Matched unrelated bone marrow transplantation for combined immunodeficiency

Abstract

Summary:Bone marrow transplantation (BMT) from siblings is the treatment of choice for severe combined immunodeficiency (SCID). The objective of this study was to evaluate the efficiency of BMT from matched unrelated donors (MUD) in congenital immunodeficiencies when a sibling donor is unavailable. Sixteen consecutive patients with SCID (n = 9) and CID (n = 7), were referred for an unrelated donor search. Acceptable donors were found for all patients. Fifteen patients received busulfan and cyclophosphamide pretransplant conditioning. One patient had an early loss of graft and was reconditioned using cyclophosphamide and total body irradiation. The graft-versus-host disease (GVHD) prophylaxis used was methylprednisolone, cyclosporin A with or without methotrexate. Neutrophil engraftment was rapid and was achieved in all patients within a mean of 15.4 days. Only 13 episodes of fever were recorded shortly after BMT. GVHD of grade II or more was apparent in 2/9 (22%) of SCID patients and in 4/7 (57%) of CID patients. Overall survival was 75% with a mean follow-up of 47.4 months (range 18-101). Six out of nine SCID patients (67%) and 6/7 (86%) of CID patients are alive and well. Eleven patients had normal humoral immunity, and cell-mediated immunity as measured by flow cytometry and mitogenic responses, was intact in all patients. Intradermal candida skin test was positive in 9/10 patients tested. We conclude that BMT from MUD results in rapid engraftment and is therefore associated with a low rate of infection contributing to the improved survival rate. Attempts to use alternative procedures have been less successful. Immunologic reconstitution following fetal thymus and/or liver transplantation is inconsistent; engraftment is achieved in less than one third of cases and a survival rate of less than 20% has been reported. 4,5 T lymphocyte-depleted, haploidentical bone marrow, usually of parental origin, is regarded by many transplant centers as the treatment of choice when fully matched sibling donors are unavailable. Although survival for all types of SCID hovers around 50%, 6 recent preliminary experience shows a higher survival rate (70-78%) in selective SCID phenotypes mainly including T − B + SCID 7,8 and ADA deficiency 8 using this method. However, this approach has serious limitations, including prolonged time to engraftment, 9-12 and very slow B lymphocyte engraftment, which ranges in large series of patients from 40 to 70%. [9][10][11][12][13]

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

“…Since 1993, Class II histocompatibility was further analyzed by DNA hybridization with sequence-specific oligonucleotide probes. 19 Since 1999, both Class I and II histocompatibilities were analyzed solely by molecular techniques.…”

“…Whole blood was analyzed for long-term donor engraftment as described previously. 19 Where a sex difference existed between donor and recipient, DNA was analyzed using a Y-specific probe (ZFX/ZFY) to confirm donor lymphocyte engraftment. In the absence of sex difference, RFLP analyses were performed by studying genetic polymorphism, which are due to a variable number of tandem repeats or (CA)n in varying regions in the genome.…”

“…8,9,[11][12][13][14][15]19 For lymphocyte proliferation studies, cells were harvested after 3 days and samples counted in a liquid scintillation counter. All assays were performed in triplicate and stimulation index was calculated as the ratio between stimulated and nonstimulated lymphocyte responses and compared with stimulation index obtained from controls.…”

“…Levels of serum Abs to tetanus were measured by ELISA and polio Ab titers were determined by complement fixation. 8,9,[11][12][13][14][15]19 Quantification of TCR excision circles The amount of signal joint TCR excision circles adjusted to CD4 þ and CD8 þ T-cell subsets was determined by real-time quantitative PCR, as described previously. 21 The number of TCR excision circles in a given sample was compared to a value obtained with 10-fold serial dilutions of an internal standard provided by Dr Daniel Douek (Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA).…”

“…Neutrophil engraftment was achieved in all patients at a mean of 12.8 days (range, [8][9][10][11][12][13][14][15][16][17][18][19], including the patients who failed previous transplants (Table 3). Engraftment of platelets was achieved within a mean of 23.1 days (range, 11-60 days).…”