Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999.

Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P <.01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.

Homing defect of cultured human hematopoietic cells in the NOD/SCID mouse is mediated by Fas/CD95.

OBJECTIVE: To determine the bone marrow homing efficiency (20 hours) of cultured compared to noncultured umbilical cord blood (UCB)-derived human hematopoietic cells in the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse, and to explain the difference in homing between these populations. METHODS: Human UCB CD34+ cells were cultured for up to 5 days, reselected, and used for transplantation, phenotype analysis, and functional studies, including adhesion and trans-endothelial migration assays. Seeding of CD34+ cells was measured after labeling of cells with 111-Indium, while homing of colony-forming cells (CFC) and SCID-repopulating (SRC) cells was determined using functional assays. RESULTS: Short-term culture was associated with a decrease in the 20-hour homing of CD34+ cells, CFC, and SRC to the BM. Although cultured compared to noncultured cells showed increased expression and function (adhesion/migration) of several cell adhesion molecules described to play a role in homing and engraftment, culture also induced expression of Fas/CD95 and rendered cells more susceptible to apoptosis. Finally, we demonstrate that the level of Fas/CD95 on cultured cells was inversely related to the ability of CFC to home to the BM, and that the homing of cultured CFC could be restored by incubating cells prior to transplantation with Fas/CD95-blocking mAb ZB4. CONCLUSION: These data implicate Fas/CD95 in the homing defect of cultured human hematopoietic cells in the NOD/SCID transplant model and suggest that prevention of apoptosis may be an important strategy to improve engraftment of ex vivo-manipulated HSC in a clinical setting.