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The CD70/CD27 Pathway Is Critical for Stimulation of an Effective Cytotoxic T Cell Response against B Cell Precursor Acute Lymphoblastic Leukemia¹

Ludmila Glouchkova^2,*,, Birgit Ackermann^2,*, Andree Zibert^*, Roland Meisel^*, Meinolf Siepermann^*, Gritta E. Janka-Schaub, Ulrich Goebel^*, Anja Troeger^3,* and Dagmar Dilloo^*

^* Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Heinrich Heine University of Duesseldorf, Duesseldorf, Germany; Institute of Cell Biology, University of Witten/Herdecke, Witten, Germany; and Clinic for Pediatric Hematology and Oncology, University Hospital, Hamburg Eppendorf, Germany

For effective immunotherapy, maintaining the frequency and cytotoxic potential of effector cells is critical. In this context costimulation via the CD70/CD27 pathway has been proven essential. CD70 has been reported to be expressed to varying degrees on malignant B cells. However, in B cell precursor acute lymphboblastic leukemia, the most common childhood malignancy, the role of CD70 in stimulation of antileukemic T cell responses has so far not been delineated. Herein we demonstrate that in B cell precursor acute lymphboblastic leukemia expression of CD70 is low but can be induced upon blast activation via CD40. Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity. Modulation of the CD70/CD27 pathway may thus represent a novel therapeutic approach for augmenting magnitude and quality of the antileukemic response in B cell precursor acute lymphboblastic leukemia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the Elterninitiative Kinderkrebsklinik e.V. Duesseldorf.

² L.G. and B.A. contributed equally to the presented work.

³ Address correspondence and reprint requests to Dr. Anja Troeger, Clinic for Pediatric Oncology, Hematology and Clinical Immunology, University Hospital, Moorenstrasse 5, 40225 Duesseldorf, Germany. E-mail address: troeger{at}med.uni-duesseldorf.de

⁴ Abbreviations used in this paper: CLL, chronic lymphocytic leukemia; ALL, acute lymphboblastic leukemia; BCP-ALL, B cell precursor ALL; CD40-stim. ALL, CD40-activated ALL blasts; SI, stimulation index; unstim. ALL, unstimulated ALL blasts.