Peripheral Mechanisms of Immunologic Tolerance

免疫耐受的外周机制

• 批准号: 7908835
• 负责人: DAVID M ROTHSTEIN
• 金额: $ 150.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908835
• 关键词: Peripheral; Mechanisms; Immunologic; Tolerance

DESCRIPTION (provided by applicant): The induction of tolerance in transplantation and autoimmunity remains an elusive clinical goal. A more thorough understanding of the fundamental mechanisms of immunologic tolerance is therefore necessary. We propose here a multidisciplinary approach to investigate peripheral mechanisms of immunologic tolerance by studying murine models of solid organ transplantation, bone marrow transplantation, and autoimmunity. A multidisciplinary approach is proposed because the mechanisms responsible for tolerance to self and foreign antigens overlap, and because significant cross-talk among the three clinical disciplines exists: bone marrow transplantation is increasingly employed to induce tolerance to solid organ allografts, and therapeutic agents used in transplantation are applicable to patients with autoimmunity (and vice versa). The PPG consists of three integrated projects and a core: histopathology. Integration among the projects is based on commonality of immunologic concepts, ongoing and future collaborations between the investigators, and the sharing of methods and resources. Project 1 will explore the mechanisms of dendritic cell maturation that lead to graft-versus-host disease (GVHD) following bone marrow transplantation. Project 2 will investigate tolerance induction via the generation of regulatory T cells (Treg) in a mouse model of inflammatory bowel disease. Project 3 will explore the phenomenon of immunologic ignorance by studying the innate and adaptive mechanisms that are responsible for continued recognition of a transplanted organ by the host's immune system. The Histopathology Core (Core B) will provide tissue processing, staining, immunohistochemistry, in situ hybridization, imaging, and interpretation services to all three projects. The Administrative Core (Core A) will provide logistical, communications and data sharing support.

描述（由申请人提供）：移植耐受和自身免疫的诱导仍然是一个难以捉摸的临床目标。因此，有必要更彻底地了解免疫耐受的基本机制。我们在此提出一种多学科方法，通过研究实体器官移植、骨髓移植和自身免疫的小鼠模型来研究免疫耐受的外周机制。提出了多学科方法，因为对自身和外来抗原的耐受机制是重叠的，而且三个临床学科之间存在显着的交叉：骨髓移植越来越多地用于诱导对实体器官同种异体移植物的耐受，移植中使用的治疗剂适用于自身免疫患者（反之亦然）。 PPG 由三个综合项目和一个核心组成：组织病理学。项目之间的整合基于免疫学概念的共性、研究人员之间正在进行和未来的合作以及方法和资源的共享。项目 1 将探讨骨髓移植后树突状细胞成熟导致移植物抗宿主病 (GVHD) 的机制。项目 2 将研究通过在炎症性肠病小鼠模型中生成调节性 T 细胞 (Treg) 来诱导耐受。项目 3 将通过研究宿主免疫系统持续识别移植器官的先天和适应性机制来探索免疫无知现象。 组织病理学核心（核心 B）将为这三个项目提供组织处理、染色、免疫组织化学、原位杂交、成像和解释服务。行政核心（核心A）将提供后勤、通信和数据共享支持。

项目成果

Digital transplantation pathology: combining whole slide imaging, multiplex staining and automated image analysis.

• DOI: 10.1111/j.1600-6143.2011.03797.x
• 发表时间: 2012-01
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Isse K;Lesniak A;Grama K;Roysam B;Minervini MI;Demetris AJ
• 通讯作者: Demetris AJ

The innate immune system in transplantation.

• DOI: 10.1016/j.smim.2011.06.006
• 发表时间: 2011-08
• 期刊: Seminars in immunology
• 影响因子: 7.8
• 作者: Oberbarnscheidt MH;Zecher D;Lakkis FG
• 通讯作者: Lakkis FG

Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice.

• DOI: 10.4049/jimmunol.0903805
• 发表时间: 2011-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wang Y;Camirand G;Lin Y;Froicu M;Deng S;Shlomchik WD;Lakkis FG;Rothstein DM
• 通讯作者: Rothstein DM

Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells.

• DOI: 10.4049/jimmunol.1002965
• 发表时间: 2011-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Li H;Matte-Martone C;Tan HS;Venkatesan S;McNiff J;Demetris AJ;Jain D;Lakkis F;Rothstein D;Shlomchik WD
• 通讯作者: Shlomchik WD

Profound depletion of host conventional dendritic cells, plasmacytoid dendritic cells, and B cells does not prevent graft-versus-host disease induction.

• DOI: 10.4049/jimmunol.1102795
• 发表时间: 2012-04-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Li H;Demetris AJ;McNiff J;Matte-Martone C;Tan HS;Rothstein DM;Lakkis FG;Shlomchik WD
• 通讯作者: Shlomchik WD