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Abstract
Despite the sustained efforts of immunologists, drugs with which to potentiate the immune system in chronic infectious disease and cancer have remained elusive. CD4+ T helper lymphocytes, activated by antigens bound to MHC class II molecules on specialised antigen presenting cells (APCs), are an important target in any immunopotentiatory strategy because they orchestrate immune responses. In addition to presenting antigen, APCs also express surface macromolecules that provide essential co-stimulatory signals through interactions with co-receptors on T-cell. As a consequence of some of these macromolecular interactions, transient covalent chemical events occur between specialised carbonyl and amino groups to form reversible Schiff bases and this process is essential for optimal immune induction. This chemical event can be mimicked by small Schiff base-forming molecules that substitute for the natural donor of carbonyl groups and directly co-stimulate T-cells, providing a class of low-molecular weight agents that potently enhance the induction of immune responses in vivo. One such molecule, tucaresol (Glaxo Wellcome), has been developed for testing as an orally bioavailable, systemically active immunopotentiatory drug. The formation of a Schiff base by tucaresol on specialised T-cell surface amines provides a co-stimulatory signal to the T-cell through a mechanism that activates Na+ and K+ transport. The signalling pathway initiated by tucaresol converges with T-cell receptor signalling at the level of tyrosyl phosphorylation of the MAP kinase ERK2. Tucaresol co-stimulation preferentially favours a Th1-type profile of cytokine production, enhancing the release of interleukin (IL)-2 and interferon-γ (IFNγ), but not IL-4 or IL-6. This may be therapeutically favourable in promoting immune responses to intracellular pathogens, such as viruses, mycobacteria and protozoal parasites, as well as responses to immunogenic tumours. The Schiff base-forming class of immunopotentiatory drug provides the first orally-active, mechanism-based immunopotentiatory agent for therapeutic testing. Tucaresol is currently undergoing pilot Phase I/ll clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.