Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis

Abstract

ObjectiveNovel 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.MethodsNineteen 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 (HDs) using 12-color flow cytometry.ResultsLong-term daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated RRMS patients from HDs. Specifically, strong enrichment of adaptive immune cells (CD4+ and CD8+ T cells and B cells) in the CSF was reversed. Similarly, daclizumab controlled MS-related increases in the innate lymphoid cells (ILCs) 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 HDs was the expansion of immunoregulatory CD56bright NK cells.InterpretationNormalization of immunological abnormalities associated with MS by long-term daclizumab therapy suggests that this drug's effects on ILCs, NK cells, and dendritic cell-mediated antigen presentation to CD4+ and CD8+ T cells are critical in regulating the MS disease process.

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…Notwithstanding these limitations, we conclude that the previously noted normalization of cellular abnormalities in the CSF of MS patients by daclizumab8 is not associated with normalization of markers of adaptive immunity in the CNS tissue. This expands the existing knowledge of persistent presence of plasma cells/plasmablasts (reflected by elevated IgG index) in treated MS patients by providing evidence for persistence of T and B cells in the intrathecal compartment of successfully treated MS patients, reflected by elevated CSF levels of sCD27 and sCD21, respectively 4.…”

“…The interesting question is how low measured intrathecal concentration of daclizumab (i.e., 15.1 ng/mL) can inhibit consumption of IL‐2 by intrathecal T cells. The answer resides in the previously published observations that in RRMS patients, virtually all CSF T cells had completely blocked CD25 after initiation of dosing by former (i.e., Zenapax)19 or current (i.e., Zinbryta)8 daclizumab formulations. This agrees with another published observation that in contrast to progressive MS, where majority of patients have inflammation compartmentalized to CNS tissue with little turnover between blood and intrathecal compartment, majority of RRMS patients have communicating inflammation, where immune cells are constantly accessing intrathecal compartment from the blood, as already activated T or B cells 20.…”

“…CSF was processed according to written standard operating procedures (SOP) 8, 9. A portion of CSF was sent to measure IgG index.…”

Impact of Immune-Modulatory Drugs on Regulatory T Cell

“…Anti-CD25 mAb can also inhibit activation of CD25 − T cells by blocking CD25 + dendritic cells from trans-presentation of IL-2 (a process of donating CD25 complexed IL-2) 41 . Other CD25 + proinflammatory cell types, such as lymphoid tissue-inducer cells and innate lymphocytes 42 , are reduced following daclizumab treatment during multiple sclerosis (MS) flares 43,44 . These immunosuppressive mechanisms may contribute to the positive clinical outcomes of anti-CD25 mAb in MS 37,45,46 .…”

Human CD56bright NK Cells: An Update

“…The proportion of CD56 dim NK cells is lower in cerebrospinal fluid, whereas CD56 bright NK cells are overrepresented and show an activated phenotype because they are able to degranulate more (65 (47,69). Thus, in a human-mouse chimera model, the adoptive transfer of CD56 bright NK cells pretreated with IL-2 complexes ameliorates the severity of experimental autoimmune encephalomyelitis (EAE), and this is also the case after transfer of CD56 dim NK cells, leading to a reduction in the capacity of microglia to transactivate the Th17 transcription factor, Rorc (70).…”