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Prepublished online as a Blood First Edition Paper on April 17, 2003; DOI 10.1182/blood-2002-08-2545.
Submitted August 21, 2002
Accepted March 18, 2003
Thymic transplantation in complete DiGeorge syndrome: immunologic safety evaluations in twelve patients
M L Markert*, Marcella Sarzotti, Daniel A Ozaki, Gregory D Sempowski, Maria E Rhein, Laura P Hale, Francoise Le Deist, Marilyn J Alexieff, Jie Li, Elizabeth R Hauser, Barton F Haynes, Henry E Rice, Michael A Skinner, Samuel M Mahaffey, James Jaggers, Leonard D Stein, and Michael R Mill
Department of Pediatrics, Duke University Medical Center, Durham, NC, USA; Department of Immunology, Duke University Medical Center, Durham, NC, USA
Department of Medicine, Duke University Medical Center, Durham, NC, USA
Department of Pathology, Duke University Medical Center, Durham, NC, USA
Department of Surgery, Duke University Medical Center, Durham, NC, USA
Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA
Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA
Department of Surgery, University of North Carolina, Chapel Hill, NC, USA
Laboratoire d'Immunologie Pediatrique, Hopital Necker Enfants Malades, Paris, France
* Corresponding author; email: marke001{at}mc.duke.edu.
Rationale: Complete DiGeorge syndrome is a fatal condition in which infants have no detectable thymic function. The optimal treatment for complete DiGeorge syndrome has not been determined. Objectives: Safety and efficacy of thymus transplantation were evaluated in twelve infants with complete DiGeorge syndrome who had less than 20 fold proliferative responses to phytohemagglutinin. All but one had <50 T cells/mm3. Allogeneic postnatal cultured thymic tissue was transplanted. T-cell development was followed by flow cytometry, lymphocyte proliferation assays, and T cell receptor V (TCRBV) repertoire evaluation. Findings: Of the 12 patients, seven are well and at home 15 months to 8.5 years after transplantation. All seven survivors developed T cell proliferative responses to mitogens of over 100,000 cpm. By one year after transplantation, 6 of 7 patients developed antigen-specific proliferative responses. The TCRBV repertoire showed initial oligoclonality that progressed to polyclonality within a year. B-cell function developed in all 3 patients tested after 2 years. Deaths were associated with underlying congenital problems. Risk factors for death included tracheostomy, long term mechanical ventilation, and cytomegalovirus infection. Adverse events in the first 3 months after transplantation included eosinophilia, rash, lymphadenopathy, development of CD4-CD8- peripheral T cells, elevated serum IgE and possible pulmonary inflammation. Adverse events related to the immune system occurring greater than 3 months after transplantation included thrombocytopenia in one patient and hypothyroidism and alopecia in one other patient. Conclusions: Thymic transplantation is efficacious, well tolerated, and should be considered as treatment for infants with complete DiGeorge syndrome.
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