TY - JOUR
T1 - Adenoviral gene transfer into dendritic cells efficiently amplifies the immune response to LMP2A antigen
T2 - A potential treatment strategy for Epstein-Barr virus-positive Hodgkin's lymphoma
AU - Gahn, Benedikt
AU - Siller-Lopez, Fernando
AU - Pirooz, Angela D.
AU - Yvon, Eric
AU - Gottschalk, Stephen
AU - Longnecker, Richard
AU - Brenner, Malcolm K.
AU - Heslop, Helen E.
AU - Aguilar-Cordova, Estuardo
AU - Rooney, Cliona M.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 2001/9/1
Y1 - 2001/9/1
N2 - The EBV-encoded LMP2A protein is consistently expressed in EBV+ Hodgkin's lymphoma and can be targeted by CTLs. CTLs stimulated conventionally by LCLs have little activity against LMP2A+ target cells. Here, we describe an alternative approach, based on the in vitro stimulation of CTLs with DCs genetically modified with 2 E1/E3-deleted recombinant adenoviruses, AdGFPLMP2A, encoding a fusion gene of GFP and LMP2A, and AdLMP2A, encoding LMP2A only. Transduction of DCs with AdGFPLMP2A at MOI 1,000 resulted in LMP2A expression in up to 88% of DCs. LMP2A protein was expressed in 40% of DCs transduced with AdLMP2A at an MOI of 100. Higher MOI resulted in DC death. CTL lines activated by transduced DCs had a higher frequency of LMP2A tetramer-specific CTLs than CTL lines activated by LCLs. CTLs stimulated with transduced DCs lysed both autologous fibroblasts infected with vaccinia virus LMP2A (FBvaccLMP2A) and autologous LCLs, which express LMP2A at lower levels. In contrast, CTLs generated from the same donors by stimulation with autologous LCLs showed minimal lysis of FBvaccLMP2A. Moreover, I donor who did not respond to LMP2A when CTLs were stimulated with LCLs became a responder when LMP2A was expressed by transduced DCs. Hence, recombinant adenoviruses encoding LMP2A effectively transduce DCs and direct the generation of LMP2A-specific CTLs. This approach will be a potent strategy in Hodgkin's lymphoma immunotherapy.
AB - The EBV-encoded LMP2A protein is consistently expressed in EBV+ Hodgkin's lymphoma and can be targeted by CTLs. CTLs stimulated conventionally by LCLs have little activity against LMP2A+ target cells. Here, we describe an alternative approach, based on the in vitro stimulation of CTLs with DCs genetically modified with 2 E1/E3-deleted recombinant adenoviruses, AdGFPLMP2A, encoding a fusion gene of GFP and LMP2A, and AdLMP2A, encoding LMP2A only. Transduction of DCs with AdGFPLMP2A at MOI 1,000 resulted in LMP2A expression in up to 88% of DCs. LMP2A protein was expressed in 40% of DCs transduced with AdLMP2A at an MOI of 100. Higher MOI resulted in DC death. CTL lines activated by transduced DCs had a higher frequency of LMP2A tetramer-specific CTLs than CTL lines activated by LCLs. CTLs stimulated with transduced DCs lysed both autologous fibroblasts infected with vaccinia virus LMP2A (FBvaccLMP2A) and autologous LCLs, which express LMP2A at lower levels. In contrast, CTLs generated from the same donors by stimulation with autologous LCLs showed minimal lysis of FBvaccLMP2A. Moreover, I donor who did not respond to LMP2A when CTLs were stimulated with LCLs became a responder when LMP2A was expressed by transduced DCs. Hence, recombinant adenoviruses encoding LMP2A effectively transduce DCs and direct the generation of LMP2A-specific CTLs. This approach will be a potent strategy in Hodgkin's lymphoma immunotherapy.
KW - Cytotoxic T lymphocytes
KW - Dendritic cells
KW - Epstein-Barr virus
KW - Hodgkin's lymphoma
KW - LMP2A
KW - Recombinant adenovirus
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U2 - 10.1002/ijc.1396
DO - 10.1002/ijc.1396
M3 - Article
C2 - 11477583
AN - SCOPUS:0035452356
SN - 0020-7136
VL - 93
SP - 706
EP - 713
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 5
ER -