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Acute Rejection of Allografted CTL-Susceptible Leukemia Cells from Perforin/Fas Ligand Double-Deficient Mice¹

Hayahito Nomi^*,, Junko Tashiro-Yamaji^*, Yumiko Yamamoto^*, Sayako Miura-Takeda^*, Masako Miyoshi-Higashino^*, Takeshi Takahashi^*, Haruhito Azuma, Haruhiko Ueda, Yoji Katsuoka, Takahiro Kubota^* and Ryotaro Yoshida^2,*

^* Department of Physiology and Department of Urology, Osaka Medical College, Takatsuki, Japan

The generation of knockout mice demonstrated that CD4⁺, but not CD8⁺, T cells were essential for the rejection of allografted skin or heart, presumably because these targets were CTL resistant. In the case of CTL-susceptible targets (e.g., P815 mastocytoma cells and EL-4 or RLmale1 T lymphoma cells), however, it is assumed that the CTL is the effector cell responsible for allograft rejection and that perforin and Fas ligand (FasL) pathways are the killing mechanisms. In the present study, we examined the role of these cytotoxic molecules in the rejection of i.p. allografted CTL-susceptible leukemia cells. Unexpectedly, the allografted leukemia cells were acutely rejected from gld (a mutation of FasL), perforin^–/–, or double-deficient mice. The peritoneal exudate cells from gld or normal mice showed T cell-, TCR-, and perforin-dependent cytotoxic activity against the allograft, whereas the exudate cells from perforin^–/– mice exhibited almost full cytotoxic activity in the presence of Fas-Fc. Furthermore, the infiltrates from double-deficient mice showed a high cytotoxic activity against the allografted cells even in the presence of anti-TCR Ab or in the absence of T cells. The cytotoxic cells appeared to be macrophages, because they were Mac-1⁺ mononuclear cells with a kidney- or horseshoe-shaped nucleus and because the cytotoxic activity was completely suppressed by the addition of N^G-monomethyl-L-arginine, an inhibitor of inducible NO synthase. These results indicate that macrophages are ready and available to kill CTL-susceptible allografts when CTLs lack both perforin and FasL molecules.

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 was supported in part by the Mori and Magai Memorial Research Funds from Osaka Medical College and by a research grant from Kissei Pharmaceutical Company.

² Address correspondence and reprint requests to Dr. Ryotaro Yoshida, Department of Physiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Japan. E-mail address: ryoshida{at}art.osaka-med.ac.jp

³ Abbreviations used in this paper: FasL, Fas ligand; AIM, allograft-induced macrophage; NMMA, N^G-monomethyl-L-arginine; PEC, peritoneal exudate cell; FCM, flow cytometry.