Wednesday, 18 March 2015

Natalizumab bone marrow stem cell mobilisation

Natalizumab has off-target effects. #MSBlog #MSResearch

"This study shows that natalizumab mobilises bone marrow or haemopoietic stem cells (HSC). Why? Bone marrow stem cells are held in their niche by adhesion molecules (biological velcro). If you block these adhesion molecules with natalizumab these cells are able to escape and enter the circulation. This may provide a new way of mobilising stem cells for HSC transplantation. COuld these cells migrate to the brain and spinal cord and repair damage? Unlikely as the MSers who have these stem cells mobilised are on natalizumab and this will block their migration across the blood-brain-barrier."

"Does this observation have any other relevance for MS? Possibly. It has been hypothesised that JCV, the virus that causes PML, resides in the bone marrow and that my mobilising HSC you also mobilise JCV and increase the risk of MS. This theory has little if no scientific support."

"Is there a problem with excessive HSC cells circulating in your blood? No. I am not aware of any adverse biological effects from this observation."
"What this study shows that a treatment that targets adhesion molecules to prevent trafficking of lymphocytes into the brain has other effects unrelated to its primary mode of action. We call the latter off target effects. Off target effects can be associated with problems."

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.
CoI: multiple

1 comment:

  1. Prof. G. very interesting this study of this possible effect of Natalizumab ... MS seems a mystery, almost 150 years after the description of the disease by Charcot and many aspects of it are still a mystery to science and patients to us also, for example or causes MS ... also super intriguing think the fact that the patient adapt well to a particular drug and has no other ...

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