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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. This Article Full Text (PDF) All Versions of this Article: 2005-01-0201v1 106/3/963    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Robertson, M. J Articles by Kaplan, M. H Search for Related Content PubMed PubMed Citation Articles by Robertson, M. J Articles by Kaplan, M. H Social Bookmarking                   What's this?  Previous Article  |  Next Article  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-12R1 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. J. Robertson, H.-C. Chang, D. Pelloso, and M. H. Kaplan Reconstitution of STAT4 Restores Defective Interferon-gamma Production and Allows Normal IFN-gamma-Dependent Responses after Autologous Stem Cell Transplantation. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 3700 - 3700. [Abstract] [PDF]

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