The purpose of this protocol is to determine whether thymic transplantation in patients with complete DiGeorge syndrome can result in T cell development in the donor thymus and appearance of functional T cells in the recipient. All patients are treated with postnatal allogeneic partially matched cultured thymic epithelial transplants. The donor thymus is obtained after informed consent from infants undergoing heart surgery in which some thymus tissue must be removed in order to perform the operation. The thymus tissue is cultured in the laboratory for 1-2 weeks prior to transplantation. After transplantation, the patient is followed for evidence of T cell function by proliferation studies, circulating naive T cells by flow cytometry, the presence of T cell rearrangement excision circles (TRECs) by PCR, and the genetic identity of the functional T cells by fluorescent in situ hybridization (FISH) for sex chromosomes or for 22q11 hemizygosity. Two of the five patients (#1, #5) have developed good T cell function and are well at home (with 5 years and 4 months followup for patients #1 and #5, respectively). Two patients (#2, #3) developed good T cell function but then died of respiratory complications within 5 months of transplantation. The final patient (#4) died of CMV (present at the time of transplant) without evidence of T cell development. Biopsy of the thymus graft in patients #1 and #5 showed normal thymopoiesis in the donor thymus tissue. In patient #5, T cell function developed at the same time that naive T cells (CD45RA+CD62L+) appeared in the circulation. The patient had no TRECs prior to transplantation, but developed TRECs in the PBMC when T cell function developed. The significance of this protocol is that it shows that host thymopoiesis can occur in donor thymic grafts in patients with profound immunodeficiency. This concept is being used in protocol 758 to attempt to reconstitute T cell function in HIV-infected adult patients who have very few T cells despite treatment with highly active antiretroviral therapy. Future plans include testing additional patients to determine how frequently reconstitution can occur in this patient population.
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