ANTIMALARIAL-DRUGS - MECHANISMS OF ACTION IN AUTOIMMUNE-DISEASE AND PROSPECTS FOR DRUG DEVELOPMENT

Antimalarial medications used in rheumatic diseases include chloroquine, hydroxychloroquine and mepacrine (quinacrine). A wide variety of mechanisms of antirheumatic action have been proposed for chloroquine and hydroxychloroquine, but any model must account for: (a) the slow onset of action (usually 8 to 12 weeks), in contrast to the rapid onset of therapeutic benefit after administration of salicylates, corticosteroids, or nonsteroidal anti-inflammatory drugs; (b) the lack of effect on bone marrow production of leucocyte precursors, a feature that distinguishes antimalarials from immunosuppressants; (c) the absence of opportunistic infections, indicating that the response to exogenous agents (including infectious organisms and vaccines) is not impaired; and (d) the potential benefit in a wide spectrum of autoimmune disorders that differ in their genetics and target organs. This review will propose a hypothesis that the immunomodulatory properties of chloroquine and hydroxychloroquine derive from their ability to influence the assembly of antigenic peptides with proteins of the class II major histocompatibility complex. Antimalarial compounds are weak diprotic bases that passively diffuse from plasma across cell membranes and become protonated within acidic cytoplasmic vesicles such as lysosomes and endosomes. The resulting slight elevation in endosomal pH in macrophages may influence the assembly and trafficking of molecules important in immune regulation. This hypothetical model of antimalarial drug action suggests methods for screening additional drugs for the ability to modulate the immune response.