Integrated Functional Histopathology of the Diabetic Human Pancreas

糖尿病人胰腺的综合功能组织病理学

• 批准号: 10306379
• 负责人: DIRK HOMANN
• 金额: $ 69.9万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-07 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306379
• 关键词: Achievement; Address; Animal Model; Antigen-Presenting Cells; Antigens; Area; Attention; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Beta Cell; Blood Glucose; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Collaborations; Complement; Complex; Conceptions; Data Analyses; Data Set; Development; Diabetes Mellitus; Disease; Endocrine; Environmental Risk Factor; Epidemiology; Europe; Evolution; Exocrine pancreas; Face; Formalin; Foundations; Funding; Generations; Genetic Risk; Goals; Histopathology; Hormones; Human; Immune; Immune response; Immunofluorescence Immunologic; Immunohistochemistry; In Situ; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interferons; Investigation; Investments; Islets of Langerhans; Knowledge; Laboratories; Lesion; Light; Lobular; Manuals; Maps; Methodology; Modality; Nature; Organ Donor; Pancreas; Paraffin Embedding; Pathogenesis; Pathologic; Pathologic Processes; Pattern; Phenotype; Population; Prediabetes syndrome; Prevention; Prevention strategy; Process; Property; Protocols documentation; Public Health; Publications; Reproducibility; Research; Resources; Sampling; Signal Pathway; Slide; Source; Specimen; Stratification; Structure of beta Cell of islet; TNF gene; Technology; Therapeutic; Therapeutic Intervention; TimeLine; Tissue Banks; Tissue Embedding; Tissue Stains; Tissues; Tumor-infiltrating immune cells; United States National Institutes of Health; Work; automated image analysis; base; carbohydrate metabolism; comparative; cytokine; design; diabetes pathogenesis; diabetic; experience; high dimensionality; human disease; improved; insight; islet; lipid metabolism; macrophage; neglect; non-diabetic; novel; preservation; programs; prophylactic; protein metabolism; reconstruction; spatiotemporal; therapeutically effective

ABSTRACT Type 1 diabetes (T1D) is a major autoimmune disease that poses significant problems to afflicted individuals, the development of effective therapeutic interventions, and public health initiatives at large. Initiated and perpetuated by a complex interplay of genetic and environmental risk factors, insulin-secreting pancreatic beta- cells are progressively destroyed by aberrant immune responses leading to elevated blood glucose levels as well as serious disturbances of protein, fat and carbohydrate metabolism. Currently, no cure or effective prevention is available, and despite insulin treatment, serious long-term complications are frequent. Much of the progress in T1D research attained over the past four decades comes from the study of animal models yet despite many insights generated, a genuine appreciation of the human disease requires better knowledge about pathological processes unfolding directly in the human pancreas. The pursuit of this goal, however, faces two major challenges: the difficulty to obtain suitable tissues from pre/diabetic donors; and the fact that pertinent pathological alterations are often mild and distributed in a variegated fashion across the pancreas. Thus, information obtainable by traditional analysis of individual pancreatic tissue sections is limited. In the present proposal, which constitutes a direct continuation of our previously NIH-funded work on pancreatic histopathology, we will address these challenges by leveraging the resources of the Network of Pancreatic Organ Donors with Diabetes (nPOD) tissue repository together with the recent development or adaptation of two novel, highly multiplexed tissue staining technologies, and with the combined expertise and long-standing interactions of the von Herrath and Homann laboratories. This particular constellation of resources, technologies and experience allows us to tackle two critical knowledge gaps in specific: the detailed in situ phenotypes, functionalities, and interactions of major immune and endocrine cell populations in the pre/diabetic pancreas; and the contribution of specific cytokine signatures to as revealed in these cells to the hyperexpression of MHC-I, a histopathognomonic feature of T1D. Accordingly, we have developed a research plan that employs high-dimensional multiplexing strategies to interrogate the precise phenotype, activation status, contextual microanatomical localization and distribution of CD8+ and CD4+T cells, antigen presenting cells and B cells, and endocrine cells across the pre/diabetic human pancreas (Aim 1), and that will correlate major cytokine expression patterns (type 1 interferons, IFNγ, TNFα) and functional signatures with their cellular sources and targets as potential causes for MHC-I hyperexpression (Aim 2). Moreover, by conducting the work with tissue specimens from the same donors using two different multiplexing technologies in two different laboratories, we seek to achieve robustness and reproducibility of experimental readouts. Altogether, we propose that an integrated analysis of up to 30 phenotypic, functional and topological parameters will define spatiotemporal pathogenetic landmarks that will permit a partial reconstruction of the highly dynamic in situ autoimmune processes operative in T1D disease. Mapping the histopathological landscape of the pre/diabetic human pancreas in exquisite detail not only is important for our conception of disease pathogenesis but ultimately may inform the development of novel or improved prevention strategies and treatment modalities.

摘要 1型糖尿病（T1 D）是一种主要的自身免疫性疾病，对患病个体造成严重问题， 制定有效的治疗干预措施，以及广泛的公共卫生举措。发起并 由于遗传和环境风险因素的复杂相互作用，胰岛素分泌胰腺β- 细胞被异常的免疫反应逐渐破坏，导致血糖水平升高 蛋白质、脂肪和碳水化合物代谢的严重紊乱。目前，没有治愈或有效的预防措施， 尽管有胰岛素治疗，但严重的长期并发症仍很常见。 在过去的四十年里，T1 D研究取得的大部分进展来自对动物的研究。 然而，尽管产生了许多见解，但真正了解人类疾病需要更好的方法。 了解直接在人类胰腺中展开的病理过程。对这一目标的追求， 然而，面临着两个主要挑战：难以从糖尿病前期/糖尿病供体获得合适的组织; 相关的病理改变通常是轻微的，并且以多样化的方式分布在整个胰腺中。 因此，通过单个胰腺组织切片的传统分析可获得的信息是有限的。在 目前的建议，这构成了我们以前NIH资助的胰腺癌研究工作的直接延续。 组织病理学，我们将通过利用胰腺器官网络的资源来应对这些挑战。 糖尿病供体（nPOD）组织库以及两种新的， 高度多路复用的组织染色技术，并结合专业知识和长期的互动， 冯·赫拉特和霍曼实验室这种资源、技术和经验的特殊组合 使我们能够解决两个关键的知识差距具体：详细的原位表型，功能， 糖尿病前/糖尿病胰腺中主要免疫和内分泌细胞群的相互作用;以及 特异性细胞因子信号，如在这些细胞中显示的MHC-I的过度表达， T1 D的特点 因此，我们开发了一个研究计划，采用高维多路复用策略， 询问精确的表型，激活状态，背景显微解剖定位和分布， 糖尿病前期/糖尿病患者中的CD 8+和CD 4 +T细胞、抗原呈递细胞和B细胞以及内分泌细胞 胰腺（目标1），并将主要细胞因子表达模式（1型干扰素，IFNγ，TNFα）和 MHC-I高表达的潜在原因是其细胞来源和靶点的功能特征（Aim 2）。此外，通过使用两种不同的多路复用对来自相同供体的组织标本进行工作， 技术在两个不同的实验室，我们寻求实现实验的鲁棒性和再现性 读数总之，我们建议，综合分析多达30个表型，功能和拓扑 参数将定义时空发病标志，这将允许部分重建的高度 T1 D疾病中的动态原位自身免疫过程。绘制了一个组织病理学景观， 糖尿病前/糖尿病人胰腺的精细细节不仅对我们的疾病发病机制的概念很重要， 但最终可能为新的或改进的预防策略和治疗方式的发展提供信息。

项目成果

Effect of IL4 and IL10 on a human in vitro type 1 diabetes model.

IL4 和 IL10 对人体外 1 型糖尿病模型的影响。

• DOI: 10.1016/j.clim.2022.109076
• 发表时间: 2022
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Pfeiffer,SusanneEM;Quesada-Masachs,Estefania;McArdle,Sara;Zilberman,Samuel;Yesildag,Burcak;Mikulski,Zbigniew;vonHerrath,Matthias
• 通讯作者: vonHerrath,Matthias

IL-17 is expressed on beta and alpha cells of donors with type 1 and type 2 diabetes.

• DOI: 10.1016/j.jaut.2021.102708
• 发表时间: 2021-09
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Rajendran S;Quesada-Masachs E;Zilberman S;Graef M;Kiosses WB;Chu T;Benkahla MA;Lee JM;von Herrath M
• 通讯作者: von Herrath M