Document Detail


In vitro co-stimulation with anti-CD28 synergizes with IL-12 in the generation of T cell immune responses to leukaemic cells; a strategy for ex-vivo generation of CTL for immunotherapy.
MedLine Citation:
PMID:  12930376     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The existence of an immune based graft-versus-leukaemia (GvL) effect highlighted the prospect of managing relapsed leukaemias with T cell-based adoptive immunotherapy. Thus, various strategies have been explored for the in vitro expansion of acute myeloid leukaemia (AML)-specific T cells. In a popular approach, AML blasts have been genetically modified to express co-stimulatory molecules essential for effective T cell priming. One such tactic has been the modification of AML cells to express the B7/CD80 co-stimulatory molecule that binds to CD28 on T cells initiating events that culminate in enhanced cytokine production, proliferation and development of effector functions by T cells. The success of these strategies has been limited by difficulties in attaining sufficient transduction efficiencies and associated high levels of CD80 expression. We demonstrate that these problems can be circumvented by using anti-CD28 monoclonal antibody. Furthermore, we show that the synergistic relationship between CD80/CD28 pathway and interleukin 12 cytokine (IL-12), documented in the generation of cytotoxic T lymphocytes (CTL) for solid tumours, also applies to AML. CD28/IL-12 synergy facilitated the proliferation of allogeneic T cells in response to stimulation with primary AML blasts. The synergy also favoured generation of a Th1-type immune response, evidenced by gamma interferon (IFN-gamma) secretion and facilitated naive and memory T cell proliferation. Unlike some methods of in vitro T cell expansion, use of CD28/IL-12 synergy left T cells in the physiologically appropriate CD45RA-/CCR7- subsets known to be associated with immediate cytotoxic functions.
Authors:
J K Orleans-Lindsay; A Deru; J I O Craig; H G Prentice; M W Lowdell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Clinical and experimental immunology     Volume:  133     ISSN:  0009-9104     ISO Abbreviation:  Clin. Exp. Immunol.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-08-21     Completed Date:  2003-10-14     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0057202     Medline TA:  Clin Exp Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  467-75     Citation Subset:  IM    
Affiliation:
Department of Haematology, Royal Free and University College Medical School, London, UK.
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MeSH Terms
Descriptor/Qualifier:
Acute Disease
Adult
Antibodies, Monoclonal / therapeutic use*
Antigens, CD28 / immunology*
Antigens, CD45 / analysis
Antigens, CD80 / immunology
Graft vs Leukemia Effect
Humans
Immunotherapy, Adoptive*
Interferon-gamma / secretion
Interleukin-12 / immunology*
Leukemia, Myeloid / immunology,  therapy*
Membrane Glycoproteins / metabolism
Perforin
Pore Forming Cytotoxic Proteins
Receptors, CCR7
Receptors, Chemokine / analysis
T-Lymphocytes, Cytotoxic / immunology*
Th1 Cells / immunology
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antigens, CD28; 0/Antigens, CD80; 0/CCR7 protein, human; 0/Membrane Glycoproteins; 0/Pore Forming Cytotoxic Proteins; 0/Receptors, CCR7; 0/Receptors, Chemokine; 126465-35-8/Perforin; 187348-17-0/Interleukin-12; 82115-62-6/Interferon-gamma; EC 3.1.3.48/Antigens, CD45
Comments/Corrections

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