Genomics of Chronic Renal Allograft Rejection

慢性同种异体移植肾排斥的基因组学

• 批准号: 8529741
• 负责人: Barbara T. Murphy
• 金额: $ 45.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529741
• 关键词: Alloantigen; Allografting; Animals; Antibodies; Antibody Formation; Arteries; Basement membrane; Bioinformatics; Biological Assay; Biopsy; Blood capillaries; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic Allograft Arteriopathy; Chronic rejection of renal transplant; Collaborations; Data; Development; Donor person; Epitopes; Event; Frequencies; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Graft Survival; Human; Immune; Immune response; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Factors; Immunologics; Immunosuppressive Agents; Individual; Indolent; Inflammatory; Inherited; Injury; Isoantibodies; Kidney Transplantation; MHC antigen; Mediating; Microarray Analysis; Molecular Profiling; Mononuclear; Morphology; Nature; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Pattern; Peptide/MHC Complex; Peptides; Peripheral Blood Lymphocyte; Predisposition; Process; Prospective Studies; Protocols documentation; Research Personnel; Resources; Risk; Role; Stratification; System; T-Lymphocyte; Techniques; Time; Transplant Recipients; Transplantation; Transplantation Immunology; Variant; allograft rejection; base; capillary; complement C4d; enzyme linked immunospot assay; glomerular basement membrane; graft function; insight; isoimmunity; kidney allograft; novel; patient population; predictive modeling; prevent; programs; prospective; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Chronic allograft nephropathy (CAN) remains the most common cause of graft loss. However, the term CAN does not delineate the specific underlying pathologic process but rather refers to the chronic injury resulting from multiple potential factors. More recently it has been suggested that the pathologic findings of chronic allograft glomerulopathy, chronic allograft arteriopathy, and lamination of the peritubular capillary basement membrane, arise due to a chronic immunologic process and therefore should be referred to as true chronic rejection. There are extensive animal and initial human studies suggesting that indirect recognition of alloantigen and/or alloantibody responses mediate this process. There are however no studies which prospectively examine whether the development of the chronic allograft rejection correlates with immune reactivity. The principal hypothesis of this project is that chronic rejection is mediated by an ongoing indolent specific immune reactivity driven by allopeptide specific CD4+ T cell clones (indirect pathway), which gives rise to cell-mediated and antibody responses directed against the mismatched MHC antigens of the graft; The specific aims of this proposal are to: 1. Determine the role of cell mediated and antibody-mediated immune responses in chronic rejection: We will determine if the pathologic finding of chronic rejection is associated with indirect alloreactivity and/or the development of de novo DSA; 2. Determine the gene expression profile associated with the development of chronic rejection: We will study intragraft expression patterns of key genes involved in the alloimmune, innate and antibody mediated responses at the time of transplantation and prospectively post-transplant to define the level of association between intragraft events and immune responses. We will determine if specific gene expression profiles predict the development of chronic rejection using microarray analysis; 3. Determine whether polymorphic variants of specific immunological genes confer susceptibility to chronic rejection: We plan to prospectively define transplant recipients genotypes for specific immunological genes in order to identify those genotypes associated with chronic rejection and the development of an immune response directed toward the graft. The results of these studies will lend greater insight to the underlying mechanisms leading to chronic rejection and help differentiate one cause of CAN.

描述(由申请人提供)：慢性移植物肾病(CAN)仍然是移植物丢失的最常见原因。然而，术语CAN并不描述具体的潜在病理过程，而是指由多种潜在因素造成的慢性损伤。最近的研究表明，慢性移植物肾小球病变、慢性移植物动脉病变和肾小管周围毛细血管基底膜片层的病理改变是由于慢性免疫过程引起的，因此应称为真正的慢性排斥反应。大量的动物和人类初步研究表明，对同种异体抗原和/或同种异体抗体反应的间接识别介导了这一过程。然而，目前还没有前瞻性的研究来检验慢性移植排斥反应的发生是否与免疫相关。 反应性。该项目的基本假设是，慢性排斥反应是由别肽特异性的CD4+T细胞克隆(间接途径)驱动的持续的惰性特异性免疫反应所介导的，该反应引起针对移植物MHC抗原错配的细胞和抗体反应，该建议的具体目的是：1.确定细胞和抗体介导的免疫反应在慢性排斥反应中的作用：我们将确定慢性排斥反应的病理发现是否与间接同种异体反应和/或从头DSA的发展有关；2.确定与慢性排斥反应发展相关的基因表达谱：我们将在移植时和预期移植后研究参与同种异体免疫、先天和抗体介导的反应的关键基因在移植物内的表达模式，以确定移植物内事件和免疫反应之间的关联程度。我们将使用微阵列分析确定特定的基因表达谱是否可以预测慢性排斥反应的发生；3.确定特定免疫基因的多态变异是否会增加慢性排斥反应的易感性：我们计划前瞻性地定义特定免疫基因的移植受者的基因类型，以确定那些与慢性排斥反应和针对移植物的免疫反应的发展相关的基因类型。这些研究的结果将有助于更深入地了解导致慢性排斥反应的潜在机制，并有助于区分CAN的一个原因。

项目成果

Deep learning identified pathological abnormalities predictive of graft loss in kidney transplant biopsies.

• DOI: 10.1016/j.kint.2021.09.028
• 发表时间: 2022-02
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Yi Z;Salem F;Menon MC;Keung K;Xi C;Hultin S;Haroon Al Rasheed MR;Li L;Su F;Sun Z;Wei C;Huang W;Fredericks S;Lin Q;Banu K;Wong G;Rogers NM;Farouk S;Cravedi P;Shingde M;Smith RN;Rosales IA;O'Connell PJ;Colvin RB;Murphy B;Zhang W
• 通讯作者: Zhang W

A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection.

用于诊断亚临床急性排斥反应的外周血基因表达特征。

• DOI: 10.1681/asn.2018111098
• 发表时间: 2019
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Zhang,Weijia;Yi,Zhengzi;Keung,KarenL;Shang,Huimin;Wei,Chengguo;Cravedi,Paolo;Sun,Zeguo;Xi,Caixia;Woytovich,Christopher;Farouk,Samira;Huang,Weiqing;Banu,Khadija;Gallon,Lorenzo;Magee,CiaraN;Najafian,Nader;Samaniego,Milagros

The Use of Genomics and Pathway Analysis in Our Understanding and Prediction of Clinical Renal Transplant Injury.

• DOI: 10.1097/tp.0000000000000943
• 发表时间: 2016-07
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Menon MC;Keung KL;Murphy B;OʼConnell PJ
• 通讯作者: OʼConnell PJ