DiGeorge syndrome is a congenital anomaly characterized by defects of the 3rd and 4th pharyngeal pouches and intervening 4th pharyngeal arch. Infants are born with defects of the heart, parathyroid and thymus. Experimental thymus transplantation has led to the development of normal immunity and also leaves the recipient tolerant of the thymus donor. Despite this advance in treatment of the immune deficiency of complete DiGeorge syndrome, the lack of parathyroid function remains problematic in approximately thirty percent of patients resulting in tetany, seizures, ectopic calcifications, hospitalizations, and infections of central lines (needed for intravenous calcium administration). Under this protocol, four children with complete DiGeorge syndrome and hypoparathyroidism will be treated with allogeneic postnatal thymus transplantation in conjunction with parental parathyroid transplantation. The recipient will be pretreated with rabbit anti human thymocyte globulin. Both tissues will be placed in the quadriceps muscle at sites separate from each other. This grant proposal will test the hypotheses that infants with complete DiGeorge syndrome will be tolerant of the parental parathyroid transplant and that the transplanted parathyroid tissue will function. For the first two patients, a parental parathyroid gland will be transplanted at the same time into a separate site in one quadriceps of the recipient. If the first two parathyroid transplants are unsuccessful, the parathyroid transplants in the third and fourth research subjects will be placed immediately adjacent to the thymus tissue in the quadriceps in one leg.
The first aim will assess parathyroid function. Parathyroid function will be considered a success if the patient can be removed from all calcium and calcitriol supplementation. If the Parathyroid ceases functioning between 3 months and 1 year, a follow up biopsy of the parathyroid tissue will be done.
The second aim focuses on immune development and tolerance to the parathyroid donor. To assess thymopoiesis, each research subject will undergo biopsy of the thymus allograft at three months (a time point that is usually before appearance of T cells in the periphery). Tolerance to the parathyroid donor will be assessed by mixed lymphocyte reactions. Indirect allorecognition as a mechanism of graft rejection will be assessed by ELISpot.
The third aim will assess safety and tolerability.
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