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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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IMMUNOBIOLOGY

Impaired interferon-{gamma} 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

From the Bone Marrow and Stem Cell Transplantation Program, Lymphoma Program, and the Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN; and the Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN.

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 {beta}1 (IL-12R{beta}1) and IL-12R{beta}2 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.


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Home page
 ASH ANNUAL MEETING ABSTRACTSHome page
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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