THERAPEUTIC POTENTIATION OF THE IMMUNE-SYSTEM BY COSTIMULATORY SCHIFF-BASE-FORMING DRUGS

IMMUNE responses are orchestrated by CD4 T lymphocytes, which receive a cognitive signal when clonally distributed receptors are occupied by major histocompatibility complex (MHC) class II-bound peptides on ant igen-presenting cells (APCs)(1,2). The APCs provide costimulatory sign als, through macromolecules such as CD80, that regulate outcomes in te rms of T-cell activation or anergy(3-6). We have studied essential com plementary chemical events in the form of Schiff base formation betwee n carbonyls and amines that are constitutively expressed on presenting cell and T-cell surfaces(7-9) and provide a new target for manipulati on of immune responses(10,11). Here we show that small Schiff base-for ming molecules can substitute for the physiological donor of carbonyl groups and provide a costimulatory signal to CD4 Th-cells through a me chanism that activates clofilium-sensitive K+ and Na+ transport. One s uch molecule, tucaresol, enhances CD4 Th-cell responses, selectively f avouring a Th1-type profile of cytokine production, in vivo tucaresol potently enhances CD4 Th-cell priming and CD8 cytotoxic T-cell priming to viral antigens, and has substantial therapeutic activity in murine models of disease.