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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
Journal article   Open access   Peer reviewed

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

Kirk R Schultz, Winnie N Su, Chih-Cheng Hsiao, Gregory Doho, Gareth Jevon, Sharon Bader, Donald E MacFarlane and Andrew L Gilman
Biology of blood and marrow transplantation, Vol.8(12), pp.648-655
2002
DOI: 10.1053/bbmt.2002.v8.abbmt080648
PMID: 12523576
url
https://doi.org/10.1053/bbmt.2002.v8.abbmt080648View
Published (Version of record) Open Access

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.
 Major Histocompatibility Complex Spleen - immunology Mice, Inbred C57BL Chloroquine - therapeutic use Spleen - drug effects Mice, Inbred Strains Graft vs Host Disease - immunology Bone Marrow Transplantation - immunology Animals T-Lymphocytes - drug effects Female Graft vs Host Disease - prevention & control T-Lymphocytes - immunology Mice Mice, Inbred BALB C Oligodeoxyribonucleotides - pharmacology Dinucleoside Phosphates Cytokines - biosynthesis

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