Bone-marrow transplantation fails to halt intrathecal lymphocyte activation in multiple sclerosis.

BACKGROUND: Given the presumed key role for autoreactive lymphocytes in multiple sclerosis (MS), treatment strategies have been developed to ablate lymphocyte activity. Intrathecal lymphocyte activation can be measured by CSF-soluble(s)CD27. OBJECTIVE: To determine the effect of maximum whole-body immune ablation on two different markers that detect lymphocyte activation in CSF-oligoclonal IgG bands and levels of CSF-sCD27. DESIGN, SETTING AND PATIENTS: The study quantified sCD27 levels and assessed the presence of oligoclonal IgG bands in CSF samples of secondary progressive patients with MS treated by autologous bone-marrow transplantation. In eight individuals, CSF was taken before and 6-9 months after conditioning. CSF-sCD27 levels were compared with other MS and non-inflammatory neurological disease controls. Regarding the effect of stem-cell transplantation on CSF oligoclonal bands, the study analysed pooled data of this and four other international studies on stem-cell transplantation in MS. RESULTS: CSF-sCD27 was significantly lower after the extremely immunoablative protocol. However, levels remained elevated compared with non-inflammatory controls and stayed within the range observed in other MS controls. The joint analysis of CSF oligoclonal bands demonstrated persistence of this immune abnormality in 88% of the reported cases (n = 34). CONCLUSIONS: The persistence of CSF lymphocyte activation markers sCD27 and intrathecal oligoclonal IgG bands after maximum immunoablative treatment indicates that complete eradication of activated lymphocytes from the CNS has not been established. This is paralleled by disease progression observed in several studies on the effect of stem-cell transplantation in MS.

A three-year study of brain atrophy after autologous hematopoietic stem cell transplantation in rapidly evolving secondary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), autologous hematopoietic stem cell transplantation (AHSCT) induces a profound suppression of clinical activity and MR imaging-detectable inflammation, but it may be associated with a rapid brain volume loss in the months subsequent to treatment. The aim of this study was to assess how AHSCT affects medium-term evolution of brain atrophy in MS. MATERIALS AND METHODS: MR imaging scans of the brain from 14 patients with rapidly evolving secondary-progressive MS obtained 3 months before and every year after AHSCT for 3 years were analyzed. Baseline normalized brain volumes and longitudinal percentage of brain volume changes (PBVCs) were assessed using the Structural Image Evaluation of Normalized Atrophy software. RESULTS: The median decrease of brain volume was 1.92% over the first year after AHSCT and then declined to 1.35% at the second year and to 0.69% at the third year. The number of enhancing lesions seen on the pretreatment scans was significantly correlated with the PBVCs between baseline and month 12 (r = -0.62; P = .02); no correlation was found with the PBVCs measured over the second and third years. CONCLUSIONS: After AHSCT, the rate of brain tissue loss in patients with MS declines dramatically after the first 2 years. The initial rapid development of brain atrophy may be a late consequence of the pretransplant disease activity and/or a transient result of the intense immunoablative conditioning procedure.

Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis.

BACKGROUND: Certain stem cell transplantation procedures might slow down inflammatory pathology in multiple sclerosis (MS). AIMS: To halt disease progression in aggressive MS by a bone marrow transplantation (BMT) protocol aimed at maximum T cell suppression. METHODS: Autologous BMT was performed in 14 patients with rapid secondary progressive MS (median EDSS score at baseline, 6; median disease duration, five years). To accomplish rigorous T cell ablation, a strong conditioning protocol was chosen--cyclophosphamide, total body irradiation, and antithymocyte globulin. To minimise the possibility of reinfusing mature T cells in the graft, bone marrow, not peripheral blood, was used as the CD34+ stem cell source. RESULTS: Median follow up was 36 months (range, 7-36). Post-transplant haemopoietic recovery was successful in all patients. Early toxicity included Epstein-Barr virus related post-transplantation lymphoproliferative disorder. Longterm effects were development of antithyroid antibodies (three) and myelodysplastic syndrome (one). One patient died of progressive disease five years after transplantation. Treatment failure, defined by EDSS increase sustained for six months or more, was seen in nine patients and stabilisation or improvement in five. Other clinical parameters generally showed the same outcome. No gadolinium enhanced lesions were seen on post-treatment magnetic resonance imaging, in either cerebral or spinal cord scans. However, cerebrospinal fluid oligoclonal bands remained positive in most cases. CONCLUSIONS: This strong immunosuppressive regimen did not prevent clinical progression in patients with aggressive secondary MS. The lack of efficacy, together with some serious side effects, does not favour the use of similar rigorous T cell depleting protocols in the future.