THE LYSOSOMOTROPIC AMINES, CHLOROQUINE AND HYDROXYCHLOROQUINE - A POTENTIALLY NOVEL THERAPY FOR GRAFT-VERSUS-HOST DISEASE

We have recently shown that the lysosomotropic amine, chloroquine, can inhibit the development of graft-versus-host disease (GVHD) secondary to minor histocompatibility (MMC) differences in mice. In addition, w e have shown that both chloroquine and hydroxychloroquine can inhibit T cell responses in vitro to minor and major histocompatibility (MHC) antigens, We review the rationale for the use of lysosomotropic amines , whose primary mechanism of action appears to be inhibition of MHC cl ass II antigen presentation, as therapy for GVHD in humans. Used in lo w concentrations, these agents appear to have no direct effect on T ce lls either in vitro or in vivo although they may have a direct effect at higher concentrations. The lysosomotropic amines, at low concentrat ions, in combination with the T cell-specific agent, cyclosporin A, sy nergistically suppresses the T cell response to MiHC and MHC in mouse and in human. We present the initial data from the human clinical tria ls using hydroxychloroquine, We hypothesize that the lysosomotropic am ines may have unique beneficial effects on immune reconstitution follo wing bone marrow transplantation. The lysosomotropic amines, hydroxych loroquine and chloroquine, represent agents with unique mechanisms of action that may be used to control GVHD in humans.