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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4353-4361.
Prepublished online as a Blood First Edition Paper on February 24, 2004; DOI 10.1182/blood-2003-10-3735.
Submitted November 3, 2003
Accepted February 8, 2004
Graft-vs-Leukemia in a Retrovirally Induced Murine CML Model:Mechanisms of T Cell Killing
Catherine C Matte, James Cormier, Britt E Anderson, Ioanna Athanasiadis, Jinli Liu, Stephen G Emerson, Warren Pear, and Warren D Shlomchik*
Medical Oncology, Yale University School of Medicine, New Haven, CT, USA
Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA
Immunobiology, Yale University School of Medicine, New Haven, CT, USA
Hematology and Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Medical Oncology, Yale University School of Medicine, New Haven, CT, USA; Immunobiology, Yale University School of Medicine, New Haven, CT, USA
* Corresponding author; email: warren.shlomchik{at}yale.edu.
The Graft-vs.-Leukemia (GVL) effect, mediated by donor T cells, has revolutionized the treatment of leukemia. However, effective GVL remains difficult to separate from GVHD and many neoplasms are GVL resistant. Murine studies aimed at solving these problems have been limited by the use of leukemia cell lines with limited homology to human leukemias and by the absence of loss-of-function leukemia variants. To address these concerns, we developed a GVL model against murine chronic phase CML (mCP-CML) induced with retrovirus expressing the bcr-abl fusion cDNA, the defining genetic abnormality of chronic phase CML (CP-CML). Via generation of mCP-CML in gene deficient mice, we have studied GVL T cell effector mechanisms. mCP-CML expression of Fas or TNF receptors is not required for CD8-mediated GVL. Strikingly, maximal CD4-mediated GVL requires cognate interactions between CD4 cells and mCP-CML cells as MHC II-/- mCP-CML is relatively GVL resistant. Nevertheless, a minority of CD4 recipients cleared MHCII-/- mCP-CML, and thus CD4 cells can also kill indirectly. CD4 GVL did not require target Fas expression. These results suggest that CP-CML's GVL sensitivity may in part be explained by the minimal requirements for T cell killing and GVL resistance may be related to MHCII expression.
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