Impaired interferon-gamma production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma.
Production of interferon gamma (IFN-gamma) is critical for optimal antitumor immunotherapy in several preclinical animal models. Interleukin-12 (IL-12)-induced IFN-gamma production is markedly defective after autologous stem cell transplantation. Quantitative deficiency in CD4 T cells, relative increase in CD25+CD4+ T cells, and bias toward T helper 2 (Th2) differentiation are not the primary mechanisms of defective IFN-gamma production. IL-12 receptor beta1 (IL-12Rbeta1) and IL-12Rbeta2 are expressed at equivalent or higher levels on posttransplantation patient peripheral blood mononuclear cells (PBMCs) as compared with control PBMCs. IL-12-induced tyrosine phosphorylation of signal transducer and activator of transcription 4 (STAT4) was undetectable or barely detectable in posttransplantation patient PBMCs, whereas IL-4-induced tyrosine phosphorylation of STAT6 did not differ in posttransplantation patient and control PBMCs. Levels of STAT4 protein were decreased by 97% in posttransplantation patient PBMCs. Levels of STAT4 mRNA were also significantly decreased in posttransplantation patient PBMCs. Incubation with IL-12 and IL-18 in combination partially reversed the defective IFN-gamma production by posttransplantation patient PBMCs. IFN-gamma production in response to IL-12 plus IL-18 did not require increased expression of STAT4 but was dependent on the activity of p38 mitogen-activated protein kinase (MAPK). These results indicate that defective IFN-gamma production is due to an intrinsic deficiency in STAT4 expression by posttransplantation patient lymphocytes and suggest strategies for circumventing this deficiency in cancer immunotherapy.
Robertson
Michael J
MJ
Bone Marrow and Stem Cell Transplantation Program, Indiana University Medical Center, 1044 W Walnut St, Rm R4-202, Indianapolis, IN 46202, USA. mjrobert@iupui.edu
Chang
Hua-Chen
HC
Pelloso
David
D
Kaplan
Mark H
MH
D016022:Case-Control Studies; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014182:Transplantation, Autologous; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004268:DNA-Binding Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases