Thymus Transplantation With Immunosuppression

Study Overview
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Brief Summary
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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
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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.

Official Title
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Thymus Transplantation With Immunosuppression, #884

Conditions
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Complete DiGeorge Syndrome, DiGeorge Syndrome, DiGeorge Anomaly, Complete DiGeorge Anomaly

Intervention / Treatment
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* Biological: Thymus Tissue for Transplantation


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Thymus Tissue for Transplantation | Biological: Thymus Tissue for Transplantation<br>* 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.<br>* Other names: Thymus Tissue Transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety & tolerability of Thymoglobulin and cyclosporine followed by thymus transplantation: Survival at 1 year post-transplantation. |  | 1 year post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Use of additional post transplant immunosuppression after that listed in the protocol. | Use of additional post transplant immunosuppression after that listed in the protocol. | The post thymus transplantation period | 
| Allograft biopsy used to evaluate graft rejection | Evidence of thymus allograft rejection by immunohistochemistry of biopsy | 2 to 4 months post-transplant | 
| CD3 count | CD3 count in cells/mm3 | 10 - 14 months post-transplantation | 
| Thymopoiesis | Evidence of thymopoiesis in thymus allograft by immunohistochemistry of a biopsy | 2-4 months after thymus transplantation | 
| CD4 count | CD4 count in cells/mm3 | 10-14 months after thymus transplantation | 
| CD8 count | CD8 count in cells/mm3 | 10-14 months after thymus transplantation | 
| naive CD4 count | naive CD4 count in cells/mm3 | 10-14 months after thymus transplantation | 
| naive CD8 count | naive CD8 count in cells/mm3 | 10-14 months after thymus transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thymus Transplantation, DiGeorge Anomaly, DiGeorge Syndrome, Athymia, Low T cell numbers, Immunoreconstitution, Immunodeficiency, Complete DiGeorge, Typical DiGeorge, Atypical DiGeorge, Complete DiGeorge Anomaly