Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

The augmentation of tumor-specific immunity using haptenic muramyl dipeptide (MDP) derivatives

I. Synthesis of a novel haptenic MDP derivative cross-reactive with Bacillus Calmette Guerin and its application to enhanced induction of tumor immunity

  • 13 Accesses

  • 3 Citations


A new haptenic compound, a muramyl dipeptide (MDP) derivative (designated as L4-MDP-ONB) cross-reactive with Bacillus Calmette Guerin (BCG) was synthesized. The cross-reactivity of L4-MDP hapten to BCG was demonstrated from the following evidence; (a) lymph node cells from BCG-primed C3H/HeN mice exhibited appreciable L4-MDP-specific proliferative responses to the in vitro stimulation of L4-MDP-modified syngeneic cells (L4-MDP-self); (b) inoculation of L4-MDP-self into footpads of BCG-primed C3H/HeN mice elicited ample delayed type-hypersensitivity (DTH) responses in vivo as measured by footpad swelling; and (c) BCG-primed mice contained L4-MDP-reactive helper T cell activity which functions to augment the generation of effector T cell responses to cell surface antigens. This crossreactivity between L4-MDP hapten and BCG as measured by the helper T cell activity was applied to enhanced induction of tumor-specific immunity. When BCG-primed C3H/HeN mice were immunized with L4-MDP-modified syngeneic X5563 tumor cells, these mice could generate augmented tumor-specific in vivo protective (tumor neutralizing) immunity as well as in vitro cytotoxic T cell responses. These results indicate the effectiveness of L4-MDP hapten in augmenting tumor-specific immunity. The present approach is discussed in the context of potential advantages of this new hapten for its future application to clinical tumor systems.

This is a preview of subscription content, log in to check access.


  1. 1.

    Corradin G, Etlinger HM, Chiller JM (1977) Lymphocyte specificity to protein antigens. I. Characterization of the antigen-induced in vitro T cell-dependent proliferative response with lymph node cells from primed mice. J Immunol 119:1048

  2. 2.

    Finberg R, Greene MI, Benacerraf B, Burakoff SJ (1979) The cytolytic T lymphocyte response to trinitrophenyl-modified syngeneic cells. I. Evidence for antigen-specific helper T cells. J Immunol 123:1205

  3. 3.

    Forman J (1975) On the role of the H-2 histocompatibility complex in determining the specificity of cytotoxic effector cells sensitized against syngeneic trinitrophenyl-modified targets. J Exp Med 142:403

  4. 4.

    Fujiwara H, Shearer GM (1981) Genetic control of cell-mediated lympholysis to trinitrophenyl (TNP)-modified murine syngeneic cells. I. Expression of Ir gene function at the cytotoxic precursor and helper cell levels in the response to TNP-H-2b-self. J Immunol 126:1047

  5. 5.

    Fujiwara H, Hamaoka T, Shearer GM, Yamamoto H, Terry WD (1980) The augmentation of in vitro and in vivo tumor-specific T cell-mediated immunity by amplifier T lymphocytes. J Immunol 124:863

  6. 6.

    Fujiwara H, Levy RB, Shearer GM (1981) Analysis of Ir gene control of cytotoxic response to hapten-modified self: Helper T cells specific for a sulfhydryl hapten can substitute for an anti-TNP-H-2b self helper defect. J Immunol 127:940

  7. 7.

    Fujiwara H, Aoki H, Yoshioka T, Tomita S, Ikegami R, Hamaoka T (1984) Establishment of tumor-specific immunotherapy model utilizing TNP-reactive helper T cell activity and its application to autochthonous tumor system. J Immunol 133:509

  8. 8.

    Fujiwara H, Moriyama Y, Suda T, Tsuchida T, Shearer GM, Hamaoka T (1984) Enhanced TNP-reactive helper T cell activity and its utilization in the induction of amplified tumor immunity which results in tumor regression. J Immunol 132:1571

  9. 9.

    Fujiwara H, Shimizu Y, Takai Y, Wakamiya N, Ueda S, Kato S, Hamaoka T (1984) The augmentation of tumor-specific immunity by virus-help. I. Demonstration of vaccinia virus-reactive helper T cell activity involved in enhanced induction of cytotoxic T lymphocyte and antibody responses. Eur J Immunol 14:171

  10. 10.

    Galili N, Naor D, Asjo B, Klein G (1976) Induction of immune responsiveness in a genetically low-responsive tumor-host combination by chemical modification of the immunogen. Eur J Immunol 6:473

  11. 11.

    Gilheany PE, Arora PK, Levy RB, Shearer GM (1981) H-2 linked genetic control of murine cell-mediated lympholysis to autologous cells modified with high and low concentration of fluorescein isothiocyanate (FITC). Cell Immunol 59:97

  12. 12.

    Hamaoka T, Fujiwara H, Teshima K, Aoki H, Yamamoto H, Kitagawa M (1979) Regulatory functions of hapten-reactive helper and suppressor T lymphocytes. III. Amplification of a generation of tumor-specific T-lymphocyte activities by suppressor T-cell-depleted hapten-reactive T lymphocytes. J Exp Med 149:185

  13. 13.

    Hashimoto Y, Yamanoha B (1976) Induction of transplantation immunity by dansylated tumor cells. Gann 67:315

  14. 14.

    Igarashi T, Okada M, Azuma I, Yamamura Y (1977) Adjuvant activity of synthetic N-acetylmuramyl-L-alanyl-D-isoglutamine and related compounds on cell-mediated cytotoxicity in syngeneic mice. Cell Immunol 34:270

  15. 15.

    Iribe H, Koga T (1984) Augmentation of the proliferative response of thymocytes to phytohemagglutinin by the muramyl dipeptide. Cell Immunol 88:9

  16. 16.

    Kobayashi H, Kodama H, Gotohda E (1977) Xenogenization of tumor cells. Hokkaido University Medical Library Series vol 9 Hokkaido Japan

  17. 17.

    Lindenmann J, Klein P (1967) Viral oncolysis: increased immunogenicity of host cell antigen associated with influenza virus. J Exp Med 126:93

  18. 18.

    Lowy I, Bona C, Chedid L (1977) Target cells for the activity of a synthetic adjuvant; Muramyl dipeptide. Cell Immunol 29:195

  19. 19.

    Martin WJ, Wunderlich JR, Fletcher F, Inman JK (1971) Enhanced immunogenicity of chemically-coated syngeneic tumor cells. Proc Natl Acad Sci USA 68:469

  20. 20.

    Mitchison NA (1970) Immunologic approach to cancer. Transplant Proc 2:92

  21. 21.

    Oberling F, Bernard C, Morin A, Chedid L, Lang JM, Choay J (1982) Effect of MDP (Glu) OnBu on the antibody response against tetanus toxoid in cancer patients. Int J Immunopharmacol 4:309

  22. 22.

    Pohlit H, Haas W, von Boehmer H (1979) Cytotoxic T-cell response to haptenated cells. I. Primary, secondary and long term cultures. Eur J Immunol 9:681

  23. 23.

    Rehn TG, Shearer GM, Koren HS and Inman JD (1976) Cell mediated lympholysis of N-(3-nitro-4-hydroxy-5-iodophenyl-acetyl)-6-alanyl-glycylglycyl-modified autologous lymphocytes: effector cell specificity to modified cell surface components controlled by the H-2K and H-2D serological regions of the murine major histocompatibility complex. J Exp Med 143:127

  24. 24.

    Shearer GM, Rehn TG, Garbarino CA (1975) Cell mediated lympholysis of trinitrophenyl-modified autologous lymphocytes. Effector cell specificity to modified cell surface components controlled by the H-2K and H-2D serological region of the murine major histocompatibility complex. J Exp Med 141:1348

  25. 25.

    Shearer GM, Schmitt-Verhulst A-M, Pettinelli CB, Miller MW, Gilheany PE (1979) H-2 linked genetic control of murine T cell-mediated lympholysis to autologous cells modified with low concentrations of trinitrobenzene sulfonate. J Exp Med 149:1407

  26. 26.

    Shimizu Y, Fujiwara H, Ueda S, Wakamiya N, Kato S, Hamaoka T (1984) The augmentation of tumor-specific immunity by virus-help. II. Enhanced induction of cytotoxic T lymphocyte and antibody responses to tumor antigens by vacciniareactive helper T cells. Eur J Immunol 14:839

  27. 27.

    Takai Y, Mizuochi T, Fujiwara H, Hamaoka T (1984) Effects of hapten epitope structure and hapten-self conjugation pattern on T cell specificity and Ir gene control in hapten-self cytotoxic and helper T cell responses. J Immunol 132:57

  28. 28.

    Takatsu K, Hamaoka T, Tominaga A, Kanamasa Y (1980) Augmented induction of tumor-specific resistance by priming with PPD-coupled syngeneic tumor cells. J Immunol 125:2367

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hamaoka, T., Takai, Y., Kosugi, A. et al. The augmentation of tumor-specific immunity using haptenic muramyl dipeptide (MDP) derivatives. Cancer Immunol Immunother 20, 183–188 (1985). https://doi.org/10.1007/BF00205573

Download citation


  • Lymph Node
  • Cell Activity
  • Cell Response
  • Surface Antigen
  • Dipeptide