TY - JOUR
T1 - Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells
T2 - Clinical application
AU - Hayashi, Toshiaki
AU - Hideshima, Teru
AU - Akiyama, Masaharu
AU - Podar, Klaus
AU - Yasui, Hiroshi
AU - Raje, Noopur
AU - Kumar, Shaji
AU - Chauhan, Dharminder
AU - Treon, Steven P.
AU - Richardson, Paul
AU - Anderson, Kenneth C.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/1
Y1 - 2005/1
N2 - Thalidomide and immunomodulatory drugs (IMiDs), which target multiple myeloma (MM) cells and the bone marrow microenvironment, can overcome drug resistance. These agents also have immunomodulatory effects. Specifically, we have reported that thalidomide increased serum interleukin-2 (IL-2) levels and natural killer (NK) cell numbers in the peripheral blood of responding MM patients. In this study, we investigated the mechanisms whereby IMiDs augment NK cell cytotoxicity. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells cultured with IMiDs were examined in the presence or absence of anti-IL-2 antibody, ciclosporin A or depletion of CD56-positive cells. IMiDs-induced signalling pathways, triggering IL-2 transcription in T cells, were also delineated. IMiDs facilitated the nuclear translocation of nuclear factor of activated T cells-2 and activator protein-1 via activation of phosphoinositide-3 kinase signalling, with resultant IL-2 secretion. IMiDs enhanced both NK cell cytotoxicity and ADCC induced by triggering IL-2 production from T cells. These studies defined the mechanisms whereby IMiDs trigger NK cell-mediated tumour-cell lysis, further supporting their therapeutic use in MM.
AB - Thalidomide and immunomodulatory drugs (IMiDs), which target multiple myeloma (MM) cells and the bone marrow microenvironment, can overcome drug resistance. These agents also have immunomodulatory effects. Specifically, we have reported that thalidomide increased serum interleukin-2 (IL-2) levels and natural killer (NK) cell numbers in the peripheral blood of responding MM patients. In this study, we investigated the mechanisms whereby IMiDs augment NK cell cytotoxicity. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells cultured with IMiDs were examined in the presence or absence of anti-IL-2 antibody, ciclosporin A or depletion of CD56-positive cells. IMiDs-induced signalling pathways, triggering IL-2 transcription in T cells, were also delineated. IMiDs facilitated the nuclear translocation of nuclear factor of activated T cells-2 and activator protein-1 via activation of phosphoinositide-3 kinase signalling, with resultant IL-2 secretion. IMiDs enhanced both NK cell cytotoxicity and ADCC induced by triggering IL-2 production from T cells. These studies defined the mechanisms whereby IMiDs trigger NK cell-mediated tumour-cell lysis, further supporting their therapeutic use in MM.
KW - Antibody-dependent cell-mediated cytotoxicity
KW - Interleukin-2
KW - Nuclear factor of activated T cells
KW - Phosphoinositide-3 kinase
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U2 - 10.1111/j.1365-2141.2004.05286.x
DO - 10.1111/j.1365-2141.2004.05286.x
M3 - Article
C2 - 15638853
AN - SCOPUS:19944430437
SN - 0007-1048
VL - 128
SP - 192
EP - 203
JO - British journal of haematology
JF - British journal of haematology
IS - 2
ER -