Complete DiGeorge Anomaly, Complete DiGeorge Syndrome, DiGeorge Anomaly, DiGeorge Syndrome
Conditions
Keywords
Thymus Transplantation, DiGeorge Anomaly, DiGeorge Syndrome, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency, Complete DiGeorge, Typical DiGeorge, Atypical DiGeorge, Complete DiGeorge Anomaly
Brief summary
The research purpose is to determine if thymus transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly. The research includes studies to evaluate whether thymus transplantation results in complete DiGeorge anomaly subjects developing a normal immune system.
Detailed description
DiGeorge anomaly is a complex of cardiac defects, parathyroid deficiency, and thymus absence, resulting in profound T-cell deficiency. There is a spectrum of disease in DiGeorge anomaly with respect to all three defects. For complete DiGeorge anomaly subjects with severe T cell defect, the PI had shown that thymus transplantation is safe and efficacious without pretransplantation immunosuppression and with pretransplantation Thymoglobulin and cyclosporine. Some DiGeorge patients have very poor T cell function and are at risk of death from infection or other immune problems; however, these patients have enough T cell function to reject grafts. This protocol was designed for these patients. Atypical phenotype and some typical phenotype DiGeorge subjects were included in this protocol. Atypical complete DiGeorge anomaly patients have rash, lymphadenopathy, and oligoclonal T cell proliferations. The T cells have no markers of thymic function (they do not co-express CD45RA and CD62L; they do not contain T cell receptor rearrangement excision circles, TRECs). Typical complete DiGeorge anomaly patients in this protocol are those whose PHA response \>20 fold. Although these patients have very low T cell function, it may be enough to reject a transplant, so Thymoglobulin was used.
Interventions
BIOLOGICALThymus Tissue for Transplantation
3 Thymoglobulin doses given prior to thymus tx. Atypical subjects given Cyclosporine (Csa) pre-tx. Desired Csa concentration 180-300ng/ml. If post-tx T cell count remained \<4000/cumm Csa weaned over 8 weeks. If T cell \>4,000/cumm, Csa held at 180-300ng/ml. Thymus tissue, donor, & mother of donor were screened for transplant safety. In operating room, thymic slices were transplanted into quadriceps muscle in 1 or both legs. Subjects had routine blood research immune evaluations. 2-3 months post-tx, open biopsy of allograft. Immune blood studies continued on surviving subjects until January 2010. Biological Mother: Mother provided blood sample used for DNA extraction, to identify/look for maternal T cell presence in recipient pre-tx, and/or for immune testing post-tx.
Sponsors
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sumitomo Pharma Switzerland GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Transplant Inclusion * No age limit * Thyroid studies must be done and if abnormal, must be on therapy DiGeorge diagnosis - must have 1 symptom from the following list: * Heart defect * Hypocalcemia requiring replacement * 22q11 hemizygosity * 10p13 hemizygosity * CHARGE association * Abnormal ears plus mother with diabetes (type I, type II, or gestational) Atypical Diagnosis: * Must have, or have had, a rash. If rash present, biopsy of rash must show T cells in skin. If rash & adenopathy resolved, must still have oligoclonal T cells. * Within 1 month of tx must have PHA response \>20 fold above background or \>5,000 cpm, whichever is higher, or response can be \< this. * Circulating CD3+ T cells \>50/mm3 but CD45RA+CD62L+CD3+ T cells \<50/mm or \<5% of CD3 count, whichever is higher (must be done 2x) * Immunoscope with \>40% oligoclonal TCRBV families. A 2nd test per sponsor discretion if T cell numbers increase or activation status changes. * If TREC done pre-tx must have TRECs \<100 per 100,000 CD3+ cells. Typical Diagnosis: * Circulating CD3+ CD45RA+ CD62L+ T cells and \<50/mm3 or \<5% of total T cells * PHA response \>20 fold above background or \>5,000 cpm, whichever is higher. * 2 studies must show similar immunological findings qualify for this study. * TRECs, if done, should be \<100/100,000 CD3 cells Transplant Exclusion: * Heart surgery \<4 weeks pre-tx date * Heart surgery anticipated w/in 3 months of proposed tx * Rejection by surgeon or anesthesiologist as surgical candidates * Lack of sufficient muscle tissue to accept 0.2 grams/kg transplant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety & tolerability of Thymoglobulin and cyclosporine followed by thymus transplantation: Survival at 1 year post-transplantation. | 1 year post-transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Allograft biopsy used to evaluate graft rejection | 2 to 4 months post-transplant | Evidence of thymus allograft rejection by immunohistochemistry of biopsy |
| CD3 count | 10 - 14 months post-transplantation | CD3 count in cells/mm3 |
| Thymopoiesis | 2-4 months after thymus transplantation | Evidence of thymopoiesis in thymus allograft by immunohistochemistry of a biopsy |
| Use of additional post transplant immunosuppression after that listed in the protocol. | The post thymus transplantation period | Use of additional post transplant immunosuppression after that listed in the protocol. |
| CD8 count | 10-14 months after thymus transplantation | CD8 count in cells/mm3 |
| naive CD4 count | 10-14 months after thymus transplantation | naive CD4 count in cells/mm3 |
| naive CD8 count | 10-14 months after thymus transplantation | naive CD8 count in cells/mm3 |
| CD4 count | 10-14 months after thymus transplantation | CD4 count in cells/mm3 |
Countries
United States
Outcome results
None listed