Role of autoreactivity in the pathogenesis of chronic GVHD

自身反应性在慢性 GVHD 发病机制中的作用

• 批准号: 9189582
• 负责人: Defu Zeng
• 金额: $ 43.4万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189582
• 关键词: Acute; Address; Allogenic; Animal Model; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocytes; BCL6 gene; Bronchiolitis; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Characteristics; Clinical; Development; Disease; Disease model; Donor person; Fibrosis; Generations; Goals; Hematologic Neoplasms; Human; IgG1; IgG3; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Inbred BALB C Mice; Infusion procedures; Intervention; Lacrimal gland structure; Lead; Long-Term Survivors; Lupus; Lymphocyte; Lymphoid Tissue; Lymphopenia; MS4A1 gene; Maintenance; Marrow; Mediating; Modeling; Molecular; Morbidity - disease rate; Onset of illness; PDCD1LG1 gene; Pathogenesis; Patients; Prevention; Prevention therapy; Recovery; Regimen; Regulatory T-Lymphocyte; Reporting; Research Personnel; Role; Salivary Glands; Scleroderma; Serum; Severities; Severity of illness; Somatic Mutation; Spleen; Structure of germinal center of lymph node; Syndrome; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Transplantation; autoreactivity; cell injury; chronic graft versus host disease; curative treatments; design; effective therapy; graft vs host disease; hematopoietic cell transplantation; insight; mortality; mouse model; novel; prevent; public health relevance; Acute; Address; Allogenic; Animal Model; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocytes; BCL6 gene; Bronchiolitis; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Characteristics; Clinical; Development; Disease; Disease model; Donor person; Fibrosis; Generations; Goals; Hematologic Neoplasms; Human; IgG1; IgG3; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Inbred BALB C Mice; Infusion procedures; Intervention; Lacrimal gland structure; Lead; Long-Term Survivors; Lupus; Lymphocyte; Lymphoid Tissue; Lymphopenia; MS4A1 gene; Maintenance; Marrow; Mediating; Modeling; Molecular; Morbidity - disease rate; Onset of illness; PDCD1LG1 gene; Pathogenesis; Patients; Prevention; Prevention therapy; Recovery; Regimen; Regulatory T-Lymphocyte; Reporting; Research Personnel; Role; Salivary Glands; Scleroderma; Serum; Severities; Severity of illness; Somatic Mutation; Spleen; Structure of germinal center of lymph node; Syndrome; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Transplantation; autoreactivity; cell injury; chronic graft versus host disease; curative treatments; design; effective therapy; graft vs host disease; hematopoietic cell transplantation; insight; mortality; mouse model; novel; prevent; public health relevance

 DESCRIPTION (provided by applicant): Chronic graft versus host disease (cGVHD), a systemic autoimmune syndrome, remains the major cause of morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT). The long- term goals of our project are to dissect the cellular and molecular mechanisms of cGVHD pathogenesis, and to develop effective therapies for prevention and treatment of cGVHD. The proposed studies will dissect the mechanisms whereby graft and de novo- generated CD4+ T cells interact with graft and de novo-generated B cells to induce cGVHD and clarify whether blockade of GC formation can prevent induction of cGVHD. We have recently developed a cGVHD model using MHC-mismatched C57BL/6 donors and BALB/c recipients. Results with this model closely reflect the transition from acute to chronic GVHD and characteristic features observed clinically in patients. Donor CD4+ T cells induced cGVHD in the presence or absence of host thymus. But donor CD8+ T cells induced cGVHD only in recipients with a functioning thymus. Donor CD8+ T cells damaged thymic negative selection, resulting in generation of autoreactive CD4+ T cells that mediate cGVHD. Donor B cells from the graft and new B cells generated de novo from the engrafted marrow after HCT augment induction of cGVHD by donor CD4+ T cells. Abnormalities in extrafollicular and follicular CD4+ T and B cell interactions have both been shown to be involved in systemic autoimmune lupus pathogenesis. Our preliminary studies using transplants from donors whose B cells are BCL6-deficient and cannot give rise to follicular germinal centers (GCs) did not reduce cGVHD severity at all. On the other hand, results from other investigators have suggested that GC formation is necessary for induction and maintenance of cGVHD. This project is designed to test two related hypotheses relevant to the role of interactions between CD4+ T cells and B cells in the pathogenesis of cGVHD. 1) Mature donor CD4+ T cells from the graft interact with mature graft B cells and de novo-generated B cells after HCT to induce cGVHD in the absence of GC formation, although certain interventions that disrupt interactions between CD4+ T and B cells can prevent cGVHD. 2) Interactions between de novo-generated CD4+ T and B cells may lead to GC formation, but autoimmunity rapidly destroys the GCs and lymphoid tissues. Thus, interventions that block GC formation are not expected to prevent cGVHD. Again, however, disruption of interactions between CD4+ T and B cells can prevent cGVHD. The proposed studies will provide new insights into how CD4+ T and B cells interact to induce and perpetuate cGVHD and will lead to the development of novel regimens for prevention and treatment of cGVHD.

 描述（由适用提供）：一种全身性自身免疫性综合征，慢性移植与宿主疾病（CGVHD）仍然是同种异体造血细胞移植（HCT）长期生存的发病率和死亡率的主要原因。我们项目的长期目标是剖析CGVHD发病机理的细胞和分子机制，并开发有效的预防和治疗CGVHD的疗法。拟议的研究将剖析晶粒和从头生成的CD4+ T细胞与谷物和从头生成的B细胞相互作用以诱导CGVHD并阐明GC形成的阻滞是否可以防止诱导CGVHD的机制。我们最近使用MHC不匹配的C57BL/6捐赠者和BALB/C受体开发了CGVHD模型。该模型的结果密切反映了从急性到慢性GVHD的过渡以及患者临床观察到的特征特征。供体CD4+ T细胞在存在或不存在宿主胸腺的情况下诱导CGVHD。但是供体CD8+ T细胞仅在胸腺功能正常的受体中诱导CGVHD。供体CD8+ T细胞损坏了胸腺阴性选择，从而导致介导CGVHD的自动反应性CD4+ T细胞产生。来自移植物和新B细胞的供体B细胞在HCT通过供体CD4+ T细胞增强CGVHD诱导后，从植入的骨髓产生了从头开始。毛囊外和卵泡CD4+ T和B细胞相互作用的异常都被证明参与了系统性自身免疫性狼疮发病机理。我们的初步研究使用B细胞缺乏BCl6的供体的移植，无法引起卵泡生发中心（GC）根本不会降低CGVHD严重程度。另一方面，其他研究人员的结果表明，GC形成对于CGVHD的诱导和维护是必需的。该项目旨在测试与CD4+ T细胞与B细胞之间相互作用在CGVHD发病机理中相互作用的作用相关的两个相关假设。 1）来自图形的成熟供体CD4+ T细胞与成熟的图形B细胞相互作用，HCT后从头产生的B细胞在没有GC形成的情况下诱导CGVHD，尽管某些相互作用破坏了CD4+ T和B细胞之间的相互作用可以预防CGVHD。 2）从头生成的CD4+ T和B细胞之间的相互作用可能导致GC形成，但是自身免疫会迅速破坏GCS和淋巴组织。那是阻止GC形成的干预措施，预计不会预防CGVHD。但是，CD4+ T和B细胞之间相互作用的破坏可以预防CGVHD。拟议的研究将提供有关CD4+ T和B细胞如何相互作用以诱导和永存CGVHD的新见解，并将导致开发用于预防和治疗CGVHD的新型方案。