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Potentiation of the Immune System by Schiff Base-Forming Drugs

Mechanism of Action and Therapeutic Potential

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  • Immunology-Based Agents
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Summary

CD4+ T lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by peptides bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. The latter cells provide costimulatory or accessory signals through macro-molecules such as B7.1 and B7.2, which interact with coreceptors on T cells to regulate outcomes in terms of T cell activation or specific nonresponsiveness. Complementary studies of the interactions between antigen-presenting cells and T helper cells at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on the surfaces of antigen-presenting cells and T cells, as an essential element in specific T cell activation. Small Schiff base-forming molecules can substitute for the natural donor of carbonyl groups and provide a costimulatory signal to the T cell.

From this class of Schiff base-forming costimulatory molecules, the small xenobiotic substituted benzaldehyde, tucaresol, has been selected for development and testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4+ T helper cell and CD8+ cytotoxic T cell responses in vivo, and selectively favours a T helper 1 profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T cell surface amines provides a costimulatory signal to the T cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The pathway utilised by tucaresol converges with T cell receptor signalling at the level of mitogen-activated protein (MAP) kinase, promoting the activation of MAP kinase kinase (MEK) and consequential tyrosyl phosphorylation of ERK2.

Tucaresol is the first orally active, mechanism-based immunopotentiatory drug available for therapeutic testing. It is currently undergoing phase I/II clinical trials in chronic hepatitis B virus infection, HIV infection and malignant melanoma.

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  1. Biao Zheng

    Present address: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

Authors and Affiliations

  1. Immunology Unit, Research Division, Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, England

    Huaqing Chen, Simon Hall, Biao Zheng &  John Rhodes

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Chen, H., Hall, S., Zheng, B. et al. Potentiation of the Immune System by Schiff Base-Forming Drugs. BioDrugs 7, 217–231 (1997). https://doi.org/10.2165/00063030-199707030-00005

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