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Objective  It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid ( CSF ) abnormalities typical of multiple sclerosis ( MS ) in the majority of treated patients. However,  CSF  cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.    Methods  Forty  MS  patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open‐label clinical trials.  MRI  contrast‐enhancing lesions ( CEL s), clinical scales, and  CSF  biomarkers quantified residual disease.    Results  Rapid decreases in  CEL s, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant ( P  < 0.0001) decreases in  CSF  levels of T‐cell activation marker  CD 27 and IgG index. Interleukin 2 ( IL ‐2)  CSF  levels increased from baseline levels during treatment, consistent with reduced  IL ‐2 consumption by T cells, as a consequence of daclizumab's saturation of high‐affinity  IL ‐2 receptors.  CSF  levels of  IL ‐12p40, chitinase‐3‐like protein‐1 ( CHI 3L1), chemokine C‐X‐C motif ligand 13, and neurofilament light chain ( NFL ) were also significantly reduced by daclizumab. Among them, inhibition of  CHI 3L1 correlated with inhibition of  NFL  and with lack of disease progression.    Interpretation  These observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of  CSF  biomarkers of myeloid lineage as a stronger determinant of reduction in clinical  MS  activity than inhibition of biomarkers of adaptive immunity.

Pharmacodynamic effects of daclizumab in the intrathecal compartment