Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients

Abstract

Complete DiGeorge syndrome is a fatal condition in which infants have no detectable thymus function. The optimal treatment for the immune deficiency of complete DiGeorge syndrome has not been determined. Safety and efficacy of thymus transplantation were evaluated in 12 infants with complete DiGeorge syndrome who had less than 20-fold proliferative responses to phytohemagglutinin. All but one had fewer than 50 T cells/mm 3 . Allogeneic postnatal cultured thymus tissue was transplanted. T-cell development was followed by flow cytometry, lymphocyte proliferation assays, and T-cell receptor V␤ (TCRBV) repertoire evaluation. Of the 12 patients, 7 are at home 15 months to 8.5 years after transplantation. All 7 survivors developed T-cell proliferative responses to mitogens of more than 100 000 counts per minute (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, longterm 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 immunoglobulin E (IgE), and possible pulmonary inflammation. Adverse events related to the immune system occurring more than 3 months after transplantation included thrombocytopenia in one patient and hypothyroidism and alopecia in one other patient. Thymic transplantation is efficacious, well tolerated, and should be considered as treatment for infants with complete DiGeorge syndrome. (Blood.

CHARGE syndrome: a review of the immunological aspects

“…For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction. 14,17,18,20,[22][23][24][25][26][27][28][29][30][31]33,[35][36][37] In our collected cohort, B-and/or NK-cell numbers were reported in only 29 of 59 patients, and of these 29 patients, 1 had low B-cell numbers, 1 had high B-cell numbers, 1 had low NK-cells numbers and 3 had high NK-cell numbers. The reported B-and NK-cells numbers of other patients were normal.…”

“…Of the 35 patients, 1 patient had T-cell lymphopenia and a transient B-cell lymphopenia, which normalized with ageing. [26][27][28] Thymic aplasia was reported in 27 of 59 patients and in 16 of 36 patients with a proven variant in CHD7. T-cell lymphopenia in our collected cohort was associated with thymic aplasia or hypoplasia in 21 of 22 (95%) patients.…”

“…T-cell lymphopenia in our collected cohort was associated with thymic aplasia or hypoplasia in 21 of 22 (95%) patients. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] T-cell function by response on mitogens was available for 28 of 59 patients and of these 28 patients 24 (86%) had a low or absent response on mitogen. For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction.…”

Flow cytometric methods for prenatal and neonatal diagnosis

“…Thymus transplantation is the recommended treatment for patients with a complete absence of T cells, or complete DiGeorge syndrome (Markert et al, 2003). Early thymus transplantation before the onset of infectious complications may promote successful immune reconstitution.…”

Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly

“…These subjects had naïve (CD45RA + CD62L + ) T cells with normal mitogen proliferative responses and normal T cell receptor repertoires and were not receiving immunosuppression. All of these subjects have been described elsewhere [8,[10][11][12].…”