Thymus transplantation for complete DiGeorge syndrome: European experience

Abstract

BackgroundThymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS).MethodsTwelve patients with cDGS underwent transplantation with allogeneic cultured thymus.ObjectiveWe sought to confirm and extend the results previously obtained in a single center.ResultsTwo patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1).ConclusionsThis study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

“…Over 90% of these had partial DiGeorge syndrome, in which T cell numbers rose over time and T cell function was judged by their immunology providers to be adequate. However, four infants with complete DiGeorge syndrome, having persistently fewer than 300 T cells per μL and/or absent naive helper T cells, received thymus transplantation therapy in an experimental protocol at Duke University, Durham, NC, three of whom have survived for at least 2 years . Trisomy 21 accounted for eight (11%) infants with syndromes; TCL resolved in three other cases of partial DiGeorge syndrome, three died of nonimmune complications, and two were lost to follow‐up.…”

“…Based on our observed genotype frequencies for SCID (Figure ), around half of all infants with SCID may be eligible for GT in the near future. Experimental thymus transplantation has also been successful in selected cases of DiGeorge thymic insufficiency, but is not widely available …”

Transplanted human thymus slices induce and support T‐cell development in mice after cryopreservation

“…Thymus tissue is removed from infants during cardiac surgery, to allow access to the heart. This discarded thymus tissue can be transplanted into athymic infants 2, 3, 4. Slices of thymus tissue are transplanted into the thigh, after a 2‐ to 3‐week culture period to deplete thymocytes.…”

“…This procedure is life‐saving, but recipients have low T‐cell counts, and may develop autoimmunity. It is not possible to attempt to MHC‐match transplants between donor and recipient because of the urgency of performing the procedure 2, 3, 5. As delays in thymus transplantation could be life‐threatening, the procedure would be improved if it were possible to freeze thymus slices for transplantation.…”

“…The slices that are transplanted into patients are approximately 1mm thick 2, 3, 4, 5. Cryopreservation of such thick pieces of tissue on the scale required for clinical use is technically challenging because of heat transfer issues, choice of cryoprotectants, cooling protocols and the control of ice nucleation, each of which are complex events that impact on viability of thawed tissue 7, 8, 12.…”