Role of autoreactivity in the pathogenesis of chronic GVHD

 描述(申请人提供)：慢性移植物抗宿主病(CGVHD)，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)长期幸存者发病和死亡的主要原因。我们项目的长期目标是剖析cGVHD发病的细胞和分子机制，并开发有效的预防和治疗cGVHD的方法。建议的研究将剖析移植物和从头产生的CD4T细胞与移植物和从头产生的B细胞相互作用以诱导cGVHD的机制，并阐明阻断GC的形成是否可以阻止cGVHD的诱导。我们最近利用MHC不相合的C57BL/6供者和BALB/c受体建立了cGVHD模型。结果表明，该模型较好地反映了GVHD从急性向慢性的过渡过程和临床观察的特点。供者CD4T细胞在宿主胸腺存在或不存在的情况下诱导cGVHD。但供者CD8T细胞仅在胸腺功能正常的受者中诱导cGVHD。供者CD8T细胞破坏了胸腺的阴性选择，导致了介导cGVHD的自身反应性CD4T细胞的产生。移植物中的供者B细胞和移植骨髓中的新B细胞在HCT增强供者CD4T细胞诱导cGVHD后产生新的B细胞。滤泡外和滤泡CD4T和B细胞相互作用的异常都被证明与系统性自身免疫性狼疮的发病有关。我们的初步研究使用了供者的移植，这些供者的B细胞是BCL6缺陷的，并且不能产生滤泡生发中心(GC)，因此根本没有降低cGVHD的严重程度。另一方面，来自其他研究人员的结果表明，GC的形成对于cGVHD的诱导和维持是必要的。本项目旨在验证两个与CD4T细胞和B细胞之间的相互作用在cGVHD发病机制中的作用相关的假说。1)来自移植物的成熟供者CD4T细胞与成熟的移植物B细胞和HCT后从头产生的B细胞相互作用，在没有GC形成的情况下诱导cGVHD，尽管某些干扰CD4T和B细胞之间相互作用的干预可以防止cGVHD。2)新生的CD4T和B细胞之间的相互作用可能导致GC的形成，但自身免疫会迅速破坏GC和淋巴组织。因此，阻止GC形成的干预措施并不能预防cGVHD。然而，同样，破坏CD4T和B细胞之间的相互作用可以预防cGVHD。拟议的研究将为CD4T和B细胞如何相互作用诱导和持续cGVHD提供新的见解，并将导致开发新的预防和治疗cGVHD的方案。

 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.