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

Abstract

Production of interferon ␥ (IFN-␥ IntroductionNon-Hodgkin lymphoma is the most common of the hematologic malignancies. 1 The incidence of non-Hodgkin lymphoma has been rising steadily for the past 50 years, and approximately 60 000 new cases are currently diagnosed annually in the United States. Because of this increased incidence, non-Hodgkin lymphoma is one of the few cancers for which mortality has increased in the past 20 years. 2 High-dose therapy and autologous hematopoietic stem cell transplantation is the treatment of choice for eligible patients with non-Hodgkin or Hodgkin lymphoma that is refractory to or has relapsed after conventional chemotherapy. [3][4][5][6] Nevertheless, greater than 50% to 60% of patients with relapsed or refractory lymphoma will ultimately develop progressive disease after autologous stem cell transplantation. Novel strategies are needed to reduce the risk of recurrent lymphoma after high-dose therapy. One approach is posttransplantation immunotherapy to eliminate chemotherapy-resistant tumor cells. 7 Immunotherapeutic approaches under investigation include posttransplantation administration of monoclonal antibodies, immunostimulatory cytokines, and cancer vaccines. [8][9][10] In attempts to stimulate effective antitumor immune responses, we have investigated the use of interleukin 12 (IL-12) after autologous stem cell transplantation. IL-12 plays an important role in the regulation of innate and adaptive immune responses. 11 In preclinical tumor models, IL-12 therapy induces regression of established primary tumors, inhibits the formation of distant metastases, and prolongs the survival of tumor-bearing mice. [12][13][14][15] In several animal models production of interferon ␥ (IFN-␥) in vivo has been shown to be necessary, but not sufficient, for the antitumor effects of 14,16,17 IL-12 mediates its immunologic effects by binding to a specific dimeric cell surface receptor complex, composed of ␤1 and ␤2 chains, which results in activation of the Janus kinases Jak2 and Tyk2. 18,19 The subsequent activation of signal transducer and activator of transcription 4 (STAT4) is required for normal responses to 20,21 Our previous studies have shown that IL-12 can be safely given in biologically active doses after autologous stem cell transplantation. 22 However, serum IFN-␥ levels during IL-12 therapy after transplantation were found to be an order of magnitude lower than those seen in patients with solid tumors not receiving a transplant who received the same doses of 23 Moreover, posttransplantation patient peripheral blood mononuclear cells (PBMCs) were shown to be intrinsically defective in their ability to produce IFN-␥ Patients, materials, and methods Patient and control subject samplesThe study was approved by the Institutional Review Board at Indiana University Medical Center, and written informed consent was obtained from each subject prior to collection of blood samples. Blood samples were obtained from patients with non-Hodgkin and Hodgkin lymphoma who were scheduled to und...

Transcriptional profiling of Epstein–Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection

“…We also found overexpression of HSPCA, which encodes heat shock protein 90, which has recently been reported as a pathologically relevant gene candidate in mantle-cell lymphoma by proteomic analysis (Ghobrial et al, 2005). Marked downregulation of IL12A in SNK/T cells allowed us to consider the possibility to adoptive immunotherapy with EBV-specific cytotoxic-T-lymphocytes (Robertson et al, 2005).…”

Impaired development of human Th1 cells in patients with deficient expression of STAT4

“…7 Control PBMCs were obtained from healthy volunteer donors. Patient blood samples were collected on a study approved by the Institutional Review Board at Indiana University Medical Center and written informed consent was obtained from each study subject in accordance with the Declaration of Helsinki.…”

“…Quantitative polymerase chain reaction (qPCR), Western blot, and flow cytometry were performed as described. 7,9 Cytokine was measured by enzyme-linked immunosorbent assay (ELISA) or Luminex (Millipore, Billerica, MA).…”

“…7 Posttransplantation STAT4 deficiency is associated with markedly defective production of IFN␥ in response to IL-12 both in vitro and in vivo. 7,8 In this report, we have used STAT4-deficient posttransplantation patient lymphocytes to define the role of STAT4 in the development of human Th1 cells. …”

SATB1: Key Regulator of T Cell Development and Differentiation

“…The Jak2 kinase specifically causes the phosphorylation of STAT-4 (Waltford et al, 2004). STAT-4 causes the expression of Interferon  and transcription factor Tbet during T H 1 differentiation (Thieu et al, 2008, Robertson et al, 2005. IL-4 secreted by the APCs engages to the IL-4 receptor on CD4 + T cells which then recruits Jak 3 kinases and causes the activation of STAT-6 (Witthuhn et al, 1994).…”