Phase I/II Thymus Transplantation With Immunosuppression #950

Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without
successful treatment, children remain immunodeficient and usually die by age 2 years. In
infants with complete DiGeorge anomaly and no T cells, thymus transplantation without
immunosuppression resulted in diverse T cell development and good T cell function. Some
infants with no thymus have some T cells that presumably developed extrathymically; these T
cells can reject a thymus graft. The purpose of this study is to design better
immunosuppression use for complete DiGeorge anomaly subjects who have some T cells and
different T cell function levels. This protocol includes 3 immunosuppression regimens to
allow subjects with different T cell function levels to be suppressed adequately.

DiGeorge infants who have successful thymus transplants but remain with hypoparathyroidism
must go to the clinic for frequent calcium levels and to the hospital for calcium infusions;
these infants are at risk for seizures from low calcium. This study had a parental
parathyroid transplant arm for subjects with hypoparathyroidism who require calcium
replacement.

Whether or not a subject was enrolled in the parathyroid arm, the immunosuppression regimen
the subject received was dependent on the immune findings as stated in the clinical protocol.

Tx Inclusion:

- Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring
replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal
ears plus mother w/diabetes (type I, type II, gestational).

- <50 CD3+ T cells/cumm or <50 CD3+ T cells/cumm that are CD62L+ CD45RA+, or <5% of CD3+
count being CD62L + CD45RA+

Atypical DiGeorge: Must have, or have had, a rash. If rash present, rash biopsy must show T
cells in skin. If rash & adenopathy resolved, must have >50/cumm T cells & naive T cell
must be <50/cumm or <5% of T cells.

Typical DiGeorge: CD3+ CD45RA+ CD62L+ T cells <50/mm3 or <5% of total T cells

- Must be eligible for 1 of 3 Regimens:

R#1 - Typical DiGeorge with PHA response >5000 cpm and >20 fold response. Must have PHA
response <50,000cpm. If PHA response >50,000 pre-tx, subject will move to R#2.

R#2 - Typical DiGeorge with PHA responses >50,000 cpm; or atypical DiGeorge with PHA
response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on
immunosuppression.

R#3 - Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA
responses >40,000cpm while on immunosuppression pre-tx.

Parathyroid Tx Additional Inclusion:

- 2 studies which PTH<5 pg/ml when ionized calcium <1.1 mmol/L. Can be done anytime
pre-tx; 1 must be done while at Duke Hospital.

- Parent(s) willing & eligible to be donors

Tx Exclusion:

- Heart surgery <4 wks pre-tx

- Heart surgery anticipated w/in 3 months after proposed tx

- Rejection by surgeon or anesthesiologist as surgical candidate

- Lack of sufficient muscle tissue to accept transplant of 4 grams/m2 BSA

- HIV infection

- Prior attempts at immune reconstitution, such as bone marrow tx or previous thymus tx

- CMV(>500 copies/ml blood by PCR on 2 tests)

- Ventilator dependence

Parathyroid Donor Inclusion:

•>18 years of age

- Serum calcium in normal range

- Normal PTH function

- HLA typing consistent with parentage

- Not on anticoagulation or can come off

- Parent chosen will share HLA-DR allele with thymus donor that was not inherited by the
recipient. If no HLA matching at all, then either parent acceptable if meet other
criteria.

Parathyroid Donor Exclusion:

- <18 years old

- Hypoparathyroidism-low PTH in presence of low serum calcium & high serum phosphate

- Hyperparathyroidism(or history)-elevated PTH in presence of high serum calcium and low
serum phosphate.

- History of cancer

- Donor only living involved parent/guardian of recipient

- Evidence of HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West
Nile virus, or Chagas disease

- Creutzfeldt Jakob disease (CJD)

- Elevated liver function studies: AST, ALT, alkaline phosphatase >3x upper normal limit

- Receipt of xenograft or risk factors for SARS, CJD and/or smallpox exposure. {If CJD
risk factors but not active disease, parent may give permission for parathyroid use.}

- Urine CMV positive

- Positive CMV IgM

- Positive IgM anti-EBV VCA

- On blood thinners and cannot stop for parathyroid donation

- Elevated PT or PTT (>ULN)

- Platelets<100,000

- Positive Toxoplasma IgM

- Donor will receive a history and physical; may be excluded based on PI's medical
judgment.

- Hemoglobin <9g/dl

- Infectious head or neck lesion

- Goiter on ultrasound

- Abnormal fiberoptic laryngoscopy of vocal cords

- HLA inconsistent with parentage

- Pregnancy

- Positive HSV IgG isn't exclusion; post-tx prophylaxis needed for recipient if donor is
HSV IgG+.

- Positive VZV IgG isn't exclusion; post-tx prophylaxis needed if donor is VZV IgG+.

- Medical concern of independent otolaryngologist.

- Concern by medical psychologist/social worker that potential donor isn't competent or
does not understand risks.

- Questionnaire responses can lead to exclusion.

Biological Mother Inclusion:

• Provides consent to use blood/buccal sample. No exclusions except unwillingness to
consent; or, provide blood/buccal sample.