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Tumoricidal Effects of Activated Macrophages in a Mouse Model of Chronic Lymphocytic Leukemia¹

Qing-Li Wu^2,*, Ilia N. Buhtoiarov^2,, Paul M. Sondel^,, Alexander L. Rakhmilevich and Erik A. Ranheim^3,*

^* Departments of Pathology and Laboratory Medicine, Human Oncology, and Pediatrics University of Wisconsin School of Medicine and Public Health, Madison, WI 53792

The Eµ-TCL1 transgenic mouse spontaneously develops a CD5⁺ B cell lymphoproliferative disorder similar to human chronic lymphocytic leukemia (CLL). Given the ineffectual T cell antitumor responses in this mouse model of CLL, we sought to determine whether combined treatment with anti-CD40 mAb (CD40) and CpG-containing oligodeoxynucleotides (CpG) could exert immunotherapeutic effects. We have previously shown that macrophages activated by sequential ligation of CD40 and TLR9 could become cytotoxic against solid tumor cell lines both in vitro and in vivo. In the current study, we find that CD40 plus CpG-activated macrophages induce tumor B cell apoptosis in vitro and that CD40 plus CpG treatment markedly retards tumor growth in immunodeficient SCID/Beige mice following transplantation of primary tumor B cells. Our results suggest a novel immunotherapeutic strategy for CLL that may be effective even in the face of tumor or chemotherapy-induced T cell immunodeficiency.

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 work is supported by National Institutes of Health Grants 5KO8CA090450-03 (to E.A.R.), CA87025 and CA032685 (to P.M.S.), and grants from the Midwest Athletes Against Childhood Cancer (MACC) Fund and The University of Wisconsin Cure Kids Cancer Coalition (UW-CKCC) (to I.N.B.).

² Q.W. and I.B. contributed equally to this study.

³ Address correspondence and reprint requests Dr. Erik A. Ranheim, 600 Highland Avenue, K4/850 CSC, Madison, WI 53792-8550. E-mail address: earanheim{at}wisc.edu

⁴ Abbreviations used in this paper: CLL, chronic lymphocytic leukemia; M, macrophage; CD40, anti-CD40; [³H]TdR, [³H]Thymidine; L-NAME, L-nitro-arginine-methyl-esterase; DiOC₆, 3,3'-dihexiloxa dicarbocyanine; PI, propidium iodide; ADCC, Ab-dependent cell cytotoxicity.