Mechanisms of Tolerance to Renal Maternal Microchimerism

肾母体微嵌合的耐受机制

• 批准号: 7319358
• 负责人: ANNE Marguerite STEVENS
• 金额: $ 41.15万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319358
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Affect; Age; Alleles; Alloantigen; Antigen Targeting; Antigen-Presenting Cells; Antigens; Apoptotic; Atypical lymphocyte; Autoimmune Diseases; Autoimmunity; Biological Assay; Blood; Blood Cells; Blood specimen; Cardiac Myocytes; Cell Communication; Cells; Child; Childhood; Chronic; Cross Presentation; DNA; Data; Dermatomyositis; Disease; Disease remission; Epithelial Cells; Fetus; Flare; Flow Cytometry; Future; Genomics; Hematological Disease; Hematopoietic; Hepatocyte; Histocompatibility Antigens; IL2RA gene; Immune Tolerance; Immune system; Immunosuppression; In Vitro; Individual; Infant; Inflammation; Inflammatory; Interleukin-10; Interleukin-4; Investigation; Kidney; Lead; Life; Lymphocyte; Microchimerism; Modeling; Necrosis; Nephritis; Newly Diagnosed Disease; Organ; Patients; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Polymerase Chain Reaction; Pregnancy; Production; Regulation; Research Personnel; Research Proposals; Role; Source; Staging; Surface; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissues; Tubular formation; cytokine; disorder control; fetal; in vivo; programs; response; trend

DESCRIPTION (provided by applicant): The proposal's overall objective is to test mechanisms by which maternal microchimerism may contribute to chronic inflammation in systemic lupus erythematosus nephritis (SLE-N). Elevated levels of fetal and maternal microchimerism (MMc) have been found within blood and tissues of patients with systemic sclerosis, SLE, and dermatomyositis. However, microchimerism is also common in healthy individuals. Moreover, previous studies were not able to control for disease activity or immunosuppression, which may affect tolerance to chimeric cells. The PI has found maternal cells in infant organs differentiated into hematopoietic cells, cardiac myocytes, hepatocytes, and renal tubular epithelial cells. Long-term persistence to MMc implies immune tolerance, and loss of tolerance to MMc may lead to chronic inflammation within target organs harboring maternal cells. The Pi's preliminary data suggests that peripheral T lymphocytes from pediatric SLE patients are hyper-reactive to maternal cells. Moreover, SLE patients showed a trend toward decreased MMc in the blood. Thus, host lymphocytes reactive to maternal antigens within tissues may also clear maternal cells from the blood. This study will be the first to directly test the correlation of MMc in blood with SLE disease activity and immunosuppression. In addition, we will test a mechanistic model for how maternal cells bearing alloantigens may stimulate the host immune system to contribute to chronic inflammatory disease. Specific Aim #1 will test the hypothesis that levels of MMc in blood correlate with disease activity and immunosuppression in pediatric patients with SLE-N. Specific Aim #2 will investigate direct T lymphocyte alloreactivity to maternal antigens in SLE-N patients compared to controls. Tolerance to maternal antigen presenting cells will be tested for correlations with disease activity, immunosuppression, and presence or absence of MMc. Specific Aim #3 will investigate indirect T lymphocyte alloreactivity to maternal antigens presented by host APC in SLE-N patients compared with controls using apoptotic or necrotic maternal cells as sources of maternal antigens. Specific Aim #4 will test the role of T regulatory cells in tolerance to maternal antigens. The finding that maternal cells are targets forT lymphocytes in SLE patients would lead to future investigations to determine which antigens are targeted. Peptides blocking host- maternal cell interactions in vitro could potentially be used in vivo as specific treatments for SLE nephritis.

描述（由申请人提供）：该提案的总体目标是测试母体微嵌合体可能导致系统性红斑狼疮肾炎（SLE-N）慢性炎症的机制。在系统性硬化症、SLE和皮肌炎患者的血液和组织中发现胎儿和母体微嵌合体（MMc）水平升高。然而，微嵌合体在健康个体中也很常见。此外，以前的研究不能控制疾病活动或免疫抑制，这可能会影响嵌合细胞的耐受性。PI发现婴儿器官中的母体细胞分化为造血细胞、心肌细胞、肝细胞和肾小管上皮细胞。对MMc的长期持续性意味着免疫耐受，对MMc的耐受性丧失可能导致携带母体细胞的靶器官内的慢性炎症。PI的初步数据表明，来自儿童SLE患者的外周血T淋巴细胞对母体细胞具有高反应性。此外，SLE患者血液中MMc呈下降趋势。因此，组织内与母体抗原反应的宿主淋巴细胞也可以从血液中清除母体细胞。本研究将首次直接检测血液中MMc与SLE疾病活动性和免疫抑制的相关性。此外，我们将测试一种机制模型，以了解携带同种异体抗原的母体细胞如何刺激宿主免疫系统，从而导致慢性炎症性疾病。具体目标#1将检验血液中MMc水平与SLE-N儿科患者的疾病活动性和免疫抑制相关的假设。具体目标#2将研究与对照相比，SLE-N患者中T淋巴细胞对母体抗原的直接同种异体反应性。将检测对母体抗原呈递细胞的耐受性与疾病活动、免疫抑制和是否存在MMc的相关性。具体目标#3将使用凋亡或坏死的母体细胞作为母体抗原的来源，与对照组相比，研究SLE-N患者中T淋巴细胞对宿主APC呈递的母体抗原的间接同种异体反应性。具体目标#4将测试T调节细胞在对母体抗原耐受性中的作用。母源细胞是SLE患者T淋巴细胞的靶细胞，这一发现将导致未来的研究以确定靶抗原。在体外阻断宿主-母体细胞相互作用的肽可能在体内用作SLE肾炎的特异性治疗。