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Mechanisms of alloantibody production following renal transplantation

Mechanisms of alloantibody production following renal transplantation
肾移植后同种抗体产生的机制
批准号:
10228265
负责人:
Anna Valujskikh
金额:
$62.1万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-02-22 至 2026-01-31

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中文摘要
翻译
摘要 急性和慢性抗体介导的排斥反应(AMR)严重威胁着移植物的生存和功能。 移植的器官。目前预防和治疗AMR的选择受到不完全的限制 了解供体特异性同种异体抗体(DSA)产生和致病的机制 功能。而高亲和力同型转换DSA的产生通常与生发有关 滤泡B细胞的中心形成,边缘带(MZ)B细胞对抗供体反应的贡献 移植后的问题以前没有被解决过。我们的初步研究确定MZ B细胞是 在协调DSA反应中的重要角色,并保证对这个B细胞亚群进行详细的调查 降低移植受者体液同种免疫的最终目标。 供体移植物长期冷缺血保存(CIS)和随后的缺血/再灌注损伤(IRI) 在移植结果不佳的主要风险因素中。使用一种小鼠肾移植模型 我们对同种异体移植物进行了6h的CIS,我们发现移植后的炎症特别是增加了生成量 介导同种异体移植肾小球损伤的II类反应性DSA。这些发现与临床高度相关。 研究显示较长的冷缺血时间、抗II类DSA与晚期AMR的相关性 移植病人。然而,移植后炎症影响血管生成的机制 致病的II类DSA和B细胞激活的供体II类抗原的来源还不清楚。 根据我们的初步数据,我们假设IRI通过以下方式放大II类DSA的产生 步骤:1)IRI上调供体内皮细胞MHC-II类的表达和EC-II类分子的释放 含有细胞外小泡(EEVS);2)脾MZ B细胞迅速获得循环中的EEVS,早期产生 DSA和促进FO B细胞进一步产生DSA;以及,3)除了供体同种异体抗原,MZ B细胞 移植物衍生的EV携带的阻尼剂以及IRI的全身效应启动和增强了激活。 因此,靶向MZ B细胞的运输、激活和功能将抑制致病II类的产生 数字减影血管造影术,改善持续顺应性肾移植的预后。我们将在三个月内检验这一假说 具体目标: 目的1.检测缺血/再灌注损伤(IRI)是否通过增强血管内皮细胞而增加II类DSA 细胞外小泡(EEV)的产生。目的2.检测MZ B细胞在肾脏DSA产生中的作用 移植。目的3.探讨MZ B细胞在致病性II类DSA形成中的作用 经长期冷缺血保存的同种异体肾。 拟议的研究将填补目前关于体液同种免疫反应的几个空白。 血管器官移植,并确定潜在的治疗干预目标,以抑制抗体- 中介性排斥。
英文摘要
ABSTRACT Acute and chronic antibody-mediated rejection (AMR) is a serious threat to the survival and function of transplanted organs. The current options for AMR prevention and treatment are limited by the incomplete understanding of the mechanisms underlying donor specific alloantibody (DSA) generation and pathogenic functions. Whereas the production of high affinity isotype-switched DSA is typically associated with germinal center formation by follicular B cells, the contribution of marginal zone (MZ) B cells to anti-donor responses following transplantation has not been previously addressed. Our preliminary studies identify MZ B cells as important players in orchestrating DSA responses and warrant detailed investigation of this B cell subset with an ultimate objective of reducing humoral alloimmunity in transplant recipients. Prolonged cold ischemia storage (CIS) of donor allografts and ensuing ischemia/reperfusion injury (IRI) remain among leading risk factors for poor transplant outcome. Using a mouse model of kidney transplantation in which allografts are subjected to 6 h CIS, we found that posttransplant inflammation specifically augments generation of class II-reactive DSA that mediate allograft glomerular injury. These findings are highly relevant to clinical studies revealing correlations between longer cold ischemia time, anti-class II DSA and late AMR in renal transplant patients. However, the mechanisms by which posttransplant inflammation affects generation of pathogenic class II DSA and the very source of donor class II antigens for B cell activation are poorly defined. Based on our preliminary data, we hypothesize that IRI amplifies class II DSA production through the following steps: 1) IRI up-regulates MHC class II expression on donor endothelial cells (EC) and EC release of class II containing extracellular vesicles (EEVs); 2) spleen MZ B cells rapidly acquire circulating EEVs, produce early DSA and facilitate further DSA production by FO B cells; and, 3) in addition to donor alloantigens, MZ B cell activation is initiated and enhanced by DAMPs carried by graft-derived EVs as well as by systemic effects of IRI. Therefore, targeting MZ B cell trafficking, activation and functions will inhibit generation of pathogenic class II DSA and improve outcome of renal allografts subjected to prolonged CIS. We will test this hypothesis in three Specific Aims: Aim 1. To test whether ischemia/reperfusion injury (IRI) augments class II DSA by enhancing endothelial extracellular vesicles (EEV) generation. Aim 2. To test the role of MZ B cells in DSA production following renal transplantation. Aim 3. To investigate the contribution of MZ B cells in the generation of pathogenic class II DSA after prolonged cold ischemia storage of renal allografts. The proposed studies will fill several gaps in current knowledge of humoral alloimmune responses to vascularized organ transplants and identify potential targets of therapeutic intervention to inhibit antibody- mediated rejection.
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Mechanisms of alloantibody production following renal transplantation
  • 批准号:
    10357956
  • 项目类别:
  • 资助金额:
    $62.1万
  • 财政年份:
    2021
  • 负责人:
    Anna Valujskikh
  • 依托单位:
Mechanisms of alloantibody production following renal transplantation
  • 批准号:
    10551197
  • 项目类别:
  • 资助金额:
    $59.68万
  • 财政年份:
    2021
  • 负责人:
    Anna Valujskikh
  • 依托单位:
Designing induction therapies to target memory T cells in high risk recipients
  • 批准号:
    9027079
  • 项目类别:
  • 资助金额:
    $39.63万
  • 财政年份:
    2015
  • 负责人:
    Anna Valujskikh
  • 依托单位:
Designing induction therapies to target memory T cells in high risk recipients
  • 批准号:
    9193613
  • 项目类别:
  • 资助金额:
    $39.63万
  • 财政年份:
    2015
  • 负责人:
    Anna Valujskikh
  • 依托单位:
海外基金