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.
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 MSpatients 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 MSpatients 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.
Authors: Ruolan Liu; Antonio La Cava; Xue-Feng Bai; Youngheun Jee; Mary Price; Denise I Campagnolo; Premkumar Christadoss; Timothy L Vollmer; Luc Van Kaer; Fu-Dong Shi Journal: J Immunol Date: 2005-12-15 Impact factor: 5.422
Authors: DeRen Huang; Fu-Dong Shi; Steffen Jung; Gary C Pien; Jintang Wang; Thais P Salazar-Mather; Toby T He; Jennifer T Weaver; Hans-Gustaf Ljunggren; Christine A Biron; Dan R Littman; Richard M Ransohoff Journal: FASEB J Date: 2006-05 Impact factor: 5.191
Authors: Bibiana Bielekova; Marta Catalfamo; Susan Reichert-Scrivner; Amy Packer; Magdalena Cerna; Thomas A Waldmann; Henry McFarland; Pierre A Henkart; Roland Martin Journal: Proc Natl Acad Sci U S A Date: 2006-04-03 Impact factor: 11.205
Authors: Astrid E Cardona; Erik P Pioro; Margaret E Sasse; Volodymyr Kostenko; Sandra M Cardona; Ineke M Dijkstra; Deren Huang; Grahame Kidd; Stephen Dombrowski; RanJan Dutta; Jar-Chi Lee; Donald N Cook; Steffen Jung; Sergio A Lira; Dan R Littman; Richard M Ransohoff Journal: Nat Neurosci Date: 2006-06-18 Impact factor: 24.884
Authors: Yan Gan; Qiang Liu; Wei Wu; Jun-Xiang Yin; Xue-Feng Bai; Rulong Shen; Yongjun Wang; Jieli Chen; Antonio La Cava; Jennifer Poursine-Laurent; Wayne Yokoyama; Fu-Dong Shi Journal: Proc Natl Acad Sci U S A Date: 2014-02-03 Impact factor: 11.205