The effect of hydroxychloroquine on alloreactivity and its potential use for graft-versus-host disease.
Hydroxychloroquine (HCQ) interferes with antigen processing and with receptor loading and recycling by raising the pH of lysosomes and endosomes. HCQ thus inhibits MHC class II-restricted antigen presentation by blocking the binding of peptides to MHC molecules. Additionally, HCQ has been shown to diminish the release of several cytokines. In light of these mechanisms of action, we felt that HCQ might be useful in the bone marrow transplant setting and therefore investigated its effect on alloreactivity in vitro. We have demonstrated that HCQ causes a dose-dependent reduction of the cytotoxicity, proliferation, and TNF alpha production resulting from allorecognition in mixed lymphocyte culture (MLC). HCQ does not mediate its effect solely through antigen processing and presentation and other early events since addition of HCQ as late as 120 h after the initiation of the MLC still has a suppressive effect on cytotoxicity. HCQ also inhibits the cytotoxicity of previously primed effectors. These results support an effect of HCQ on terminal mechanisms of cytotoxicity that have not been previously reported. HCQ's ability to reduce the cytotoxicity, proliferation, and TNF alpha production resulting from allorecognition suggests that it may be useful in the prevention and treatment of graft-versus-host disease (GVHD).
Gilman
A L
AL
Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA.
Beams
F
F
Tefft
M
M
Mazumder
A
A
D016572:Cyclosporine / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000517:prevention & control; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D006886:Hydroxychloroquine; D016572:Cyclosporine