Transcriptional Control of Memory Responses to Red Blood Cell Alloimmunization

红细胞同种免疫记忆反应的转录控制

基本信息

批准号：
9017157
负责人：
CHANCE MARION JOHN LUCKEY
金额：
$ 11.84万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017157
关键词：
Transcriptional Control Memory Responses Red

项目摘要

DESCRIPTION (provided by applicant): RBC alloimmunization remains a common clinical problem in transfusion medicine. Alloantibodies are responsible for hemolytic transfusion reactions; leading to substantial morbidity and occasional mortality. For those patients unfortunate enough to make multiple alloantibodies, provision of compatible RBCs can be both time and resource intensive. In some cases, this can result in an inability to locate an otherwise life-saving therapy. Despite their clinical importance, our understanding of how long-lived memory RBC alloantibody responses are generated by the weak stimulus of RBC transfusion remains limited. Given that memory lymphocytes share functional attributes typically reserved for stem cells such as homeostatic self-renewal, we and others have hypothesized that they have reactivated a portion of the hematopoietic stem cell genetic program. In support of this idea, we published a common transcriptional signature shared between memory B cells, memory CD8+ T cells and hematopoietic stem cell. We have gone on to show that the transcription factor Pou6f1 is selectively upregulated in memory B and CD8+ T cells relative to shorter-lived cells. Pou6f1 is a member of the Pou-domain family of transcription factors and is a paralog of Pou5f1 (aka Oct4). Oct4 serves as one of the master regulators of embryonic stem cell self-renewal; establishing a stable, self-reinforcing genetic circuit that directs active transcription of self-renewal genes while maintaining differentiation specific transcription factor in an off, but poised state. We believe Pou6f1 functions in memory T and B cells in a manner similar to Oct4 in embryonic stem cells. The central hypothesis is that Pou6f1 directs memory antibody responses to RBC alloimmunization. This hypothesis leads to a set of predictions that we will test in vivo in a series of genetic and biochemical experiments combining Pou6f1 floxed mice we have recently generated with both the k and HOD RBC alloimmunization models. Aim 1 is to test the prediction that Pou6f1 expression in both T and B cells is required for the generation of long-lived, boostable RBC alloantibody responses. Aim 2 is to test the prediction that continued Pou6f1 expression in memory T and B lymphocytes is required to maintain recall responses to RBC alloimmunization, and that Pou6f1 is required to maintain responsiveness of antigen specific memory lymphocytes to homeostatic cytokine signals. In the fullness of time, we anticipate that identification of the molecular circuitry driving RBC antibody production will provide therapeutic and diagnostic targets for further clinical development.

描述（由申请人提供）：RBC同种免疫仍然是输血医学中常见的临床问题。同种抗体负责溶血输血反应；导致大量发病率和偶尔死亡率。对于那些不幸的患者来说，足以制造多种同种抗体，提供兼容的RBC可能是时间和资源密集型。在某些情况下，这可能导致无法定位原本挽救生命的疗法。尽管它们的临床重要性，但我们对RBC输血弱刺激产生的长期记忆RBC反应的理解仍然有限。鉴于记忆淋巴细胞具有通常用于稳态自我更新等干细胞的功能属性，我们和其他人假设它们已重新激活了造血干细胞遗传程序的一部分。为了支持这一想法，我们发表了记忆B细胞，内存CD8+ T细胞和造血干细胞之间共享的常见转录特征。我们继续表明，相对于寿命较短的细胞，在记忆B和CD8+ T细胞中，转录因子POU6F1在记忆B和CD8+ T细胞中被选择性上调。 POU6F1是转录因子的POU域家族的成员，是POU5F1的旁系同源物（又称OCT4）。 OCT4是胚胎干细胞自我更新的主要调节剂之一。建立一个稳定的，自我增强的遗传回路，该回路指导自我更新基因的主动转录，同时在OFF但保持平衡状态下保持分化特定的转录因子。我们认为，POU6F1在胚胎干细胞中类似于OCT4的方式在记忆T和B细胞中起作用。中心假设是POU6F1指导对RBC同种异体免疫化的内存抗体响应。该假设导致了一系列预测，我们将在一系列遗传和生化实验中测试，结合了POU6F1 Floxed小鼠，我们最近与K和HOD RBC同染色模型一起生成。 AIM 1是测试预测，即产生长寿，可增强的RBC同种抗体反应所必需的POU6F1表达。 AIM 2是测试以下预测，即需要在记忆T和B淋巴细胞中持续的POU6F1表达来维持对RBC同种异体免疫的召回反应，并且需要POU6F1来维持抗原特定记忆淋巴细胞对稳态细胞因子信号的反应性。在时间的饱满状态下，我们预计鉴定驱动RBC抗体产生的分子电路将为进一步的临床发育提供治疗和诊断靶标。