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（alloAb）在实体器官和细胞移植后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，细胞移植可能有较高的排斥和移植物损失风险。尽管体液异体免疫在临床移植中的重要性，但对于移植后同种异体抗体的同型、数量、特异性和致病性的调控却知之甚少。本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。我们出版的手稿首次证明了IFN？+CD8+ T细胞抑制移植后同种异体抗体的产生。我们的研究阐明了这种新的cd8依赖性移植后同种异体抗体调节机制，这代表了一种范式转变，是确定新的细胞和分子治疗靶点所必需的。在Aim 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/细胞因子受体在cd8介导的移植后同种异体抗体产生抑制中的关键作用。在目标2中，我们将鉴定cd8介导的杀伤异源B细胞所必需的细胞毒效应分子和MHC分子，并鉴定高和低异源抗体产生者中与异源B细胞相关的基因和蛋白质表达谱。在Aim 3中，我们将确定mTOR和CN抑制如何在体内差异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.