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Biological response modifiers (BRM) as antigens

III. T cell lines specific for BRM kill tumor cells in a BRM-specific manner

  • Original Article
  • Biological Response Modifier, T Cell Lines
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

In order to investigate tumoricidal effector cells in therapy by biological response modifiers (BRM) such asPropionibacterium acnes, bacillus Calmette-Guérin (BCG),Streptococcus pyogenes and a protein-bound polysaccharide (PSK), we established T cell lines specific for each BRM from BALB/c mice immunized with the corresponding BRM. These T cell lines proliferated and produced interleukin-2-(IL-2) and/or IL-4, but only in the presence of the relevant BRM and BALB/c spleen cells as the antigen and antigen-presenting cells respectively. Cross-functional experiments indicated that each BRM acts as a nominal antigen, but not as a non-specific immunostimulator. In addition, the T cell lines killed Ia-positive syngeneic B lymphoma cells, but only in the presence of the relevant BRM. These experiments excluded the possibility of cytotoxic effects by each BRM. The T cell lines and clones also killed Ia-negative bystander target cells, but only in the presence of both a relevant antigen and antigen-presenting cells. The T cell clones specific forS. pyogenes orP. acnes tested were Thy1+, L3T4+ and Lyt2. These results indicate that some BRM exert tumoricidal activity by inducing T cells that recognize them as an antigen and kill tumor cells in an antigen-specific manner. The T cells killed tumor targets in either a tumor-necrosis-factor(TNF)-dependent or a TNF-independent manner. The mediator of the latter pathway remains to be elucidated.

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References

  1. Oldham RK (1983) Biological response modifiers. J Natl Cancer Inst 70:789

    PubMed  Google Scholar 

  2. Mizutani Y, Nio Y, Fukumoto M, Yoshida O (1994) Enhanced antitumor effect of bacillus Calmette-Guerin in combination with fibrinogen on urinary bladder tumor. J Urol 151:1420

    PubMed  Google Scholar 

  3. Shu SY, Chou T, Sakai K (1989) Lymphocytes generated by in vivo priming and in vitro sensitization demonstrate therapeutic efficacy against a murine tumor that lacks apparent immunogenicity. J Immunol 143:740

    PubMed  Google Scholar 

  4. Uchida A, Micksche M (1983) Lysis of fresh tumor cells by autologous peripheral blood and pleural effusion lymphocytes activated by OK-432. J Natl Cancer Inst 71:673

    PubMed  Google Scholar 

  5. Saito M, Ichimura O, Kataoka M, Moriya Y, Ueno K, Sugawara Y, Nanjou M, Ishida N (1986) Pronounced antitumor effect of LAK-like cells induced in the peritoneal cavity of mice after intraperitoneal injection of OK-432, a killed streptococcal preparation. Cancer Immunol Immunother 22:161

    PubMed  Google Scholar 

  6. Tugakoshi S, Hashimoto Y, Fujii G, Kobayashi H, Nomoto K, Orita K (1984) Krestin (PSK) Cancer Treat Rev 11:131

    Google Scholar 

  7. Vanky F, Wang P, Klein E (1992) Th polysaccharide K (PSK) potentiates in vitro activation of the cytotoxic function in human blood lymphocytes by autologous tumour cells. Cancer Immunol Immunother 35:193

    PubMed  Google Scholar 

  8. Hirai R, Oguchi Y, Sugita N, Matsunaga K, Nomoto K (1993) Enhancement of T-cell proliferation by PSK. Int J Immunopharmacol 15:745

    PubMed  Google Scholar 

  9. Tite JP, Janeway CA Jr (1984) Cloned helper T cells can kill B lymphoma cells in the presence of specific antigen: Ia restriction and cognate vs. noncognate interactions in cytolysis. Eur J Immunol 14:25

    Google Scholar 

  10. Ju ST, Ruddle NH, Strack P, Dorf ME, DeKruyff RH (1990) Expression of two distinct cytolytic mechanisms among murine CD4 subsets. J Immunol 144:23

    PubMed  Google Scholar 

  11. Liu AY, Mikovsky EP, Stanjope PE, Siliciano RF (1992) Production of transmembrane and secreted forms of tumor necrosis factor (TNF)-α by HIV-1-specific CD4+ cytolytic T lymphocyte clones: evidence for a TNF-α-independent cytolytic mechanism. J Immunol 148:3789

    PubMed  Google Scholar 

  12. Tite JP (1990) Evidence of a role for TNF-α in cytolysis by CD4+, class II MHC-restricted cytotoxic T cells. Immunology 71:208

    PubMed  Google Scholar 

  13. Ozaki S, Suginoshita T (1989) Biological response modifier as antigen: OK-432-specific T-cell clone as an anti-tumor effector cell. Cell Immunol 120:477

    PubMed  Google Scholar 

  14. Ozaki S, Suginoshita T, Watanabe T, Obayashi H (1990) Mechanism of tumoricidal activity of OK-432-specific L3T4+ Lyt2 T-cells Cancer Res 50:4630

    PubMed  Google Scholar 

  15. Nakane A, Minagawa T, Kata K (1988) Endogenous tumor necrosis factor (Cachectin) is essential to host resistance againstListeria monocytogenes infection. Infect Immun 56:2563

    PubMed  Google Scholar 

  16. Nakane A, Minagawa T, Kohanawa M, Chen Y, Sato H, Moriyama M, Tsuruoka N (1989) Interactions between endogenous gamma interferon and tumor necrosis factor in host resistance against primary and secondaryListeria monocytogenes infections. Infect Immun 57:3331

    PubMed  Google Scholar 

  17. Kim KJ, Kanellopoulos-Langevin C, Merwin RM, Sachs DH (1979) Establishment and characterization of BALB/c lymphoma lines with B cell properties. J Immunol 122:549

    PubMed  Google Scholar 

  18. Hyman R, Stallings V (1974) Complementation patterns of Thy-1 variants and evidence that antigen loss variants “pre-exist’ in the parental population. J Natl Cancer Inst 52:429

    PubMed  Google Scholar 

  19. Ozaki S, York-Jolley J, Kawamura H, Berzofsky JA (1987) Cloned protein antigen-specific, Ia-restricted T cells with both helper and cytolytic activities: mechanisms of activation and killing. Cell Immunol 105:301

    PubMed  Google Scholar 

  20. Berkower I, Matis LA, Buckenmeyer GK, Gurd FRN, Longo DL, Berzofsky JA (1984) Identification of distinct predominant epitopes recognized by myoglobin-specific T cells under the control of different Ir genes and characterization of representative T cell clones. J Immunol 132:1370

    PubMed  Google Scholar 

  21. Watson J (1979) Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med 150:1510

    PubMed  Google Scholar 

  22. Okazaki T, Ozaki S, Nakao K (1994) CD4+ cells require adhesion via LFA-1/ICAM-1 to induce target apoptosis in TNF-independent pathway. Cell Immunol 156:135

    PubMed  Google Scholar 

  23. Schmid DS, Tite JP, Ruddle NH (1986) DNA fragmentation: manifestation of target cell destruction mediated by cytotoxic T-cell lines, lymphotoxin-secreting helper T-cell clones, and cell-free lymphotoxin-containing supernatant. Proc Natl Acad Sci USA 83:1881

    PubMed  Google Scholar 

  24. Ju ST (1991) Distinct pathways of CD4 and CD8 cells induce rapid target DNA fragmentation. J Immunol 146:812

    PubMed  Google Scholar 

  25. Takayama H, Shinohara N, Kawasaki A, Someya Y, Hanaoka S, Kojima H, Yagita H, Okumura K, Shinkai Y (1991) Antigen-specific directional target cell lysis by perforin-negative T lymphocyte clones. Int Immunol 3:1149

    PubMed  Google Scholar 

  26. Grogg D, Hahn S, Erb P (1992) CD4+ T cell-mediated killing of major histocompatibility complex class II-positive antigen-presenting cells (APC) III. CD4+ cytotoxic T cells induces apoptosis of APC. Eur J Immunol 22:267

    PubMed  Google Scholar 

  27. Yasukawa M, Yakushijin Y, Hasagawa H, Miyake M, Hitumoto Y, Kimura S, Takeuchi N, Fujita S (1993) Expression of perforin and membrane-bound lymphotoxin (tumor necrosis factor-β) in virus-specific CD4+ human cytotoxic T-cell clones. Blood 81:1527

    PubMed  Google Scholar 

  28. Duke RC, Persechini PM, Chang S, Liu CC, Cohen JJ, Young JD-E (1989) Purified perforin induces target cell lysis but not DNA fragmentation. J Exp Med 170:1451

    PubMed  Google Scholar 

  29. Yonehara S, Ishii A, Yonehara M (1989) A cell-killing monoclonal antibody (Anti-Fas) to a cell surface antigen codown-regulated with the receptor of tumor necrosis factor. J Exp Med 169:1747

    PubMed  Google Scholar 

  30. Itoh N, Yonehara S, Ishii A, Yonehara M, Samashima M, Hase A, Seto Y, Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233

    PubMed  Google Scholar 

  31. Rouvier E, Luciani M-F, Golstein P (1993) Fas involvement in Ca2+-independent T cell-mediated cytotoxicity. J Exp Med 177:195

    PubMed  Google Scholar 

  32. Suda T, Takahashi T, Golstein P, Nagata S (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75:1169

    PubMed  Google Scholar 

  33. Stalder T, Hahn S, Erb P (1994) Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J Immunol 152:1127

    PubMed  Google Scholar 

  34. Ju S-T, Cui H, Panka DJ, Ettinger R, Marshak-Rothstein A (1994) Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells. Proc Natl Acad Sci USA 91:4185

    PubMed  Google Scholar 

  35. Hanabuchi S, Koyanagi M, Kawasaki A, Shinohara N, Matsuzawa A, Nishimura Y, Kobayashi Y, Yonehara S, Yagita Y, Okumura K (1994) Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity. Proc Natl Acad Sci USA 91:4930

    PubMed  Google Scholar 

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Ozaki, S., Okazaki, T. & Nakao, K. Biological response modifiers (BRM) as antigens. Cancer Immunol Immunother 40, 219–227 (1995). https://doi.org/10.1007/BF01519895

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  • DOI: https://doi.org/10.1007/BF01519895

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