Heat Shock Proteins as Target for the Induction of Antigen-Specific Tolerance in Rheumatoid Arthritis and other Chronic Inflammatory Diseases

Abstract

The critical causative factor of chronic inflammatory diseases such as rheumatoid arthritis (RA) is the faulty regulation of self-tolerance. Despite good results in patients that do respond to potent immunosuppressive therapies, in most of the cases only partial responses are achieved leaving them unduly susceptible to risks, such as infections. More importantly, immunosuppressive measures do not alter the basic condition, so that disease returns when therapy is halted. Antigen-specific therapies may represent a better and more physiological approach for manipulating the immune response avoiding the generalized immune suppression in patients and possibly leading to a state of permanent disease remission. The selection of auto-antigens without necessarily being the initiator of disease and with the ability to induce regulatory T cells is crucial for the development of antigen-specific therapies. Heat Shock Proteins (HSPs) are up-regulated during inflammation and HSP-responses are immuno-dominant. HSP-derived peptides have proved to be able to produce a shift from a pro-inflammatory to a tolerogenic phenotype in pathogenic T cells and endogenous HSP have been shown to act as targets for anti-inflammatory Tregs that control disease without general immune suppression.