Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation

Ann Neurol. 2011 Apr;69(4):721-34. doi: 10.1002/ana.22339. Epub 2011 Mar 18.


Objective: The role of natural killer (NK) cells in regulating multiple sclerosis (MS) is not well understood. Additional studies with NK cells might provide insight into the mechanism of action of MS therapies such as daclizumab, an antibody against the interleukin (IL)-2R α-chain, which induces expansion of CD56(bright) NK cells.

Methods: In a relapsing-remitting form of the experimental autoimmune encephalomyelitis (EAE) model of MS induced in SJL mice, we expanded NK cells with IL-2 coupled with an anti-IL-2 monoclonal antibody (mAb) and evaluated the effects of these NK cells on EAE. Further, we investigated the effect of the human version of IL-2/IL-2 mAb on NK cells from MS patients and its effect on central nervous system (CNS) inflammation and pathology in a human-mouse chimera model and assessed the underlying mechanisms.

Results: IL-2/IL-2 mAb dramatically expands NK cells both in the peripheral lymphoid organs and in the CNS, and attenuates CNS inflammation and neurological deficits. Disease protection is conferred by CNS-resident NK cells. Importantly, the human version of IL-2/IL-2 mAb restored the defective CD56(+) NK cells from MS patients in a human-mouse chimera model. Both the CD56(bright) and CD56(dim) subpopulations were required to attenuate disease in this model.

Interpretation: These findings unveil the immunotherapeutic potential of NK cells, which can act as critical suppressor cells in target organs of autoimmunity. These results also have implications to better understand the mechanism of action of daclizumab in MS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Autoimmunity
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Proliferation
  • Central Nervous System / immunology*
  • Central Nervous System / pathology
  • Cytokines / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Female
  • Flow Cytometry
  • Granzymes / metabolism
  • Humans
  • Immunotherapy / methods*
  • Inflammation / immunology
  • Interleukin-2 / immunology*
  • Interleukin-2 / pharmacology*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Leukocytes, Mononuclear / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Perforin / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Severity of Illness Index
  • T-Lymphocytes, Regulatory / immunology


  • Antibodies, Monoclonal
  • Cytokines
  • Interleukin-2
  • Perforin
  • Granzymes