Figure 8.

Therapeutic intervention in MS with αB-crystallin. A significant memory T-cell response against αB-crystallin is a normal part of the human adult immune repertoire. This is illustrated by the proliferative response of CD45RO + memory T cells as measured by dilution of the cellular marker carboxyfluorescein succinimidyl ester (CFSE) in an example assay using fresh blood from a normal healthy adult (A). As many as 3–5% of all memory T cells frequently respond to αB-crystallin in this way. This T-cell response is associated with the production of IFN-γ, as illustrated by another example assay in panel B. Yet, approximately 10-fold higher concentrations of αB-crystallin are required to trigger this T-cell response as compared to the TLR2-mediated response by macrophages that induces IL-10 production. This difference offers a therapeutic concentration window for tolerance induction. As long as the maximum serum concentration of intravenously administered αB-crystallin remains below the threshold for T-cell activation of around 10 μg/mL, benefit can be taken from the tolerizing macrophage response while avoiding the pathogenic IFN-γ response by T cells. Intravenous doses of either 7.5 or 12.5 mg αB-crystallin lead to sub-immunogenic peak serum concentrations of well below 5 μg/mL. After three bimonthly doses at these levels the total number as well as total volume of gadolinium-enhancing MRI lesions in MS patients are significantly suppressed by about 75% (previously published in part by van Noort et al. 2015, Ref. 21).