Epub: Mattoscio et al. Hematopoietic mobilization: Potential biomarker of response to natalizumab in multiple sclerosis. Neurology. 2015 Mar 11.
OBJECTIVE: To ascertain the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-α-4 integrin antibody natalizumab in MSers.
METHODS: We evaluated CD45lowCD34+ HSPC frequency by flow cytometry in blood from 45 natalizumab-treated MSers (12 of whom were prospectively followed during the first year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated MSers with MS, and 24 healthy donors. In the natalizumab-treated group, we also assessed sorted HSPC cell cycle status, T- and B-lymphocyte subpopulation frequencies (n = 29), and HSPC differentiation potential (n = 10).
RESULTS: Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and non-mobilizer subgroups. Non-mobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD103+CD8+ regulatory T cells persistently increased, more significantly in mobilizer MSers, who also showed a specific naive/memory B-cell profile.
CONCLUSIONS: The data suggest that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment’s mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab.