Open AccessPharmacodynamic effects of daclizumab in the intrathecal compartment
Author(s) -
Komori Mika,
Kosa Peter,
Stein Jason,
Zhao Vivian,
Blake Andrew,
Cherup Jamie,
Sheridan James,
Wu Tianxia,
Bielekova Bibiana
Publication year - 2017
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.427
Subject(s) - medicine , pharmacodynamics , daclizumab , compartment (ship) , intrathecal , pharmacology , anesthesia , pharmacokinetics , surgery , transplantation , oceanography , geology , tacrolimus
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.