Mitoxantrone is one of the few drugs approved for the treatment of progressive multiple sclerosis
(MS). However, the prolonged use of this potent immunosuppressive agent
is limited by the appearance of severe side effects. Apart from its
general cytotoxic effect, the mode of action of mitoxantrone on the
immune system is poorly understood.
Thus, to develop safe therapeutic
approaches for patients with progressive MS, it is essential to
elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated
a prospective single-arm open-label study with 19 secondary progressive
MS patients. We investigated long-term effects of mitoxantrone on
patient peripheral immune subsets using flow cytometry. While we
corroborate that mitoxantrone persistently suppresses B cells in vivo,
we show for the first time that treatment led to an enrichment of
neutrophils and immunomodulatory CD8(low) T cells. Moreover, sustained
mitoxantrone applications promoted not only persistent NK cell
enrichment but also NK cell maturation. Importantly, this
mitoxantrone-induced NK cell maturation was seen only in patients that
showed a clinical response to treatment. Our data emphasize the complex
immunomodulatory role of mitoxantrone, which may account for its benefit
in MS. In particular, these results highlight the contribution of NK
cells to mitoxantrone efficacy in progressive MS.
In my mind it is not clear how mitoxantrone influences progression,
unless it inhibits immune activity in progressive MS and indeed this
study suggests that is only active in people with some form of altered
immune activity and indicates that it affects natural killer cells.
This is a type of immune cell that usually gets rid of cancerous cells.
What they do in MS is obscure but it seems that dacluzimab, which is an
anti CD25-specif therapeutic antibody that inhibits relapsing MS (in
phase II trials) also affects Natural Killer cell function, so this may
be a way to target this subset of cells without the side-effect problems
(cancer and damage of heart muscle) associated with mitoxantrone use.
Labels: mitoxantrone, natural killer cells