CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound
peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules 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 non-responsiveness. Complementary studies at the chemical level have implicated
Schiff base formation between specialised carbonyls and
amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential
element in specific T-cell activation. The small
xenobiotic Schiff base forming molecule
tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory
drug.
Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type 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 signalling pathway utilised by
tucaresol converges with
T-cell receptor signalling at the level of MAP
kinase, promoting the tyrosyl phosphorylation of ERK2 by
MEK (
mitogen-activated protein kinase kinase). The
Schiff base forming class of immunopotentiatory
drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing.
Tucaresol is currently undergoing pilot phase I/II clinical trials as an
immunopotentiator in
chronic hepatitis B virus infection,
HIV infection and
malignant melanoma.