Parathyroid and Thymus Transplantation in DiGeorge #931

Overview

This study has three primary purposes: to assess parathyroid function after parathyroid transplantation in infants with Complete DiGeorge syndrome; to assess immune function development after transplantation; and, to assess safety and tolerability of the procedures. This is a Phase 1, single site, open, non-randomized clinical protocol. Enrollment is closed and study intervention is complete for all enrolled subjects; but subjects continue for observation and follow-up. Subjects under 2 years old with complete DiGeorge syndrome (atypical or typical) received thymus transplantation. Subjects received pre-transplant immune suppression with rabbit anti-human-thymocyte-globulin. Subjects with hypoparathyroidism and an eligible parental donor received thymus and parental parathyroid transplantation. A primary hypothesis: Thymus/Parathyroid transplant subjects will need less calcium and/or calcitriol supplementation at 1 year post-transplant as compared to historical controls.

Detailed: DiGeorge Syndrome is a complex of three problems, 1) cardiac defects, 2) parathyroid deficiency, and 3) absence of the thymus, resulting in profound T-cell deficiency. There is a spectrum of disease in DiGeorge syndrome with respect to all three defects. There is no safe and effective treatment for DiGeorge Syndrome and most patients die by the age of two. For patients with a severe T cell defect, the PI has shown that thymus transplantation is safe and efficacious under other clinical protocols. Subjects with complete typical and atypical DiGeorge syndrome were eligible for this study. Subjects with athymia and profound hypoparathyroidism were eligible for parental parathyroid transplantation in this protocol. DiGeorge syndrome infants, who have successful thymus transplants but have hypoparathyroidism, must go to the clinic for frequent calcium levels and to the hospital for calcium infusions; infants with hypoparathyroidism are at risk for seizures from low calcium. Approximately ½ of infants with profound hypoparathyroidism will develop nephrocalcinosis. Depending on T cell phenotype and function, subjects were given one of two different immunosuppression regimens. Typical complete DiGeorge subjects (with proliferative T cell function \< 50,000 cpm) received Thymoglobulin pre-transplantation. Typical complete DiGeorge subjects (with proliferative cell response to PHA \> 50,000 cpm) and atypical DiGeorge subjects (with proliferative T cell response to PHA \< 75,000 cpm) received Thymoglobulin (pre-transplantation) and cyclosporine (pre-transplantation and post-transplantation). Thymoglobulin was used in part to prevent graft rejection and also to deplete any T cells in the donor parathyroid. Cyclosporine was used to deplete activated T cells in the recipient. For all subjects, acetaminophen, diphenhydramine, and methylprednisolone were given concurrently with the rabbit anti-human thymocyte globulin. The thymus was cultured in standard medium for 10-21 days to deplete mature thymocytes which could cause GVHD. In the operating room, thymus tissue was placed in the quadriceps muscle in one or both legs. The parathyroid donation was preferably done at the same time as the thymus transplantation. Parathyroid tissue was placed in the quadriceps muscle in only one leg, using the same incision as the thymus transplantation. Depending on post-transplant immune status, subjects may have received cyclosporine and steroids. For 3 months after thymus transplantation, T cells were monitored by flow cytometry approximately every 2-4 weeks. Alternatively, absolute lymphocyte count was used as the maximum possible T cell number. At 2-3 months post-transplant, the subject may have had a thymus allograft biopsy, done under general anesthesia in the operating room. The biopsy was approximately 4 pea-sized (3x3mm) portions of muscle tissue where the thymus transplant had been inserted. Using immunohistochemistry, the biopsy determined thymopoiesis and any graft rejection. The parathyroid was not biopsied because it is very small; doing a biopsy could remove all of the parathyroid tissue. A research skin biopsy (at site of skin incision at the time of transplantation) was done to determine whether T cells were present pre-transplantation. A skin biopsy was also done at the time of thymus graft biopsy to look for clonal T cell populations. For all subjects who developed T cells, post-transplantation pneumocystis prophylaxis was used for approximately 1 year and IV immunoglobulin for approximately 2 years.