Dys/Regulation of the Immune System in Autoimmunity

描述（由申请人提供）：该计划的目标是了解自身免疫中免疫系统的调节和失调。该计划涉及三个部门成员之间的协作互动，并由三个核心设施组织成四个项目。免疫学、分子生物学和生物化学领域的专业知识将集中于启动和维持自身免疫反应的事件，以及包括自身免疫在内的调节过程。我们将回答以下问题。启动自身免疫反应的条件是什么？自身免疫反应是否受到调节，如果有，通过什么机制？正常情况下免疫调节是否包含自身免疫反应？最后，持续的自身免疫反应是否仍然是慢性的，因为它们从单一的初始反应多样化到对来自同一组织的其他自身抗原的反应？这些问题将通过这些项目的主要研究人员之间的协作互动来解决，具体方式如下：

DESCRIPTION (provided by applicant): The goal of this program is to understand the regulation and disregulation of the immune system in autoimmunity. The program involves collaborative interactions between members of three departments, and is organized into four projects supported by three core facilities. Expertise in the field of immunology, molecular biology, and biochemistry will focus on the events that initiate and sustain autoimmune responses, and the regulatory processes, which contain autoimmunity. We will address the following questions. What are the requirements to initiate autoimmune responses? Are autoimmune responses regulated, and if so, by what mechanisms? Does immune regulation contain autoimmune responses under normal circumstances? Finally, do sustained autoimmune responses remain chronic because they diversify from a single initiating response to responses to other autoantigens from the same tissue? These questions will be addressed by collaborative interactions between the Principal Investigators of these projects, which are as follows: (1) R.A. Flavell -Dr. Flavell will address the role of IL-10 in autoimmune disease. First, he will develop a novel model system to visualize IL-10 production in vitro and in vivo. Using a GFP knock-in strategy, IL-10 producing cells will be detectable through GFP expression. This will be used to visualize IL-10 production during EAE and IBD and can be used to monitor the effects on IL-10 of a number of interventional strategies, including Dr. Janeway's "therapeutic vaccination" using skin patch. He will also address whether IL-10 acts on T cells or antigen presenting cells in mediating its effects on EAE and IBD using mice transgenic for receptors that block IL-10 action. He has previously used this approach successfully for the other regulatory cytokine TGF-beta. This approach therefore appears promising. (2) C.A. Janeway Jr. -This project will examine the ability to generate suppressor or regulatory T cells in mice that are transgenic for the TCR of the MBP specific clone on a B10.PL background. They have recently observed that they can generate such cells in both induced and spontaneous disease. They will determine if they can observe the same phenotype in normal B10.PI mice, and mice reactive to other autoantigens. (3) M.J. Shlomchik -Transgenic mouse models will be used to study the regulation of B cells expressing a disease- related autoantibody, rheumatoid factor (RF), in normal and autoimmune mice. These B cells are activated spontaneously in autoimmune-prone mice, yet remain quiescent in normal mice. This system will be used to: 1 ) determine the factors -environmental and genetic -that are required for the onset and early propagation of disease; 2) define the cascade of events that leads from an initial nidus of proliferating autoreactive B cells to chronic, ongoing disease; and 3) determine the identities, at the phenotypic and molecular level, of the unique B lineage cells that have escaped peripheral tolerance. (4) M.J. Mamula -Overall, this proposal will examine B cell- T cell interactions in systemic autoimmune disease. The work will make use of autoantibody transgenic mice to determine their role in the maintenance of immune tolerance in normal strains of animals versus the induction of autoimmunity and pathology in autoimmune prone mice. Additional studies will examine how the levels and exposure to self antigens in vivo control the induction and perpetuation of B and T cell autoimmunity. These four projects will be supported by an Administrative Core (Core A) to coordinate the project as a whole, a genetically modified mouse core (Core B) to provide gene targeted and transgenic rodents essential to most of these studies, and a Cell Separation Core (Core C) to allow us to isolate cells and to analyze cells in all of these projects. The program is coordinated by frequent meetings of the program faculty and research workers bringing together these diverse approaches to address a common goal.