Abstract
As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5. Trial Registration: ClinicalTrials.gov Phase I: NCT02442557; Phase IIa: NCT02442570
Highlights
multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), affecting an estimated 2.3 million people worldwide
As explained in the introduction, key to successful therapeutic application of HspB5 in humans is the definition of intravenous doses at which its anti-inflammatory and neuroprotective actions are not thwarted by an antigen-specific response of IFN-γ-secreting HspB5-reactive memory T cells that are part of a normal human immune repertoire
As recently shown by us, IFN-γ changes the otherwise IL-10-dominated protective TLR2-mediated of microglia and macrophages to HspB5 into a destructive classical response that is dominated by the production of large amounts of TNF-α, IL-1β, IL-12 and reactive oxygen species [23]
Summary
MS is a chronic demyelinating disease of the central nervous system (CNS), affecting an estimated 2.3 million people worldwide. Consistent are findings of both focal and diffuse biochemical and histological abnormalities in the CNS, in association with signs of oxidative stress [1]. One of these abnormalities is the selective accumulation of the stress-inducible small heat-shock protein HspB5 in myelin-forming oligodendrocytes during MS, which is part of an anti-apoptotic response by these cells to oxidative stress [2]. Several studies have clarified that HspB5 levels regularly increase up to 20-fold during MS [3,4,5,6,7,8], in areas of the CNS that are not yet visibly affected by inflammation and myelin damage [9]. It has gradually become clear that this remarkable accumulation of HspB5 serves broader functions that just protection from oxidative stress
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