Mechanisms of Tolerance to Renal Maternal Microchimerism

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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.