CpG stimulation of precursor B-lineage acute lymphoblastic leukemia induces a distinct change in costimulatory molecule expression and shifts allogeneic T cells toward a Th1 response.
Immunostimulatory DNA containing unmethylated cytosine-phosphate-guanosine (CpG) induces the development of T helper 1 (Th1) immune responses. The response of B cells to CpG stimulation involves increased proliferation, cytokine production, and costimulatory molecule expression. Similar effects have been observed following CpG stimulation of a variety of malignant B cells. Pediatric precursor B acute lymphoblastic leukemia (B-ALL) cells express low levels of costimulatory molecules and are generally poor stimulators of T-cell responses. In this study, we evaluated the impact of CpG stimulation on precursor B-ALL cell lines and pediatric patient-derived samples. The ability to respond to CpG oligodeoxynucleotides was determined by the level of Toll-like receptor 9 (TLR9) expression. In contrast to both nonleukemic B-cell precursors and mature B cells, the response of precursor B-ALL cells was characterized by increased CD40 expression but only small changes in CD86 levels and no induction of CD80 expression. CpG stimulation of ALL blasts produced increased levels of interleukin-6 (IL-6), IL-8, and IL-10 but no detectable IL-12p70 and led to a skewing of allogeneic T cells, with enhanced interferon gamma (IFN-gamma) production and reduced secretion of IL-5. These results demonstrate the functional relevance of CpG stimulation of precursor B-ALL cells and provide a rational basis for study of these agents for use in treatment of this disease.
Reid
Gregor S D
GS
Room 217, BCRI, 950 W 28th Ave, Vancouver, BC V5Z 4H4, Canada. grogreid@interchange.ubc.ca.
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Kevin
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Terrett
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Food
Michael R
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Trudeau
Jacqueline D
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Schultz
Kirk R
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D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D051217:Toll-Like Receptor 9; D014183:Transplantation, Heterologous
D004268:DNA-Binding Proteins; D015226:Dinucleoside Phosphates; D007378:Interleukins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; D051217:Toll-Like Receptor 9; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; C015772:CpG dinucleotide