Mechanisms of Tolerance to Renal Maternal Microchimerism

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、系统性红斑狼疮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，以前的研究无法控制疾病活动或免疫抑制，这可能会影响对嵌合细胞的耐受性。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的长期耐受意味着免疫耐受，而对MMC耐受性的丧失可能导致含有母体细胞的靶器官的慢性炎症。PI的初步数据表明，儿童SLE患者的外周T淋巴细胞对母体细胞具有高反应性。此外，SLE患者血液中的MMC有下降的趋势。因此，组织内对母体抗原起反应的宿主淋巴细胞也可以清除血液中的母体细胞。这项研究将首次直接测试血液中MMC与SLE疾病活动性和免疫抑制的相关性。此外，我们将测试一个机制模型，以确定携带同种异体抗原的母体细胞如何刺激宿主免疫系统导致慢性炎症性疾病。具体目标#1将检验血液中MMC水平与儿童SLE-N患者的疾病活动性和免疫抑制相关的假设。具体目的#2将调查SLE-N患者与对照组相比对母体抗原的直接T淋巴细胞同种异体反应性。将测试对母体抗原提呈细胞的耐受性与疾病活动性、免疫抑制和是否存在MMC的相关性。具体目标#3将研究SLE-N患者与使用凋亡或坏死的母体细胞作为母体抗原来源的对照组的间接T淋巴细胞对宿主APC呈递的母体抗原的同种异体反应性。具体目标#4将测试T调节细胞在母体抗原耐受性中的作用。母细胞是SLE患者淋巴细胞的靶标，这一发现将导致未来的研究，以确定哪些抗原是靶标。体外阻断宿主-母体细胞相互作用的多肽在体内可能被用于SLE肾炎的特异性治疗。

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.