title: Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production.
abstract: The 4-aminoquinolines, chloroquine and hydroxychloroquine, are established, with a 52% response rate, as therapy for human steroid-refractory GVHD after BMT. Chloroquine affects numerous mechanisms that play a role in GVHD, including inhibition of major histocompatibility complex (MHC) class II antigen presentation, cytokine production, and antigen-presenting cell activation by bacterially derived CpG oligodeoxynucleotides (ODNs). Using an MHC-disparate murine model, we evaluated the effect of chloroquine treatment on the development of acute GVHD. We assessed the effect of chloroquine on the immunostimulatory responses induced by CpG ODNs after BMT. We also evaluated the impact of chloroquine on cytokine-producing populations known to affect GVHD, including CD4+ and CD8+ T-cell and CD3(+)/NK1.1(+) natural killer T-cell (NKT cell) populations. Twelve (86%) of 14 mice receiving phosphate-buffered saline solution (PBS) developed lethal GVHD; only 4 (29%) of 14 mice receiving chloroquine 20 mg/kg 3 times per week developed lethal GVHD (P < .01). Chloroquine significantly suppressed CpG ODN-induced splenic proliferation and interleukin 6 (IL-6) production associated with GVHD. Chloroquine suppressed CD8+ T-cell production of IL-2 and IL-4 associated with GVHD in this model and maintained an early expansion (day 7) of splenic NKT cells. These results indicate that the 4-aminoquinolines are effective in therapy for or prevention of acute GVHD secondary to MHC disparities. Chloroquine actions may include inhibition of CpG ODN augmentation of GVHD. Other mechanisms involved may include suppression of CD8+ T-cell production of IL-2 and IL-4 and an increase in NKT cells associated with GVHD inhibition by chloroquine.
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia and British Columbia's Children's Hospital, Vancouver, British Columbia, Canada. kschultz@interchange.ubc.ca
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
authors.forename: Winnie N
authors.initials: WN
authors.lastname: Su
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Hsiao
authors.forename: Gregory
authors.initials: G
authors.lastname: Doho
authors.forename: Gareth
authors.initials: G
authors.lastname: Jevon
authors.forename: Sharon
authors.initials: S
authors.lastname: Bader
authors.forename: Donald E
authors.initials: DE
authors.lastname: MacFarlane
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gilman
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002738:Chloroquine / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D015226:Dinucleoside Phosphates; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D002738:Chloroquine; D016207:Cytokines; D015226:Dinucleoside Phosphates; D009838:Oligodeoxyribonucleotides; C015772:CpG dinucleotide