2000 Fiscal Year Final Research Report Summary
BREAKING IMMUNOLOGICAL TOLERANCE TO TUMOR CELLS AS A NOVEL IMMUNOTHERAPY FOR CANCER
| Project/Area Number |
11670235
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | TOKYO METROPOLITAN INSTITUTE OF GERONTOLOGY |
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Principal Investigator |
SHIMIZU Jun TOKYO METROPOLITAN INSTITUTE OF GERONTOLOGY, DEPARTMENT OF IMMUNOPATHOLOGY, RESEARCH SCIENTIST, 免疫病理部門, 研究員 (60291134)
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| Co-Investigator(Kenkyū-buntansha) |
SAKAGUCHI Shimon KYOTO UNIV.INSTITUTE FOR FRONTIER MEDICAL SCIENCES, DEPARTMENT OF EXPERIMENTAL PATHOLOGY, 再生医科学研究所, 教授 (30280770)
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| Project Period (FY) |
1999 – 2000
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| Keywords | CD25^+ T CELLS / TUMOR IMMUNOLOGY / ANERGY |
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| Research Abstract |
We show that removal of a T cell subpopulation can evoke effective tumor immunity in otherwise non-responding animals. Elimination of CD25-expressing T cells, which constitute 5-10% of peripheral CD4^+ T cells in normal naive mice, elicited potent immune responses to syngeneic tumors in vivo and eradicated them. The responses were mediated by tumor-specific CD8^+ CTLs and tumor-nonspecific CD4^-8^- cytotoxic cells akin to NK cells. Furthermore, in vitro culture of CD25^+4^+ T cell-depleted splenic cell suspensions prepared from tumor-unsensitized normal mice led to spontaneous generation of similar CD4^-8^- cytotoxic cells capable of killing a broad spectrum of tumors ; reconstitution of CD25^+4^+ T cells inhibited the generation. In this culture, self-reactive CD25^-4^+ T cells responding to self peptides/class II MHC complexes on APCs spontaneously proliferated upon removal of CD^+4^+ T cells, secreting large amounts of IL-2. The IL-2 thus produced appeared to be responsible for the generation of CD4^-8^- NK cells as lymphokine-activated killer cells, because direct addition of an equivalent amount of IL-2 to the culture of CD4^-8^- cells generated similar lymphokine-activated killer/NK cells, whereas coculture of normal CD4^-8^- cells with CD25^-4^+ T cells from IL-2-deficient mice did not. Thus, removal of immunoregulatory CD25^+4^+ T cells can abrogate immunological unresponsiveness to syngenic tumors in vivo and in vitro, leading to spontaneous development of tumor-specific effector cells as well as tumor-nonspecific ones. This novel way of evoking tumor immunity would help to devise effective immunotherapy for cancer in humans.
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[Publications] Sakaguchi, S., Takahashi, T., Yamazaki, S., Kuniyasu, Y., Itoh, M., Sakaguchi, N., and Shimizu, J.: "Immunologic self-tolerance maintained by T cell-mediated control of self-reactive T cells : implications for autoimmunity and tumor immunity."Res. in Immunol.. (in press). (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T.W., and Sakaguchi, S.: "Immunologic self-tolerance maintained by CD25^+CD4^+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4."J.Exp. Med.. 92. 303-309 (2000)
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[Publications] Kuniyasu, Y., Takahashi, T., Itoh, M., Shimizu, J., Toda, G., and Sakaguchi, S.: "Naturally anergic andsuppressive CD25^+CD4^+ T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation."Int. Immunol.. 12. 1145-1155 (2000)
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[Publications] Onizuka, S., Tawara, I., Shimizu, J., Sakaguchi, S., Fujita, T., and Nakayama, E.: "Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody."Cancer Res.. 59. 3128-3133 (1999)
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[Publications] Itoh, M., Takahashi, T., Sakaguchi, N., Kuniyasu, Y., Shimizu, J., Otsuka, F., and Sakaguchi, S.: "Thymus and autoimmunity : production of CD25^+CD4^+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance."J.Immunol.. 162. 5317-5326 (1999)
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