Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3- T cells in complete DiGeorge anomaly.

The development of T cells with a regulatory phenotype after thymus transplantation has not been examined previously in complete DiGeorge anomaly (cDGA). Seven athymic infants with cDGA and non-maternal pretransplantation T cell clones were assessed. Pretransplantation forkhead box protein 3 (Foxp3)(+) T cells were detected in five of the subjects. Two subjects were studied in greater depth. T cell receptor variable ß chain (TCR-Vß) expression was assessed by flow cytometry. In both subjects, pretransplantation FoxP3(+) and total CD4(+) T cells showed restricted TCR-Vß expression. The development of naive T cells and diverse CD4(+) TCR-Vß repertoires following thymic transplantation indicated successful thymopoiesis from the thymic tissue grafts. Infants with atypical cDGA develop rashes and autoimmune phenomena before transplantation, requiring treatment with immunosuppression, which was discontinued successfully subsequent to the observed thymopoiesis. Post-transplantation, diverse TCR-Vß family expression was also observed in FoxP3(+) CD4(+) T cells. Interestingly, the percentages of each of the TCR-Vß families expressed on FoxP3(+) and total CD4(+) T cells differed significantly between these T lymphocyte subpopulations before transplantation. By 16 months post-transplantation, however, the percentages of expression of each TCR-Vß family became significantly similar between FoxP3(+) and total CD4(+) T cells. Sequencing of TCRBV DNA confirmed the presence of clonally amplified pretransplantation FoxP3(+) and FoxP3(-) T cells. After thymus transplantation, increased polyclonality was observed for both FoxP3(+) and FoxP3(-) cells, and pretransplantation FoxP3(+) and FoxP3(-) clonotypes essentially disappeared. Thus, post-transplantation thymic function was associated with the development of a diverse repertoire of FoxP3(+) T cells in cDGA, corresponding with immunological and clinical recovery.

Factors affecting success of thymus transplantation for complete DiGeorge anomaly.

Thymus transplantation shows promise for the treatment of athymia in complete DiGeorge anomaly. This report reviews the effects of dose of thymus tissue, ABO compatibility, HLA matching, culture conditions, age of donor and immunosuppression of recipient on immune outcomes at 1 year after transplantation. Forty-nine athymic subjects have been treated with cultured postnatal allogeneic thymus tissue; 36 (73%) survive with only one subject on immunosuppression at 1.5 years. Of 31 surviving subjects more than 1 year after transplantation, 30 (97%) developed naive T cells, T-cell proliferative responses to mitogens and a diverse T-cell receptor beta variable (TCRBV) repertoire. The dose of thymus tissue, HLA matching and use of immunosuppression had nonsignificant effects on these outcome variables. Removal of deoxyguanosine from culture medium and length of culture did not adversely affect outcomes. Use of thymus tissue from donors over 1 month of age, versus under 1 month, resulted in higher total T-cell numbers (p = 0.03). However, this finding must be confirmed in a prospective trial. Although subtle immune effects may yet be associated with some of the factors tested, it is remarkable that consistently good immune outcomes result despite variation in dose, HLA matching and use of immunosuppression.