MOLECULAR AND CELLULAR REGULATION OF TOLERANCE

这是一个综合性的研究工作，以了解和定义基本的 宽容的机制。组织各个项目， 调节免疫诱导和维持的过程 对自身抗原无反应这个节目的统一主题是 容忍是一个复杂的过程， 以及解剖学影响和B T细胞在决定对自身的反应性方面起着关键作用， 病原体相关抗原。因此，试图理解宽容， 机械水平必须利用实验来考虑这种复杂性 系统，便于定义公差机制， 这种复杂性的背景。拟议的方案将通过以下方式实现这一目标： 将具有以下专业知识的研究人员聚集在一起： 定义免疫调节的复杂性和研究承诺， 理解宽容的机制。每一个实验室 在B和T细胞免疫生物学以及这些细胞如何 相互作用以及与其他免疫系统部分相互作用。在 项目1和项目4将采用创新的新技术， 体外复杂细胞和分子过程的定义 模拟耐受和活化的体内过程的培养物。在 项目2，一个新发现的与无反应性T细胞相关的分子 将用于从复杂的离体群体中分离这些细胞 然后定义T细胞无反应性的分子基础。项目3利用 一项新的发现，即B细胞是T细胞臀位所必需的， NOD小鼠自身免疫的耐受性。养父 参与自身免疫的特定细胞成分的转移 反应将允许定义诱导的细胞基础， 自身免疫性糖尿病的小鼠模型。主要研究者 参与这些项目的科学家有着悠久的科学互动历史， 他们希望通过成功的资助来维持和扩大 这个应用程序。

This is an integrative research effort to understand and define basic mechanisms of tolerance. Individual projects are organized to define processes regulating induction and maintenance of immunologic unresponsiveness to self-antigens. The unifying theme of this program is that tolerance is a complex process in which the inherent responsiveness of immune cells as well as anatomic influences and interactions between B and T cells play pivotal roles in determining responsiveness to self and pathogen-associated antigens. As such, attempts to understand tolerance at the mechanistic level must consider this complexity utilize experimental systems that facilitate definition of tolerance mechanism within the context of this complexity. The program proposed will accomplish this by bringing together individual investigators with demonstrated expertise in defining the complexity of immunoregulation and a research commitment to understanding mechanisms of tolerance. Each of the laboratories involved has specific expertise in B and T cell immunobiology and how these cells interact with one another and with other immune system moieties. In Projects 1 and 4, an innovative new technology will be used to allow definition of cellular and molecular processes within complex in vitro cultures that model the in vivo process of tolerance and activation. In Project 2, a newly discovered molecule associated with anergic T cells will be exploited to isolate these cells from complex ex vivo populations and then define the molecular basis of T cell anergy. Project 3 exploits a new finding that B cells are necessary for the breech of T cell tolerance that accounts for autoimmunity in the NOD mouse. Adoptive transfer of specific cellular components involved in the autoimmune reaction will allow the definition of the cellular basis for induction of autoimmune diabetes in this mouse model. The principal investigators involved with these projects have a long history of scientific interaction that they wish to maintain and expand through the successful funding of this application.