Duke University
Grant: $464,942 - National Institutes of Health - Sep. 23, 2009
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Award Description: This application, to be supported for 1 year with bridge funds from ARRA, explores the long term outcomes of thymus transplantation. Over the last 15 years, our laboratory has established that thymus transplantation is a successful therapeutic strategy for infants born with complete DiGeorge anomaly (DGA) who are athymic and thus have a fatal immunodeficiency. Thymus transplantation results in host T cell reconstitution and survival of approximately 75% of subjects. We now will address unanswered questions about the basic biology of thymus transplantation in our long term survivors. Questions include the following: 1) Why do T cell numbers remain in the 10th percentile after subjects develop T cells and T cell function? 2) Is there low thymic output, and if so, is it secondary to small size or does the thymus undergo senescence after transplantation? 3) Are host T cells restricted to host HLA or to the HLA of the unmatched thymus donor? To address these questions, we will pursue two aims. The first specific aim will assess the etiology of low T cell numbers after transplantation. Thymic output will be investigated by deuterated water loading in infants with complete DGA and subsequent assessment of deuterium incorporation in naïve T cells. Thymic output will also be assessed by quantification of the ratios of signal joint to ß T cell receptor rearrangement excision circles (TREC). Telomere length will assess the replicative history of peripheral T cells. The length of thymus functioning will be assessed by performing these assays over time. The second specific aim will assess the binding of T cell receptors to Major Histocompatibility Complex (MHC) using tetramer experiments. It is thought that developing T cells learn what is host MHC from the MHC expressed on thymus epithelium (which is 'donor' in our subjects). We have not detected binding to donor MHC but have found binding to host MHC in our preliminary Class I tetramer experiments. The binding of T cells to class I and class II tetramers will be compared between subjects with and without MHC matching to the thymus donor. These comparisons will allow us to determine if thymus transplantation across an MHC barrier contributes to lack of or low affinity of T cell receptor binding to MHC.
Project Description: See Award Description
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 23, 2009. Help expand these official descriptions using the wiki below.
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