Novel Mechanisms Regulating Posttransplant Humoral Alloimmunity

描述(由申请人提供)：临床和实验数据支持MHC导向的同种异体抗体在固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定的免疫疗法来抑制体液同种免疫给临床带来了巨大的挑战。由于体液免疫，细胞移植可能有更高的排斥反应和移植物丢失风险。尽管体液免疫在临床移植中具有重要意义，但对移植后同种异体抗体的亚型、数量、特异性和致病性的调控知之甚少。这一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同种异体抗体产生的基本细胞和分子机制。我们的手稿首次证明了干扰素？+CD8+T细胞在抑制移植后同种异体抗体的产生中起着关键作用。我们的研究旨在阐明移植后同种异体抗体调节的这种新的CD8依赖机制，这是识别新的细胞和分子治疗靶点所必需的范式转变。在目标1中，我们将研究先天和获得性免疫细胞亚群以及细胞因子/细胞因子受体在CD8介导的抑制移植后同种异体抗体产生中的关键作用。在目标2中，我们将确定CD8介导的异体重组B细胞杀伤所必需的细胞毒效应分子和MHC分子，并在高和低异基因抗体产生者中鉴定与异体重组B细胞相关的基因和蛋白表达谱。在目标3中，我们将确定mTOR和CN抑制如何在体内不同地抑制移植后同种异体抗体的产生。

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.