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 antigen-presenting cells (APCs). The APCs provide costimulatory signals, through macromolecules such as CD80, that regulate outcomes in terms of T-cell activation or anergy. We have studied essential complementary chemical events in the form of Schiff base formation between carbonyls and amines that are constitutively expressed on presenting cell and T-cell surfaces and provide a new target for manipulation of immune responses. Here we show that small Schiff base-forming molecules can substitute for the physiological donor of carbonyl groups and provide a costimulatory signal to CD4 Th-cells through a mechanism that activates clofilium-sensitive K+ and Na+ transport. One such molecule, tucaresol, enhances CD4 Th-cell responses, selectively favouring 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.
Rhodes
J
J
Molecular Immunology Group, Wellcome Research Laboratories, Beckenham, Kent, UK.
Chen
H
H
Hall
S R
SR
Beesley
J E
JE
Jenkins
D C
DC
Collins
P
P
Zheng
B
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000588:Amines / Q000276:immunology; D000818:Animals; D000941:Antigens / Q000276:immunology; D001547:Benzaldehydes / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004577:Electron Probe Microanalysis; D006801:Humans; D051379:Mice; D011188:Potassium / Q000378:metabolism; D012545:Schiff Bases / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D000588:Amines; D000941:Antigens; D001547:Benzaldehydes; D001565:Benzoates; D016207:Cytokines; D012545:Schiff Bases; D012964:Sodium; C059629:tucaresol; D011188:Potassium