesBeta CellCD8-Positive T-LymphocytesCell physiologyCellsChronicCollaborationsCollectionCoxsackie B VirusesCytomegalovirusCytoskeletonCytotoxic T-LymphocytesDataDatabasesDevelopmentDiabetes MellitusDiseaseDisease ProgressionDrug or chemical Tissue DistributionEndocrineEnterovirusEpitopesEventExocrine pancreasFreezingFrequenciesG6PC2 geneGoalsHLA-A2 AntigenHerpesviridaeHistocompatibility Antigens Class IHistopathologyHumanHuman Herpesvirus 4Human Herpesvirus 6ImmuneImmune mediated destructionIn SituIn VitroIndividualInflammationInstitutesInsulinInsulin-Dependent Diabetes MellitusInterferonsIslets of LangerhansKnowledgeLaboratoriesLeadLesionMapsMethodsNucleic AcidsOrganOrgan DonorPancreasPathogenesisPathologicPathologyPathway interactionsPatientsPeptidesPhenotypePlayPopulationPrediabetes syndromeProductionProteinsRNAResearchRoleRunningSamplingSpecificityStainsStructure of beta Cell of isletT-LymphocyteT-Lymphocyte EpitopesTimeTimeLineTissuesTumor-infiltrating immune cellsUniversity HospitalsUp-RegulationValidationViralViral AntigensViral GenomeViral ProteinsVirusVirus DiseasesWorkautoreactivitybasebiobankcell injurycell typecytokinedesigndiabetes pathogenesisdiabeticexperimental studyillness lengthin vitro Assayinflammatory milieuinsulitisinterestisletneoantigensnon-diabeticnovelnovel therapeuticsphenotypic biomarkerrepositorytherapeutic targetviral detectionvirology
项目摘要
PROJECT SUMMARY
Human type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing
pancreatic beta cells. CD8 T cells are the most common [immune] cell found in insulitic lesions and are the
principal T cell type implicated in beta cell destruction. Studies performed within this project have already
revealed significant [and novel] findings including: 1) the first identification of auto-reactive CD8 T cells in the
islets of patients with T1D using a specially [designed method of] tetramer staining and 2) [the first description
of high] numbers of CD8 T cells infiltrating the exocrine pancreas in T1D patients compared with non-diabetic
individuals. Based on these findings, we anticipate that only a proportion of the cells that infiltrate the pancreas
are indeed auto-reactive. Thus, the pool of `bystander' CD8 T cells that recognize other, for example viral,
antigens might significantly contribute to the inflammatory environment of the organ. At present, the overall
specificities and frequencies of CD8 T cells in the pancreas and the cause for their entry and activation are not
fully understood. Possible targets are known autoantigens derived from beta cells such as insulin, IGRP, IA-2
and GAD (see Table 2 for abbreviations) and cellular matrix proteins, which could become presented [and
modified] when beta cells are destroyed, but viral proteins, for example enteroviral determinants are also
possible candidates. The overall objective of this renewal application is therefore to compare the
specificity, phenotype and function of CD8 T lymphocytes from human islets with those found in
exocrine tissue, and to assess whether their presence correlates with islet-specific pathology (e.g.
viral infections and their detectable footprints). We will study patients with recent-onset and longstanding
T1D in order to build a road map of specificities and to further understand how the relationship between the
CD8 T cell infiltrate and the disease course might evolve [both quantitatively and qualitatively over time. A
unique strength is not only the access to very unique organ repositories but also the newly established
collaboration with Dr. Alessandro Sette and Dr. Bjoern Peters' laboratories, which maintain the Immune
Epitope Database (IEDB) at La Jolla institute and are part of an epitope discovery initiative led by Novo
Nordisk. Using the information contained in the IEDB and in vitro assays, neo-epitopes to modified
autoantigens and new viral CD8 T cell epitopes restricted to HLA-A2 will be mapped and the information
shared with our laboratory. Overall, our findings should give us a better understanding of how and why T1D
develops and thus help ultimately with the development of new therapeutic options.]
Our first goal is to systematically and quantitatively detect autoreactive CD8 T cells within human islets and
exocrine pancreas and to correlate the number and activation status of these cells with the local
histopathology of the organ. In situ tetramer staining of freshly frozen human pancreata available from the
Network for Pancreatic Organ Donors with Diabetes (nPOD), the Diabetes Biobank Brussels (DBB) and the
Biobank at Oslo University Hospital will be performed. [The discovery of new post-translationally-modified
epitopes using the information contained in the IEDB and the expertise at La Jolla Institute in conjunction with
our experiments in situ will provide, for the first time,] information on the precise tissue distribution of antigen-
specific CD8 T cells in the pancreas. In addition, we will further characterize their phenotype and function. This
will allow for the identification of key antigens with significant polarization towards the islets, which are more
likely to be involved in the pathogenesis of disease. It will also help us to understand why exocrine pancreas
inflammation is often present in T1D.
Our second goal is to search for virus-specific T cells within islets and exocrine tissue. [This will help to
ascertain whether one virus might trigger the disease (hit-and-run event) or whether numerous viral attacks
are required (multiple hits) or several viral strains of the same genus or even different viruses that trigger
common pathways might play a role in the pathogenesis of the disease (multiple viruses)]. Pancreas tissue
sections from donors with recent-onset and long duration of T1D will therefore be probed with virus-specific
tetramers, and we will detect any viral proteins and nucleic acids in these samples in collaboration with the
nPOD-Virology group in order to investigate the manner of viral infection (hit-and-run; multiple hits or multiple
viruses). We will initially focus our attention on enteroviruses (EV), as only the association with group B
coxsackieviruses has thus far been sufficiently documented. [For this purpose, we will aim to identify new EV
epitopes through our collaboration with Dr. Sette and Dr. Peters' laboratories and the use of the IEDB as well
as their expertise on the discovery and validation of cytotoxic and T cell epitopes presented by HLA Class I
molecules]. The frequency of EV-specific cells will be compared to that of other common viruses such as
cytomegalovirus (CMV) and Epstein-Barr virus (EBV). We will also investigate the possible presence of
herpesvirus-6 (HHV6) and HHV6-specific CD8 T cells, because recent evidence suggests that this virus might
be present in the pancreas of T1D donors. In addition, we will correlate our findings with the local
histopathology of the organ (MHC-I expression, interferon signature, CD8 T cell phenotype, cytokine
production and presence/absence of viral protein or genome).
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Matthias G. Von Herrath其他文献
Matthias G. Von Herrath的其他文献
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$ 45万 - 项目类别:
Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes
人类 1 型糖尿病中胰腺 CD8 T 细胞的特异性、表型和功能
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