title: Differential immune effects mediated by Toll-like receptors stimulation in precursor B-cell acute lymphoblastic leukaemia.
abstract: Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy and, although current therapy is widely effective, relapse remains a significant clinical problem for which new treatment strategies are required. The ligation of Toll-like receptors (TLR) on antigen-presenting cells stimulates the generation of strong T-cell helper type 1 (Th1) adaptive immune responses. Although TLR9 ligation has been shown to enhance immunogenicity of a number of leukaemia cell types, there have been few reports of the effects mediated through other TLR. In this study we analysed both the expression of TLR by B-cell precursor ALL cell lines and the effects of individual TLR ligation on the ability of ALL cells to stimulate allogeneic T cells. While ligation of TLR2, TLR 7 and TLR9 led to detectable changes in ALL costimulatory molecule expression, only TLR2 and TLR9 stimulation influenced T-cell responses. The TLR2 ligand Pam3CysSerLys4 provoked the most significant changes in T-cell response, dramatically augmenting interferon-gamma production. These results suggest that TLR ligands, in addition to TLR9 agonists, may provide a strategy to enhance the generation of anti-ALL immune activity by skewing responding T cells towards a Th1 response.
authors.affiliation: Division of Haematology, Oncology, Bone Marrow Transplantation, Department of Pediatrics, University of British Columbia and British Columbia's Children's Hospital, Vancouver, BC, Canada.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Corthals
authors.forename: Kristin
authors.initials: K
authors.lastname: Wynne
authors.forename: Kevin
authors.initials: K
authors.lastname: She
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Darko
authors.initials: D
authors.lastname: Curman
authors.forename: Kristy
authors.initials: K
authors.lastname: Garbutt
authors.forename: Gregor S D
authors.initials: GS
authors.lastname: Reid
mesh_terms: D019013:CD40 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D008024:Ligands; D010457:Peptidoglycan / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D008024:Ligands; D010457:Peptidoglycan; D012333:RNA, Messenger; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D006151:Guanosine; D007371:Interferon-gamma; C068562:loxoribine