This 5 year competing application describes an opportunity to explore the long term outcomes of thymus transplantation in detail, with particular focus on the role of thymic activity and T cell function. Over the last 15 years, our laboratory has established that thymus transplantation is a successful therapeutic strategy for infants born with complete DiGeorge anomaly 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 reconstitute T cell numbers and function? 2) Does the thymus undergo senescence soon after transplantation with resulting low thymic output or, alternatively, is homeostasis altered due to premature apoptosis? 3) Are host T cells restricted to host HLA or to the HLA of the unmatched thymus donor? Lastly, it appears that there are some subclinical defects in T cell function. We will ask whether these differences are due to the lymphopenia of the subjects or are due to an inherent defect resulting from thymus transplantation. To address these questions, we will pursue three 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 and quantification of signal joint to ? T cell receptor rearrangement excision circle ratios. The length of thymic function after thymus transplantation will be assessed using positron emission tomography (PET) scans. Studies of apoptosis will address whether peripheral apoptosis contributes to the low T cell numbers found in subjects with complete DiGeorge anomaly. The second specific aim will assess the binding of T cell receptors to MHC by tetramer experiments. The binding to class I and class II tetramers will be compared between subjects with and without matching to the thymus donor and by comparing complete DiGeorge anomaly subjects to those with partial DiGeorge anomaly and healthy adults. The third specific aim focuses on T cell function. Studies are planned to distinguish the general effects of lymphopenia from potential inherent defects in the T cells after thymus transplantation. The T cell defects include the lack of or low level of T cell response to insoluble CD3, low numbers of T cells, and low interferon gamma (IFN-?) production by T cells. By comparing the outcomes of the experiments from complete DiGeorge subjects to those with partial DiGeorge anomaly, who have lymphopenia, we can determine if thymus transplantation across an MHC barrier contributes to defects in T cell functioning after transplantation.
Thymus transplantation is a promising therapy being developed for the fatal congenital anomaly, complete DiGeorge anomaly. Detailed evaluation of the research subjects will elucidate immune defects that remain in the subjects after transplantation which may allow improved medical management for these subjects and extension of this therapy to other patient groups.
| Li, Bin; Li, Jie; Devlin, Blythe H et al. (2011) Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol 140:244-59 |
| Renner, Ellen D; Hartl, Dominik; Rylaarsdam, Stacey et al. (2009) Comèl-Netherton syndrome defined as primary immunodeficiency. J Allergy Clin Immunol 124:536-43 |
