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Blood, 1 August 2005, Vol. 106, No. 3, pp. 963-970.
Prepublished online as a Blood First Edition Paper on April 7, 2005; DOI 10.1182/blood-2005-01-0201.
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Submitted January 24, 2005
Accepted March 31, 2005
Impaired interferon- production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma
Michael J Robertson*, Hua-Chen Chang, David Pelloso, and Mark H Kaplan
Bone Marrow and Stem Cell Transplantation Program, Indiana University School of Medicine, Indianapolis, IN, USA; Lymphoma Program, the Division of Hematology/Oncology, and Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
* Corresponding author; email: mjrobert{at}iupui.edu.
Production of interferon (IFN)- is critical for optimal antitumor immunotherapy in several preclinical animal models. Interleukin-12 (IL-12)-induced IFN- production is markedly defective after autologous stem cell transplantation. Quantitative deficiency in CD4 T cells, relative increase in CD25+ CD4+ T cells, and bias towards Th2 differentiation are not the primary mechanisms of defective IFN- production. IL-12R 1 and IL-12R2 are expressed at equivalent or higher levels on post-transplant patient as compared to control peripheral blood mononuclear cells (PBMCs). IL-12-induced tyrosine phosphorylation of STAT4 was undetectable or barely detectable in post-transplant patient PBMCs, whereas IL-4-induced tyrosine phosphorylation of STAT6 did not differ in post-transplant patient and control PBMCs. Levels of STAT4 protein were decreased by 97% in post-transplant patient PBMCs. Levels of STAT4 mRNA were also significantly decreased in post-transplant patient PBMCs. Incubation with IL-12 and IL-18 in combination partially reversed the defective IFN- production by post-transplant patient PBMCs. IFN- production in response to IL-12 plus IL-18 did not require increased expression of STAT4 but was dependent on the activity of p38 MAPK. These results indicate that defective IFN- production is due to an intrinsic deficiency in STAT4 expression by post-transplant patient lymphocytes and suggest strategies for circumventing this deficiency in cancer immunotherapy.
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