Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants

Abstract

The purpose of this study was to characterize a large group of infants with complete DiGeorge anomaly and to evaluate the ability of thymus transplantation to reconstitute immune function in these infants. DiGeorge anomaly is characterized by varying defects of the heart, thymus, and parathyroid glands. Complete DiGeorge anomaly refers to the subgroup that is athymic (< 1%). The characteristics of 54 subjects at presentation and results from 44 consecutive thymus transplantations are reported. Remarkably, only 52% had 22q11 hemizygosity and only 57% had congenital heart disease requiring surgery. Thirty-one percent developed an atypical phenotype with rash and lymphadenopathy. To date, 33 of 44 subjects who received a transplant survive (75%) with post-transplantation follow-up as long as 13 years. All deaths occurred within 12 months of transplantation. All 25 subjects who were tested 1 year after transplantation had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Adverse events developing after transplantation included hypothyroidism in 5 subjects and enteritis in 1 subject. In summary, diagnosis of complete DiGeorge anomaly is challenging because of the variability of presentation. Thymus transplantation was well tolerated and resulted in stable immunoreconstitution in these infants. (Blood. 2007; 109: [4539][4540][4541][4542][4543][4544][4545][4546][4547]

Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly

“…Immune evaluation of thymus recipients surviving beyond 1 year reveals the presence of naïve T cells with normal mitogen proliferative responses and diverse T cell receptor repertoires. These data suggest that the thymus grafts are both functioning and not being rejected after transplantation [8].…”

“…Thymus transplantation using postnatal cultured allogeneic HLA-nonmatched thymus tissue provides immunoreconstitution [7,8]. These thymus grafts provide an environment for recipient thymocyte precursors to enter, undergo positive and negative selection, and emerge in the peripheral circulation as functional naïve T cells.…”

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.…”