Thymus Transplantation Dose in DiGeorge #932

• Thymus transplantation efficacy: survival is recorded. Immune reconstitution efficacy: T cell phenotypic and functional parameters are evaluated. This is evaluated in descriptive fashion. [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
• Parental parathyroid transplantation efficacy: number of subjects who are off calcium and calcitriol supplementation. The time that calcium supplementation needs to be resumed is recorded. [ Time Frame: 1 year post-transplantation ] [ Designated as safety issue: No ]
• Safety. Particular attention on oligoclonal T cell development; pulmonary complications; infections; and autoimmune diseases. Dose is correlated with number of subjects who get rashes lasting >1 week with development of wheezing or oxygen requirement. [ Time Frame: Ongoing - Post-Transplantation ] [ Designated as safety issue: Yes ]
• Correlations between dose and other immune parameters and factors which might affect outcome including HLA matching and thymus donor heart defect. Evaluate whether HLA-DR matching results in increased total CD4 T cell numbers. [ Time Frame: 1 year post-transplantation & ongoing ] [ Designated as safety issue: No ]

• Thymus transplantation efficacy: survival is recorded. Immune reconstitution efficacy: T cell phenotypic and functional parameters are evaluated. This will be evaluated in descriptive fashion. [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
• Parental parathyroid transplantation efficacy: number of subjects who are off calcium and calcitriol supplementation. The time that calcium supplementation needs to be resumed is recorded. [ Time Frame: 1 year post-transplantation ] [ Designated as safety issue: No ]
• Safety. Particular attention on oligoclonal T cell development; pulmonary complications; infections; and autoimmune diseases. Dose is correlated with number of subjects who get rashes lasting >1 week with development of wheezing or oxygen requirement. [ Time Frame: Ongoing - Post-Transplantation ] [ Designated as safety issue: Yes ]
• Correlations between dose and other immune parameters and factors which might affect outcome including HLA matching and thymus donor heart defect. Evaluate whether HLA-DR matching results in increased total CD4 T cell numbers. [ Time Frame: 1 year post-transplantation & ongoing ] [ Designated as safety issue: No ]

One purpose of this study is to determine whether the amount of thymus tissue transplanted into DiGeorge anomaly infants has any effect on the immune outcome. Another purpose of this study is to determine whether parental parathyroid gland transplantation (in addition to thymus transplantation) can help both the immune and the calcium problems in DiGeorge infants with hypocalcemia. [Funding Source - FDA OOPD]

DiGeorge anomaly is a congenital disorder in which infants are born with defects of the thymus, heart and parathyroid gland. Complete DiGeorge Anomaly is usually fatal within the first two years of life. This trial evaluates the role of thymus tissue dose in thymus transplantation in complete (typical) DiGeorge anomaly infants, and continues safety assessments.

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. Approximately ½ of infants with profound hypoparathyroidism will develop nephrocalcinosis. This protocol had a parental parathyroid transplant arm for complete DiGeorge infants with athymia and profound hypoparathyroidism.

• DiGeorge Anomaly
• DiGeorge Syndrome
• Complete DiGeorge Anomaly
• Complete DiGeorge Syndrome

• Biological: Thymus Tissue for Transplantation
  Thymus tissue (from unrelated donor), donor, and donor's mother screened for safety. Thymus transplantation done under general anesthesia. Thymus transplanted into quadriceps. Thymus dose at least 4grams/m2 body surface area (0.2 grams/kg body weight) and not >18 grams/m2 body surface area (1.0 grams/kg body weight). At time of transplant, skin biopsy obtained to look for preexisting T cells. 2-3 months post-transplant allograft biopsy done to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. (Allograft biopsy not done if subject medically unstable.) Post-transplant, subjects followed by immune evaluations, using blood samples.
  Other Name: Thymus Tissue for Transplantation
• Other: Parathyroid Tissue for Transplantation
  Parental parathyroid donors screened for eligibility and transplant safety. If both parents meet eligibility criteria, the parathyroid will be harvested from parent who shares the most HLA alleles with thymus donor. Parathyroid harvest & transplant preferably done at same time as thymus transplant. (If parathyroid transplant cannot be done at same time, then it is done within 3-8 weeks of thymus transplant.) Parathyroid harvest done under general anesthesia. One parathyroid gland is minced & placed in quadriceps muscle; there is no dose in mg. No biopsy done of the parathyroid. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely.

• Experimental: 2
  Thymus Tissue for Transplantation With Parathyroid Tissue for Transplantation
  Interventions:

  • Biological: Thymus Tissue for Transplantation
  • Other: Parathyroid Tissue for Transplantation
• Experimental: 1
  Thymus Tissue for Transplantation Without Parathyroid Tissue for Transplantation
  Intervention: Biological: Thymus Tissue for Transplantation

• Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. Epub 2007 Feb 6.
• Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May;135(2):236-46. Epub 2010 Mar 16. Review.
• Markert ML, Devlin BH, Chinn IK, McCarthy EA, Li YJ. Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant. 2008 Aug;8(8):1729-36. Epub 2008 Jun 28.
• Markert ML, Li J, Devlin BH, Hoehner JC, Rice HE, Skinner MA, Li YJ, Hale LP. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. J Immunol. 2008 May 1;180(9):6354-64.
• Hudson LL, Louise Markert M, Devlin BH, Haynes BF, Sempowski GD. Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection. Semin Immunol. 2007 Oct;19(5):297-309. Epub 2007 Nov 26. Review.
• Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70.
• Chinn IK, Devlin BH, Li YJ, Markert ML. Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol. 2008 Mar;126(3):277-81. Epub 2007 Dec 26.
• Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003 Aug 1;102(3):1121-30. Epub 2003 Apr 17.
• Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol. 2011 Sep;140(3):244-59. doi: 10.1016/j.clim.2011.04.004. Epub 2011 Apr 16.

Thymus Transplant Inclusion:

• Typical Complete DiGeorge Anomaly diagnosis
• On 2 separate tests must have < 50 CD3+ T cells/cumm (or < 50 CD3+ T cells/cumm that are CD62L+ CD45RA+), or < 5% naïve phenotype T cells
• Must have < 20 fold response to PHA (or < 5,000 cpm) on 2 separate tests
• 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 with diabetes (type I, type II, gestational)

Exclusion Criteria:

• Must not be anticipated to need heart surgery 4 weeks prior or 3 months post-transplantation
• Present or past lymphadenopathy
• Rash associated with T cell infiltration of the dermis and epidermis
• Rejection by the surgeon or anesthesiologist as surgical candidate
• Lack of sufficient muscle tissue to accept transplant
• Prior attempts at immune reconstitution (e.g, BMT or thymus transplantation)
• HIV infection
• Ventilator Dependence

Additional Inclusion Criteria for Parathyroid Transplant Recipient:

• 2 tests showing: intact parathyroid hormone (PTH) < 5 pg/ml when ionized calcium < 1.1 mmol/L
• 2 involved parents

Exclusion for Parathyroid Transplant Recipient:

• Parents do not meet enrollment criteria.
• Parent(s) decline to be parathyroid donor(s).

Parental Parathyroid Donor Inclusion:

• > 18 years old
• Answers all questionnaire items and meets safety screening criteria
• Normal serum calcium
• Normal PTH function
• HLA typing consistent with parentage
• Parent chosen for donation will share HLA-DR allele in thymus donor; if not applicable, then either parent will be selected (if meet all other criteria).
• Must not be on anticoagulation or can come off for donation/transplantation

Parental Parathyroid Donor Exclusion:

• Donor is only living involved parent or caretaker of the recipient
• Hypoparathyroidism - low parathyroid hormone (PTH) in presence of low serum calcium and high serum phosphate
• Hyperparathyroidism (or history of) - elevated PTH in presence of high serum calcium and low serum phosphate
• History of cancer
• Evidence of any of following: HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Trypanosoma Cruzi (Chagas disease)
• Elevated AST, ALT, alkaline phosphatase > 3 times upper limit of normal
• History including receipt of a xenograft or risk factors for SARS, Mad Cow - Disease or smallpox. Note: if parent has Mad Cow Disease risk factors (but not active disease), parent(s) may give permission for transplantation.
• CMV positive urine
• Positive CMV IgM antibodies
• Positive IgM anti-EBV VCA
• On blood thinners and cannot stop for the parathyroid donation
• Elevated PT or PTT (> ULN)
• Platelets < 100,000
• Positive Toxoplasma IgM
• The donor will receive a history and physical; may be excluded based on PI's medical judgment
• Hemoglobin < 9 g/dl
• Infectious lesion on head or neck
• Goiter on ultrasound
• Abnormal fiberoptic laryngoscopy of vocal cords
• Pregnancy
• Positive HSV IgG is not an exclusion; however, post transplantation prophylaxis is needed
• Positive VZV IgG is not an exclusion; however, post transplantation prophylaxis is needed
• Medical concern of otolaryngologist
• Concern by medical psychologist or social worker including. Parents are interviewed together and separately regarding following areas: medical history; health habits; substance use; relationships and support; education/work history; mental status/psychological history; readiness for donation.
• Questionnaire (safety screening) responses can lead to exclusion.

Biological Mother of DiGeorge Subject Inclusion Criteria:

• Competent to provide consent
• Willing to provide blood for testing (No other inclusion/exclusion for mother)

• 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)