Thymic transplantation in complete DiGeorge syndrome is a model system in which to study early events in human T cell development. Infants with complete DiGeorge syndrome have thymic aplasia with no measurable T cell function. We are developing the thymic transplant procedure to answer important questions which relate to post-natal T cell development. Specific questions which will be addressed are 1) Can host bone marrow stem cells home to a transplanted donor post-natal thymic epithelial graft? 2) Will host T cell function develop after transplantation of donor thymic epithelium into DiGeorge patients? 3) If thymic education is necessary for bone marrow stem cells to develop into T cells, is HLA matching of the DiGeorge patient (source of host bone marrow stem cells) and the donor thymus necessary? 4) Will HLA restriction develop to both donor and host antigens? 5) Will tolerance develop to both donor and host antigens? 6) If T cells develop which are not functional, where did the T- cell receptor (TCR) gene rearrangements occur? Is extrathymic development of T cells associated with lack of T cell function? Lastly, the use of readily available post-natal thymic tissue potentially will allow application of this work to other disorders of primary and acquired immunodeficiency. This project complements the other projects in this RFA proposal. Buckley studies development of donor bone marrow stem cells in the context of host thymus. She examines natural killer cell function and B cell function in great detail. This expertise will be applied to the evaluation of patients who have received thymic transplants in this project (Markert). Haynes focuses on human thymic biology. The findings in this project will be directly applied by Markert to determine whether the donor thymic epithelium functions normally in the recipient. Williams examines RAG gene expression in a subgroup of SCID infants whose molecular defect may be in the RAG genes. The expertise from this project will be used to detect extrathymic RAG gene expression leading to TCR rearrangements in DiGeorge patients. All of these projects focus on better understanding human immune development. This project contributes to the overall objectives of the RFA by development of thymic transplantation as therapy for immunodeficiency and more importantly by elucidating the mechanisms involved in thymic transplantation.
Showing the most recent 10 out of 14 publications
