Role of autoreactivity in the pathogenesis of chronic GVHD

 描述（由申请人提供）：慢性移植物抗宿主病（cGVHD）是一种全身性自身免疫综合征，仍然是异基因造血细胞移植（HCT）长期存活者发病和死亡的主要原因。本课题的长期目标是深入研究cGVHD发病的细胞和分子机制，并开发出有效的防治cGVHD的方法。拟议的研究将剖析移植物和新生产生的CD 4 + T细胞与移植物和新生产生的B细胞相互作用以诱导cGVHD的机制，并阐明阻断GC形成是否可以防止cGVHD的诱导。我们最近开发了一个cGVHD模型，使用MHC不匹配的C57 BL/6供体和BALB/c受体。该模型的结果密切反映了从急性到慢性GVHD的转变以及在患者中临床观察到的特征。供体CD 4 + T细胞在存在或不存在宿主胸腺的情况下诱导cGVHD。但供体CD 8 + T细胞仅在具有功能性胸腺的受体中诱导cGVHD。供体CD 8 + T细胞破坏胸腺阴性选择，导致产生介导cGVHD的自身反应性CD 4 + T细胞。来自移植物的供体B细胞和HCT后从移植的骨髓从头产生的新B细胞增强了供体CD 4 + T细胞对cGVHD的诱导。滤泡外和滤泡CD 4 + T和B细胞相互作用的异常均被证明参与系统性自身免疫性狼疮的发病机制。我们的初步研究使用来自供体的移植物，供体的B细胞是BCL 6缺陷的，并且不能产生滤泡生发中心（GC），根本没有降低cGVHD的严重程度。另一方面，来自其他研究者的结果表明GC形成对于cGVHD的诱导和维持是必要的。本研究旨在验证CD 4 + T细胞和B细胞之间相互作用在cGVHD发病机制中的作用的两个相关假设。1)来自移植物的成熟供体CD 4 + T细胞与成熟移植物B细胞和HCT后新生B细胞相互作用，以在不存在GC形成的情况下诱导cGVHD，尽管某些破坏CD 4 + T和B细胞之间相互作用的干预可以预防cGVHD。2)新生CD 4 + T和B细胞之间的相互作用可能导致GC形成，但自身免疫迅速破坏GC和淋巴组织。因此，阻断GC形成的干预措施预计不会预防cGVHD。然而，再次，破坏CD 4 + T和B细胞之间的相互作用可以预防cGVHD。拟议的研究将为CD 4 + T细胞和B细胞如何相互作用以诱导和维持cGVHD提供新的见解，并将导致预防和治疗cGVHD的新方案的开发。

 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.