Novel Mechanisms Regulating Posttransplant Humoral Alloimmunity

描述（由申请人提供）：临床和实验数据支持MHC定向同种抗体（alloAb）在实体器官和细胞移植后的急性和慢性排斥反应中的致病作用。缺乏监测工具来检测和特异性免疫疗法来抑制体液同种异体免疫提出了重大的临床挑战。由于体液免疫，细胞移植可能有更高的排斥和移植物丢失风险。尽管体液同种免疫在临床移植中的重要性，但关于同种抗体在移植后的同种型、数量、特异性和致病性的调节相对知之甚少。该研究项目的总体重点是了解在存在或不存在常规免疫抑制的情况下调节alloAb产生的基本细胞和分子机制。我们出版的手稿提供了IFN？+ CD 8 + T细胞在抑制移植后alloAb产生的幅度中起作用。我们的研究阐明了这种新的移植后alloAb调控的CD 8依赖性机制，代表了识别新的细胞和分子治疗靶点所必需的范式转变。在目的1中，我们将研究先天性和适应性免疫细胞亚群和细胞因子/细胞因子受体对CD 8介导的移植后alloAb产生抑制的关键作用。在目标2中，我们将鉴定CD 8介导的同种异体致敏B细胞杀伤所必需的细胞毒性效应子和MHC分子，并鉴定在高和低同种异体抗体产生者中与同种异体致敏B细胞相关的基因和蛋白质表达谱。在目标3中，我们将确定mTOR和CN抑制如何在体内差异抑制移植后alloAb的产生。

DESCRIPTION (provided by applicant): Clinical and experimental data support a pathogenic role for MHC-directed alloantibodies (alloAb) in both acute and chronic rejection after solid organ and cell transplantation. The absence of monitoring tools to detect and specific immunotherapies to suppress humoral alloimmunity presents significant clinical challenges. Cellular transplants are likely at higher risk for rejection and graft loss due to humoral immunity. Despite the importance of humoral alloimmunity in clinical transplant, there is relatively little known about the regulation of isotypes, quantity, specificity and pathogenicity of alloAb after transplant. The overall focus of this research project is to understand fundamental cellular and molecular mechanisms regulating alloAb production in the presence or absence of conventional immunosuppression. Our manuscript in press provides first evidence of the pivotal role that IFN?+CD8+ T cells play in inhibiting the magnitude of post transplant alloAb production. Our studies to elucidate this novel CD8-dependent mechanism of post transplant alloAb regulation represents a paradigm shift necessary to identify new cellular and molecular therapeutic targets. In Aim 1, we will investigate the role of innate and adaptive immune cell subsets and cytokines/cytokine receptors critical to CD8-mediated inhibition of post transplant alloAb production. In Aim 2 we will identify cytotoxic effector and MHC molecules necessary for CD8-mediated killing of alloprimed B cells and identify gene and protein expression profiles associated with alloprimed B cells in high and low alloAb producers. In Aim 3 we will determine how mTOR and CN inhibition differentially suppress posttransplant alloAb production in vivo.