Impaired interferon-γ production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma

Michael J. Robertson, Hua Chen Chang, David Pelloso, Mark H. Kaplan

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Production of interferon γ (IFN-γ) is critical for optimal antitumor immunotherapy in several preclinical animal models. Interleukin-12 (IL-12)-induced IFN-γ 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-γ production. IL-12 receptor β1 (IL-12Rβ1) and IL-12Rβ2 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 post-transplantation 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-γ production by post-transplantation patient PBMCs. IFN-γ 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-γ production is due to an intrinsic deficiency in STAT4 expression by posttransplantation patient lymphocytes and suggest strategies for circumventing this deficiency in cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)963-970
Number of pages8
JournalBlood
Volume106
Issue number3
DOIs
StatePublished - Aug 1 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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