Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome

Abstract

Complete DiGeorge syndrome is a fatal congenital disorder characterized by athymia, hypoparathyroidism, and heart defects. Less than half of patients are 22q11 hemizygous. The goal of this study was to assess if immune suppression followed by postnatal thymus transplantation would lead to T-cell function in 6 infant patients who had host T cells at the time of transplantation. All infants had fewer than 50 recent thymic emigrants (CD3 ؉ CD45RA IntroductionDiGeorge syndrome is a congenital disorder characterized by defects in the third and fourth pharyngeal pouches, although abnormalities can be found extending from the first through sixth pharyngeal arches. 1 Typically, defects are found in the heart, parathyroid gland, and thymus. [2][3][4][5][6] The immune defect in DiGeorge syndrome usually is mild. In fewer than 1% of cases, there is profound immune deficiency secondary to athymia. 7 Athymic patients are categorized as having complete DiGeorge syndrome. 2,8 Patients with complete DiGeorge syndrome usually die within the first 2 years of life. 2 Severe recurrent infections are a major problem. 2 Peripheral blood testing can be used to identify those patients with DiGeorge syndrome who are athymic. Naive T cells (recent thymic emigrants) coexpress CD45RA and CD62L. 9 We define athymic patients as those having less than 50 naive T cells/cubic millimeter (mm 3 ). 10 In patients having a sufficient blood volume for testing, we also quantitate the number of T-cell receptor rearrangement excision circles (TRECs) in circulating T cells. [11][12][13] TRECs are episomal DNA circles that form when T-cell receptor (TCR) gene segments rearrange in the thymus. Athymic patients have less than 100 TRECs/100 000 T cells (normal value for a newborn is approximately 10 000 TRECs/100 000 T cells). 10 Most athymic patients with DiGeorge syndrome have very low proliferative responses to mitogens and very low T-cell numbers. These patients can be treated with postnatal allogeneic thymus transplantation without immunosuppression. 10 The mechanism of this experimental treatment is the migration of host bone marrow cells to slices of cultured donor thymus that are implanted into the patient's muscle. In the donor graft, the host bone marrow cells develop via thymopoiesis into host T cells that then emigrate out of the thymus into the peripheral blood.We report the results of postnatal allogeneic thymus transplantation in 6 athymic patients with DiGeorge syndrome who had some T cells and T-cell proliferative responses to mitogens. Because of their T-cell function, these patients would likely have rejected allotransplants if no immunosuppression had been given. Thus, all patients were initially treated with Thymoglobulin (rabbit antithymocyte globulin, Imtix-SangStat, Lyon, France). This treatment was immediately followed by postnatal cultured allogeneic thymus transplantation. The excellent clinical and immunologic results in this group of patients supports the use of Thymoglobulin together with thymus transplantation to effect normal...

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.…”

“…14,[16][17][18][19][20][21][22] Three patients had features resembling Omenn syndrome, a form of severe combined immune deficiency, characterized by autoimmune-like features and macular skin rash due to the formation of abnormal, autoreactive T cells. 18,23 Other severe presentations included a patient with recurrent oral candidiasis, recurrent severe infections, and septic shock due to colonization with multiresistant species of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinobacter (Janda et al, 22 Table 1B); another patient with severe general dermatitis and ulcers of the colon (Boudny et al, 24 Table 1B); and a patient with CHARGE association and T-cell deficiency with a chronic viral infection of the gut (Wood et al, 25 Table 1C).…”

“…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.…”

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].…”

“…Lymphocyte proliferative responses to mitogens were performed before and after transplantation according to standard protocols [8,11]. The data from proliferative responses to phytohemagglutinin (PHA) (Sigma-Aldrich, St. Louis, MO) in studies performed either simultaneously with the experimental assays described below or at the date most proximal to those assays were used for comparative analyses.…”