Thymus transplantation in complete DiGeorge anomaly

Abstract

Complete DiGeorge anomaly is characterized by athymia, congenital heart disease, and hypoparathyroidism. This congenital disease is fatal by age 2 years unless immune reconstitution is successful. There are multiple underlying syndromes associated with complete DiGeorge anomaly including 22q11 hemizygosity in approximately 50%, CHARGE association in approximately 25%, and diabetic embryopathy in approximately 15%. Approximately one-third of patients present with rash and lymphadenopathy associated with oligoclonal "host" T cells. This condition resembles Omenn syndrome. Immunosuppression is necessary to control the oligoclonal T cells. The results of thymus transplantation are reported for a series of 50 patients, of whom 36 survive. The survivors develop naïve T cells and a diverse T cell repertoire.

Figures

Figure 1

Oligoclonal T cells found in atypical complete DiGeorge anomaly. Flow cytometry with antibodies reactive with members of T cell receptor beta chain variable families is shown. Family 5.1 represented 80% of the circulating CD4 T cells. The distribution of the patient is shown as filled symbols and that of the healthy adult control by open symbols.

Figure 2

Activated phenotype of the oligoclonal T cells in atypical complete DiGeorge anomaly. Flow cytometry was used to examine CD3 T cells with antibody directed against the T cell activation markers HLA-DR and CD71. The left panel includes a healthy adult control; the right panel is a patient with atypical complete DiGeorge anomaly prior to thymus transplantation. Eighty six percent of the patient’s CD3 T cells are activated expressing both markers.

Figure 3

Rash in atypical complete DiGeorge anomaly. This patient had not yet received any immunosuppression.

Figure 4

Liver involvement in atypical complete DiGeorge anomaly. A) Low power view of liver with portal triad and central vein. B) High power view of liver with mononuclear cells, granulomatous inflammation and fibrous expansion in the portal triad. C) High power view of T cells visualized by brown color on immunohistochemistry in the portal triad.

Figure 5

Thymus graft of a typical subject taken 75 days after thymus transplantation. A) CD1a, B) Ki-67, C) CD3, and D) cytokeratin reactivity. The T cells express CD1, characteristic of cortical thymocytes. The cytokeratin is lacey, a normal pattern.

Figure 6

Kaplan Meier analysis of survival of 50 subjects with complete DiGeorge anomaly treated with thymus transplantation. Both typical and atypical subjects are included. Thirty six subjects survive.

Figure 7

T cell outcomes after thymus transplantation. A) CD3, B) CD4, C) CD8, D), naïve CD4, and E) naïve CD8 T cells in subjects with typical complete DiGeorge anomaly treated with thymus transplantation without immunosuppression. The 10th, mean, and 90th percentiles are from Shearer et al.[22]

Figure 8

Flow cytometry showing naïve CD4 T cells. CD4 T cells were analyzed with CD45RA and CD62L antibodies. The CD4 T cells in the upper right quadrant are naïve T cells. A) Healthy adult volunteer, B) Patient with atypical complete DiGeorge anomaly on day 271 after thymus transplantation.