Immune Deregulation and Chronic Humoral Rejection of Kidney Allografts in Humans

人类肾同种异体移植物的免疫失调和慢性体液排斥

• 批准号: 8956579
• 负责人: Emmanuel Zorn
• 金额: $ 29.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956579
• 关键词: Allografting; Animal Model; Antibodies; Antibody Formation; Autoantibodies; B-Cell Activation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Complication; Development; Drug usage; End stage renal failure; Frequencies; Functional disorder; Generations; Goals; Graft Rejection; Graft Survival; Human; Immune; Immunity; Immunosuppressive Agents; In Vitro; Incidence; Isoantibodies; Kidney Transplantation; Lead; MHC Class I Genes; Mediating; Modeling; Molecular; Neoadjuvant Therapy; Outcome; Patients; Peripheral; Population; Preventive; Process; Production; Proteomics; Regulatory T-Lymphocyte; Reporting; Research; Role; Sampling; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic immunosuppression; Time; Transplant Recipients; Transplantation; United States; base; differentiated B cell; improved; kidney allograft; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): The number of kidney transplants performed every year in the US is increasing. While early graft survival has improved over the past decade, long-term survival has not significantly changed during the same time and remains unsatisfactory. Accumulating evidence suggests that chronic humoral rejection (CHR) is responsible for a large proportion of late kidney graft losses. Seemingly, CHR does not respond well to conventional immunosuppressive therapies. A better understanding of the pathophysiology of this complication will lead to the development of new treatments and reduce the rate of rejection. The long-term goal of our proposed research is to understand the immune mechanisms leading to CHR. CHR is characterized by the development of donor specific antibodies. These antibodies presumably result from a CD4+ T cell dependent B cell response directed to the allograft. Yet, direct evidence of this mechanism is scarce. On the other hand, deficiency in regulatory T cells leads to aberrant B cell activation and autoantibody production in humans. Autoantibodies are prevalent in transplant recipients. It is also known that immunosuppressive drugs used to prevent rejection, directly impair Treg function. We propose that CHR results from Treg deficiency leading to the deregulation of peripheral B cells and concomitant development of allo- and autoantibodies. In a comprehensive analysis, our studies will determine whether Treg deficiency and the co-development of allo- and autoantibodies correlate with CHR in kidney transplant recipients. We will also examine possible mechanisms whereby Treg deficiency induces B cells deregulation in patients with CHR. Experiments to verify our proposed model will be carried out in 3 specific aims: Aim-1. To examine whether CHR is associated with increased autoantibody titers. Utilizing a proteomics array approach, we will identify autoantigenic targets of antibody responses in CHR. We will then assess the co development of autoantibodies to these targets as well as alloantibodies in correlation with the occurrence of CHR. Aim-2. To determine whether CHR correlates with Treg deficiency Phenotypic and molecular assessment of Treg populations in patient samples will determine whether CHR correlates with reduced numbers and frequencies of these cells. In vitro cell based assays will also be used to assess whether CHR correlates with reduced Treg suppressive activity. Aim-3. To define mechanisms of B cell deregulation in CHR Phenotypic and functional assessment of B cell subsets will determine whether deregulation in CHR patients is due to defective B cell development or exacerbated B cell activation in the periphery. In vitro cell based assays will investigate the cellular mechanisms whereby Treg control B cell activation. Lastly, we will examine the possibility that B cells differentiate directly in the graft in patients with CHR.

描述(由申请人提供)：在美国，每年进行的肾移植手术的数量正在增加。虽然移植物的早期存活率在过去十年中有所改善，但长期存活率在同一时间内并没有显著变化，仍然不令人满意。越来越多的证据表明，慢性体液排斥反应(ChR)是晚期肾移植损失的主要原因。似乎，CHR对传统的免疫抑制疗法没有很好的反应。更好地了解这种并发症的病理生理学机制将有助于开发新的治疗方法，降低排斥反应的发生率。我们提出的研究的长期目标是了解导致慢性肾衰的免疫机制。CHR的特点是产生供体特异性抗体。这些抗体可能源于依赖于CD4+T细胞的B细胞对同种异体移植物的反应。然而，这种机制的直接证据很少。另一方面，调节性T细胞的缺乏会导致人类B细胞的异常激活和自身抗体的产生。自身抗体在移植受者中很普遍。众所周知，免疫抑制药物用于预防排斥反应，直接损害Treg功能。我们认为，慢性再生障碍性贫血是由于Treg缺乏导致外周B细胞的松弛以及伴随的同种抗体和自身抗体的发展。在综合分析中，我们的研究将确定Treg缺陷以及同种异体抗体和自身抗体的共同发展是否与肾移植受者的CHR相关。我们还将研究Treg缺陷导致慢性阻塞性肺疾病患者B细胞去调节的可能机制。为了验证我们提出的模型，我们将在三个特定的目标下进行实验：Aim-1。以检查CHR是否与自身抗体效价升高有关。利用蛋白质组学阵列方法，我们将确定CHR抗体反应的自身抗原靶点。然后，我们将评估针对这些靶点的自身抗体以及同种异体抗体与慢性阻塞性肺疾病发生的相关性。AIM-2。要确定ChR是否与Treg缺乏症相关，对患者样本中Treg群体的表型和分子评估将确定ChR是否与这些细胞的数量和频率减少相关。体外基于细胞的分析也将被用来评估ChR是否与Treg抑制活性降低相关。AIM-3。明确慢性阻塞性肺疾病中B细胞调节失调的机制，对B细胞亚群的表型和功能评估将决定慢性阻塞性肺疾病患者的调节失调是由于B细胞发育缺陷还是外周B细胞活化加剧。在体外，基于细胞的分析将研究Treg控制B细胞激活的细胞机制。最后，我们将研究慢性阻塞性肺疾病患者移植物中B细胞直接分化的可能性。

项目成果

Chronic humoral rejection of human kidney allografts associates with broad autoantibody responses.

• DOI: 10.1097/tp.0b013e3181d72091
• 发表时间: 2010-05-27
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Porcheray F;DeVito J;Yeap BY;Xue L;Dargon I;Paine R;Girouard TC;Saidman SL;Colvin RB;Wong W;Zorn E
• 通讯作者: Zorn E

Chronic humoral rejection of human kidney allografts is associated with MMP-2 accumulation in podocytes and its release in the urine.

• DOI: 10.1111/j.1600-6143.2010.03290.x
• 发表时间: 2010-11
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Wong W;DeVito J;Nguyen H;Sarracino D;Porcheray F;Dargon I;Pelle PD;Collins AB;Tolkoff-Rubin N;Smith RN;Colvin R;Zorn E
• 通讯作者: Zorn E

Polyreactive antibodies developing amidst humoral rejection of human kidney grafts bind apoptotic cells and activate complement.

在人肾移植体的体液排斥过程中产生的多反应性抗体结合凋亡细胞并激活补体。

• DOI: 10.1111/ajt.12394
• 发表时间: 2013
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Porcheray,F;Fraser,JW;Gao,B;McColl,A;DeVito,J;Dargon,I;Helou,Y;Wong,W;Girouard,TC;Saidman,SL;Colvin,RB;Palmisano,A;Maggiore,U;Vaglio,A;Smith,RN;Zorn,E
• 通讯作者: Zorn,E

B-cell immunity in the context of T-cell tolerance after combined kidney and bone marrow transplantation in humans.

• DOI: 10.1111/j.1600-6143.2009.02738.x
• 发表时间: 2009-09
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Porcheray F;Wong W;Saidman SL;De Vito J;Girouard TC;Chittenden M;Shaffer J;Tolkoff-Rubin N;Dey BR;Spitzer TR;Colvin RB;Cosimi AB;Kawai T;Sachs DH;Sykes M;Zorn E
• 通讯作者: Zorn E

Expansion and somatic hypermutation of B-cell clones in rejected human kidney grafts.

• DOI: 10.1097/tp.0000000000000124
• 发表时间: 2014-10-15
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Ferdman J;Porcheray F;Gao B;Moore C;DeVito J;Dougherty S;Thomas MV;Farkash EA;Elias N;Kawai T;Malek SK;Tullius SG;Wong W;Zorn E
• 通讯作者: Zorn E