phase i/ii thymus transplantation with immunosuppression #950

Conditions: DiGeorge Anomaly; Complete DiGeorge Anomaly; Complete Atypical DiGeorge Anomaly; Complete DiGeorge Syndrome; Complete Atypical DiGeorge Syndrome

Summary: the study purpose is to determine if cultured thymus tissue implantation (ctti) (previously described as transplantation) with tailored immunosuppression based on the recipient's pre-implantation t cell population is a safe and effective treatment for complete digeorge anomaly. this study will also evaluate whether cultured thymus tissue implantation and parathyroid transplantation with immunosuppression is a safe and effective treatment for complete digeorge anomaly and hypoparathyroidism.

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, cultured thymus tissue implantation (ctti) 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 tailor immunosuppression use for complete digeorge anomaly subjects who have some t cells and different t cell function levels. this protocol includes tailored immunosuppression regimens to allow subjects with different t cell function levels to be suppressed adequately. patients with complete digeorge often have hypoparathyroidism, a life threatening condition. successful ctti does not result in improvement of the hypoparathyroidism. the patients 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.

Eligibility criteria:
thymus transplantation 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+ (cluster of differentiation 45ra) (naïve phenotype), 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 parathyroid transplantation additional inclusion: * 2 studies in recipient 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 thymus transplantation 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 is acceptable if the parent meets 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. mother of digeorge inclusion: • provides consent to use blood/buccal sample. no exclusions except unwillingness to consent; or, provide blood/buccal sample.

Keywords: digeorge anomaly thymus transplantation digeorge syndrome athymia parathyroid transplantation hypocalcemia hypoparathyroidism low t cell numbers immunoreconstitution immunodeficiency complete digeorge anomaly complete atypical digeorge anomaly complete digeorge syndrome complete atypical digeorge syndrome cultured thymus tissue implantation (ctti)