DiGeorge syndrome is a congenital disorder characterized by defects of the heart, parathyroid, and thymus. """"""""Complete"""""""" DiGeorge syndrome refers to the subset of infants who are born with no thymus and suffer from profound primary immune deficiency. We have treated 24 infants with complete DiGeorge syndrome with allogeneic postnatal thymus transplantation. This treatment results in development of host T cells with a polyclonal T cell repertoire and robust proliferative T cell function. Survival has increased from an expected 0% without transplantation to 71% (17 of 24) with no deaths from graft failure. This system has not only generated excellent clinical results, but it now gives us a unique opportunity to study the mechanisms by which functional T cells develop in the thymus and repopulate the periphery.
The first aim continues previous studies of this R01 by assessing T cell development and function after thymus transplantation. Developing T cells will be characterized by changes in phenotype, function, and gene expression patterns. We will test the hypothesis that partial HLA-matching may improve results after thymus transplantation by correlating HLA-DR matching with naive T cell count and total T cell count at 2 years.
The second aim will study HLA restriction. First HLA restriction for selected pathogens (cytomegalovirus, Epstein Barr virus, influenza A, respiratory syncytial virus) by MHC class I molecules will be assessed using tetramer technology. We hypothesize that host, not donor, MHC restriction will be found. We will evaluate why the developing T cells don't reject the donor thymus using assays for indirect allorecognition and determining the role of regulatory T cells.
The third aim will assess the length of thymic function and T cell function after thymus transplantation. The length of thymus function will be assessed by quantifying the level of naive T cells (those co-expressing CD45RA and CD62L, measuring the number of T cell receptor rearrangement excision circles (TRECs), and estimating the turnover of naive T cells though the use of deuterium labeled water incorporated into DNA.
The fourth aim will assess qualitative aspects of the thymus used for transplantation. Ectopic expression of self proteins in medullary thymic epithelium has been shown to contribute to tolerance for these proteins and to prevent development of autoimmune disease. We will assess the ectopic expression of 9 self proteins. We will also study expression of 4 genes important in thymus organogenesis. These four aims will provide a foundation of understanding of mechanisms involved in T cell development after thymus transplantation.
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