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The Anti-Human Tumor Effect and Generation of Human Cytotoxic T Cells in SCID Mice Given Human Peripheral Blood Lymphocytes by the in Vivo Transfer of the Interleukin-6 Gene Using Adenovirus Vector¹

Departments of Clinical Genetics [F. T., M. A., T. S., M. O.] and Surgical Oncology [T. A.], Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, Oita 874; Central Institute for Experimental Animals, Kawasaki, Kanagawa 210 [T. N.]; Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Fukuoka 812 [K. S.]; and Department of Medicine III, Osaka University Medical School, Suita, Osaka 565 [T. K.], Japan

Interleukin-6 (IL-6) was found to function as a late-acting killer helper factor in the differentiation of CTLs. In the model of tumor-bearing mice, the systemic administration of recombinant IL-6 was found to mediate the antitumor effect on the immunogenic murine tumors via the in vivo induction of murine CTLs but not on the poorly immunogenic murine tumors in our previous study. However, an in vivo experimental model capable of analyzing the anti-human tumor effect via the in vivo induction of human CTLs has not yet been established. Therefore, in the present study, severe combined immunodeficient mice were given human peripheral blood lymphocytes (SCID-PBL/hu), and thereafter human tumor cells were administered i.p. into these SCID-PBL/hu mice as a model of human patients with cancer. When these SCID-PBL/hu mice bearing allogeneic human CESS B blastoid tumor cells were treated in vivo with recombinant adenovirus vector expressing IL-6 cDNA, both the induction of CD8⁺ human CTLs against CESS cells in the spleen cells and peritoneal exudate cells and a prolongation in the survival of these mice were observed. Furthermore, SCID-PBL/hu mice were given peripheral blood lymphocytes from patients with cancer (gastric or rectal cancers) and autologous human tumor cells. The in vivo administration of recombinant adenovirus vector expressing IL-6 cDNA induced CD8⁺ human CTLs specific for autologous human tumor cells from human precursor T cells. The in vivo injection of the IL-6 gene also inhibited growth and metastasis in autologous human cancers. Based on the above findings, the experimental model using SCID-PBL/hu mice and the IL-6 gene delivered in vivo by an adenovirus vector might therefore provide a new strategy capable of analyzing an anti-human tumor effect and the in vivo induction of human CTLs by cytokine gene therapy without using the human body.

¹ This work was supported by Grants-in-Aid for Scientific Research on Priority Areas of Cancer 06282244 and 04253226 and Grant-in-Aid for Scientific Research (type C) 3963 from the Ministry of Education, Science, Sports and Culture of Japan.

² To whom requests for reprints should be addressed. Phone: 81-977-27-1666; Fax: 81-977-27-1607.

Received 8/19/96. Accepted 1/31/97.

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