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 (MiHC) differences in mice. In addition, we 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 class II antigen presentation, as therapy for GVHD in humans. Used in low concentrations, these agents appear to have no direct effect on T cells either in vitro or in vivo although they may have a direct effect at higher concentrations. The lysosomotropic amines, at low concentrations, in combination with the T cell-specific agent, cyclosporin A, synergistically suppresses the T cell response to MiHC and MHC in mouse and in human. We present the initial data from the human clinical trials using hydroxychloroquine. We hypothesize that the lysosomotropic amines may have unique beneficial effects on immune reconstitution following bone marrow transplantation. The lysosomotropic amines, hydroxychloroquine and chloroquine, represent agents with unique mechanisms of action that may be used to control GVHD in humans.
Schultz
K R
KR
Department of Pediatrics, University of British Columbia, Vancouver, Canada.
Gilman
A L
AL
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006183:H-2 Antigens / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007519:Isoantigens / Q000276:immunology; D008247:Lysosomes / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D006183:H-2 Antigens; D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D007519:Isoantigens; D006886:Hydroxychloroquine; D016572:Cyclosporine; D002738:Chloroquine