Interleukin antitumor therapy

Further evidence for the importance of imine formation for T cell function was derived from the discovery that tucaresol and other small molecules with an aromatic aldehyde moiety capable of forming Schiff bases, produces a signal to CD4+ T helper (Th) cells [62]. Tucaresol reacts in vitro with free CD4+ T cell surface amines from receptors like CD2 within seconds to cause a co-stimulatory signal to produce a Thl response with the release of interferon y (IFN-y) and a 5- to 10-fold increase of interleukin 2 (IL-2). Such a Thl response is believed to be important for intracellular pathogens such as viruses, mycobacteria, protozoa and tumors. Studies in vivo show that low concentrations of tucaresol enhance not only CD4+ Th cells in response to antigens but also CD 8+ CTL and that this response has a beneficial effect in antiviral and antitumor therapy in animal models. Mechanistically, formation of Schiff bases with tucaresol has been shown to greatly affect intracellular potassium and sodium ion concentrations by the co-stimulation of mitogen-activated protein kinase (MAP kinase) and thus activation of ion channels in T cells [62,102]. Some of these mechanistic features are depicted in Fig. 19. 

Ewend MG, Thompson RC, Anderson R, Sills AK, Staveley-O Carroll K, Tyler BM, Hanes J, Brat D, Thomas M, Jaffee EM, Pardoll DM, Brem H. Intracranial paracrine interleukin-2 therapy stimulates prolonged antitumor immunity that extends outside the central nervous system. J Immunother 2000 23 438-448. 

Mendrratta, S.K., A. Quezada, M. Matar, N.M. ThuU, J.S. Bishop, J.L. Nordstrom, and F. Pericle, Combination of interleukin 12 and interferon alpha gene therapy induces a synergistic antitumor response against colon and renal cell carcinoma. Hum Gene Ther, 2000.11(13) 1851-62. 

Tahara, H. and Lotze, M.T. (1995) Antitumor effects of interleukin-12 (IL-12) applications for the immunotherapy and gene therapy of cancer. Gene Then, 2, 96-106. 

Zitvogel L, Robbins PD, Storkus WJ, et al. Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors. Eur J Immuno 1996 26 1335-41. 

SiKuki K, Nakazato H, Matsui H, Hasumi M, Shibata Y, Ito K, et al (2001) NK cell-mediated antitumor immune response to human prostate cancer cell, PC-3 immunogene therapy using a highly secretable form of interleukin-15 gene transfer. J Leukoc Biol 69 531-537... 

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