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Autoreactive and Heat Shock Protein 60-recognizing CD4⁺ T-Cells Show Antitumor Activity against Syngeneic Fibrosarcoma¹

Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812 [M. H., G. M., N. K., S. K., H. T., K. N.], and Laboratory of Germfree Life, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Nagoya 466 [Y. Y.], Japan

A CD4⁺ heat shock protein (hsp) 60-recognizing autoreactive T-cell line (BASL1) and clone (BASL1.1) were examined for their antitumor activity against major histocompatibility complex class II^- syngeneic Meth A fibrosarcoma (Meth A), which was immunofluorescently stained with monoclonal antibody specific for hsp 60. In in vitro proliferative assay, BASL1.1 was suggested to recognize Meth A-derived hsp 60-presented by syngeneic antigen-presenting cells in a major histocompatibility complex class II-restricted manner. This cell line and clone showed antitumor activity in tumor-neutralizing (Winn) assay. BASL1 and BASL1.1 cells produced -interferon, tumor necrosis factor, and interleukin 2 but not interleukin 4 by the stimulation with syngeneic spleen cells. In cytolytic assay, these cell lines and clones showed neither direct nor indirect (bystander) cytolysis against Meth A. In cytostatic assay, these cells inhibited the proliferation of Meth A in the presence of syngeneic macrophages, and this activity was abrogated by the addition of anti--interferon monoclonal antibody. Recombinant -interferon could induce cytostatic activity only in the presence of macrophages, and tumor necrosis factor synergized this activity. Antitumor activity induced by BASL1 was abrogated by the administration of anti-CD8 monoclonal antibody in vivo, suggesting that CD8⁺ cytotoxic T-lymphocytes are essential and final effector cells for BASL1-mediated Meth A rejection. These findings indicate that CD4⁺ autoreactive and hsp 60-recognizing T-cells show two types of antitumor activity: cytostasis and induction of tumor-specific cytotoxic T-lymphocytes. Furthermore, these results imply that tumor-specific immunity could be elicited by CD4⁺ helper T-cells which recognize hsp.

¹ Supported in part by a grant to G. M. from the Ministry of Education, Science and Culture, and grants to Y. Y. from the Ministry of Education, Science and Culture, the Ministry of Health and Welfare, Sapporo Research Foundation, Fukuoka Cancer Society, and Special Coordination Funds of the Science and Technology Agency of the Japanese Government. This work also received financial support from the Comprehensive 10-year Strategy for Cancer Control and the UNDP/World Bank/WHO Special Program for Research and Training in Tropical Disease.

² To whom requests for reprints should be addressed.

Received 6/ 1/92. Accepted 10/15/92.