Cytokine Synergy in Immunotherapy

  • John W. Hadden
  • Piotr Malec
  • Anutosh Saha
  • Elba M. Hadden


The normal function of the immune system involves a myriad of synergistic interactions among cytokines of many types (e.g. lymphokines, monokines and thymic hormones). It seems then eminently logical that efforts to modify immune function with exogenous cytokines should involve the employment of combinations. It will be the intent of this chapter to summarize our recent efforts to employ combination therapy to restore and direct the thymus-dependent T cell system.


Thymic Epithelial Cell Thymic Involution Thymic Hormone Immature Thymocyte Recurrent Squamous Cell Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    K. Komuro and E.A. Boyse, Induction of T lymphocytes from precursor cells in vitro by a product of the thymus, J. Exp. Med. 138: 479–484 (1973).PubMedCrossRefGoogle Scholar
  2. 2.
    A.L. Goldstein, Ed., “Thymic hormones and lymphokines”, Plenum Press, New York (1984).Google Scholar
  3. 3.
    S.S. Chen, J.S. Tung, S. Gillis, R.A. Good and J.W. Hadden, Changes in surface antigens of immature thymocytes under the influence of T cell growth factor and thymic factors, Proc. Natl. Acad. Sci. 80: 5980–5984 (1983).PubMedCrossRefGoogle Scholar
  4. 4.
    P. Andrews, K. Shortman, R. Scollay, E.F. Potworowski, A.M. Kruisbeek, G. Goldstein, N. Trainin and J-F. Bach, Thymus hormones do not induce proliferative ability or cytolytic function on PNA+ cortical thymocytes. Cell. Immunol. 91: 455–466 (1985).Google Scholar
  5. 5.
    P.J. Conlon, C.S. Henney and S. Gillis, Cytokine-dependent thymocyte responses, J. Immunol. 128: 797–804 (1982).PubMedGoogle Scholar
  6. 6.
    J.W. Hadden, S. Specter and E.M. Hadden, Effects of T cell growth factor (interleukin 2) and thymic hormones on prothymocytes and immature thymocytes, Lymph. Res. 5: 49–54 (1986).Google Scholar
  7. 7.
    W. Falk, B. Kyewski, D. Mannel and P.H. Kramer, Growth of double negative mouse thymocytes is initiated by the combined action of interleukin I and interleukin 2, Lymph. Res. 6: 75 (1987).Google Scholar
  8. 8.
    J.W. Hadden, H. Chen, Y. Wang and E.M. Hadden, Strategies of immune reconstitution: effects of lymphokines on murine T cell development in vitro and in vivo, Life Sci. AIDS Comm. 44: 5–12 (1989).Google Scholar
  9. 9.
    J.W. Hadden, Thymic endocrinology, Int. J. Immunopharmacol. 14: 345–352 (1992).PubMedCrossRefGoogle Scholar
  10. 10.
    P.T. Le, L. W. Vollger, B.F. Haynes and K.H. Singer, Ligand binding to the LFA-3 cell adhesion molecule induces IL-1 production by human thymic epithelial cells, J. Immun. 144: 4541–4547 (1990).PubMedGoogle Scholar
  11. 11.
    M. Wiranowska, T. Kaido, G. Caspritz, J. Cook and J.W. Hadden, Interleukin-2 and coculture with thymic epithelial cells synergistically induce prothymocyte differentiation and proliferation, Thymus 10: 231–235 (1987).PubMedGoogle Scholar
  12. 12.
    S.M. Denning, J. Kurtzburg, P.T. Le, D.T. Tuck, K.H. Singer and B.F. Haynes, Human thymic epithelial cells directly induce activation of autologous immature thymocytes, Proc. Natl. Acad. Sci. 85: 3125–3129 (1988).PubMedCrossRefGoogle Scholar
  13. 13.
    A. Galy, E.M. Hadden, J-P. Touraine and J.W. Hadden, Effects of cytokines on human thymic epithelial cells in culture: IL1 induces thymic epithelial cell proliferation and change in morphology, Cell Immunol. 124: 13–27 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    A. Galy, C.A. Dinarello, T.S. Kupper and J.W. Hadden, Production of cytokines by recombinant ILl-stimulated human thymic epithelial cells in vitro, Cell Immunol. 129: 161–175, (1990).PubMedCrossRefGoogle Scholar
  15. 15.
    J.A. Coto, E.M. Hadden, M. Sauro, N. Zorn and J.W. Hadden, Interleukin 1 regulates secretion of zinc-thymulin by thymic epithelial cells and its action on T lymphocyte proliferation and nuclear protein kinase C, Proc. Natl. Acad. Sci. (1992, in press).Google Scholar
  16. 16.
    M.B. Sztein, S.R. Serrate and A.L. Goldstein, Modulation of interleukin 2 receptor expression on human lymphocytes by thymic hormones, Proc. Natl. Acad. Sci. 83: 6107–6111 (1986).PubMedCrossRefGoogle Scholar
  17. 17.
    E.M. Hadden, P. Malec, M. Sosa and J.W. Hadden, Mixed interleukins and thymosin fraction V synergistically induce T lymphocyte development in hydrocortisone-treated aged mice, Cell. Immunol. (1992, in press).Google Scholar
  18. 18.
    E. Mocchegiani and N. Fabris, “In vivo” and “in vitro” effect of zinc on thymic efficiency in old age, in: “Abstracts of 6th Int. Cong. of Int. Assoc. Biol. Gerontol.”, Ancona, Italy, (1991).Google Scholar
  19. 19.
    J.W. Hadden, E.M. Hadden, P. Baekey, P. Skipper and J.N. Endicott, Adjuvant nonrecombinant interleukins and contra-suppressive agents induces immune regression in head and neck cancer, Arch. Otolaryngol. (1992, in press).Google Scholar
  20. 20.
    N.T. Berlinger, E.Y. Hilal, H.F. Oettgen and R.A. Good, Deficient cell-mediated immunity in head and neck cancer patients secondary to autologous suppressive immune cells, Laryngoscope 88: 470–481 (1978).PubMedCrossRefGoogle Scholar
  21. 21.
    G.T. Wolf, Head and neck tumor immunology, in: “Immunobiology, Histophysiology and Tumor Immunology in Otolaryngology”, Proc. 2nd Int. Acad. Conf., Utrecht, The Netherlands, (1987).Google Scholar
  22. 22.
    H.J. Wanebo, T. Jones, R. Pace, R. Cantrell and P. Levine, Immune restoration with interleukin-2 in patient with squamous cell carcinoma of the head and neck, Amer. J. Surg. 158: 356–360 (1989).CrossRefGoogle Scholar
  23. 23.
    D. Berd, H.C. Maguire and M.J. Mastrangelo, Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide, Cancer Res. 44: 5439–5443 (1984).PubMedGoogle Scholar
  24. 24.
    D. Berd, H.C. Maguire Jr., P. McCue and M.J. Mastrangelo, Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients, J. Clin. Oncol. 8: 1858–1867 (1990).PubMedGoogle Scholar
  25. 25.
    M.S. Mitchell, R.A. Kempf, W. Harel, H. Shau, W.D. Boswell, S. Lind, G. Dean, J. Moore and E.C. Bradley, Efficacy of low-dose cyclophosphamide and interleukin-2 in melanoma, in: “Advances in Immunopharmacology 4”, J.W. Hadden, F. Spreafico, Y. Yamamura, K.F. Austen, P. Dukor and K. Masek, eds, Pergamon Press, Oxford (1989).Google Scholar
  26. 26.
    J.H.L. Playfair and A.W. Heath, Cytokines–The new generation of adjuvants for vaccines?, in: “Immunotherapeutic prospects of infectious diseases”, K.N. Masihi and W. Lange, eds., Springer-Verlag, Berlin, (1990).Google Scholar
  27. 27.
    K. Kelly, Harvey, Sadler and D. D.monde, Accelerated cytodifferentiation of antibody-secreting cells in Guinea pig lymph nodes stimulated by sheep erythrocytes and lymphokines, Clin. Exp. Immunol. 21: 141–154 (1975).Google Scholar
  28. 28.
    M.S. Pulley, V. Nagendran, J.M. Edwards, D.C. Dumonde, Intravenous, intralesional and endolymphatic administration of lymphokines in human cancer, Lymph. Res. 5: S157–S163, (1986).Google Scholar
  29. 29.
    G. Cortesina, A. DeStefani, M. Giovarelli, M.G. Barioglio, G.P. Cavallo, C. Jemma and G. Forni, Treatment of recurrent squamous cell carcinoma of the head and neck with low doses of interleukin-2 injected perilymphatically, Cancer 62: 2482–2485, (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    G. Cortesina, A. DeStefani, E. Galeazzi, M. Bussi, C. Giordano, G.P. Cavallo, C. Jemma, S. Vai, G. Forni and G. Valente, The effect of preoperative local interleukin-2 (IL-2) injections in patients with head and neck squamous cell carcinoma, Acta. Otolaryngol. 111: 428–433 (1991).Google Scholar
  31. 31.
    V. Mattijssen, P.H. DeMulder, J.H. Schornagel, J. Verweij, P. Van den Broak, A. Galazka, S. Roy and D.J. Ruiter, Clinical and immunopathological results of a phase II study of perilymphatically injected recombinant interleukin 2 in locally far advanced, nonpretreated head and neck squamous cell carcinoma, J. Immunother. 10: 63–68 (1991).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • John W. Hadden
    • 1
  • Piotr Malec
    • 1
  • Anutosh Saha
    • 1
  • Elba M. Hadden
    • 1
  1. 1.Department of Internal MedicineUniversity of South Florida Medical CollegeTampaUSA

Personalised recommendations