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.

TLR9 Blockade Inhibits Activation of Diabetogenic CD8+ T Cells and Delays Autoimmune Diabetes

“…daily for 5 d as a loading dose and two to three times weekly thereafter) or PBS. This dosing regimen has been shown to inhibit the progression of murine graft-versus-host disease (27). Again, the spontaneous onset of diabetes was delayed ( Fig.…”

“…+ T cell activation in response to b cell-derived Ags TLR9 activation is blocked by inhibitory oligonucleotides, such as ODN 2088 (26) or chloroquine (27). Chloroquine blocks CpG-TLR9 interaction by reducing endosomal acidification and is effective in treating B cell autoimmune diseases, such as SLE (28).…”

“…Chloroquine blocks CpG-TLR9 interaction by reducing endosomal acidification and is effective in treating B cell autoimmune diseases, such as SLE (28). In addition, chloroquine reduces CD8 + T cell activation and consequent tissue damage in murine graft-versus-host disease (27). We examined the effect of ODN 2088 and chloroquine on CpG-induced 8.…”

Hydroxychloroquine causes severe vacuolar myopathy in a patient with chronic graft‐versus‐host disease

“…Hydroxychloroquine inhibits cytotoxicity caused by T cells, induces apoptosis in T cells, and in high concentrations, blocks T-cell activation [2][3][4]. It inhibits antigen processing and presentation through the major histocompatibility complex class II pathway and modulates cytokine production of, for example, IL-1, IL-6, and TNF [1,[5][6][7][8]. Hydroxychloroquine is an amphiphilic drug structurally similar to chloroquine but with a hydroxylated side chain as its name implies.…”

“…Hydroxychloroquine is an amphiphilic drug structurally similar to chloroquine but with a hydroxylated side chain as its name implies. Both chloroquine and hydroxychloroquine have been used in experimental and clinical models of GVHD [1,8]. It is synergistic with other drugs such as cyclosporine, tacrolimus, and sirolimus [9,10].…”