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Objective  Novel treatments such as natalizumab and fingolimod achieve their therapeutic efficacy in multiple sclerosis ( MS ) by blocking access of subsets of immune cells into the central nervous system, thus creating nonphysiological intrathecal immunity. In contrast, daclizumab, a humanized monoclonal antibody against the alpha chain of the  IL ‐2 receptor, has a unique mechanism of action with multiple direct effects on innate immunity. As cellular intrathecal abnormalities corresponding to  MS  have been well defined, we asked how daclizumab therapy affects these immunological hallmarks of the  MS  disease process.    Methods  Nineteen subpopulations of immune cells were assessed in a blinded fashion in the blood and 50‐fold concentrated cerebrospinal fluid ( CSF ) cell pellet in 32 patients with untreated relapsing‐remitting  MS  ( RRMS ), 22 daclizumab‐treated  RRMS  patients, and 11 healthy donors ( HD s) using 12‐color flow cytometry.    Results  Long‐term daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated  RRMS  patients from  HD s. Specifically, strong enrichment of adaptive immune cells ( CD 4+ and  CD 8+ T cells and B cells) in the  CSF  was reversed. Similarly, daclizumab controlled  MS ‐related increases in the innate lymphoid cells ( ILC s) and lymphoid tissue inducer cells in the blood and  CSF , and reverted the diminished proportion of intrathecal monocytes. The only marker that distinguished daclizumab‐treated  MS  patients from  HD s was the expansion of immunoregulatory  CD 56 bright   NK  cells.    Interpretation  Normalization of immunological abnormalities associated with  MS  by long‐term daclizumab therapy suggests that this drug's effects on  ILC s,  NK  cells, and dendritic cell‐mediated antigen presentation to  CD 4+ and  CD 8+ T cells are critical in regulating the  MS  disease process.

Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis