Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Graft-versus-host disease (GVHD) caused by T-cell recognition of minor histocompatibility (MiHC) antigens is a major complication of bone marrow transplantation. GVHD therapy has focused on removal or suppression of donor T cells, but modulation of MiHC antigen presentation to CD4+ T cells may represent an alternative approach. Chloroquine is known to inhibit major histocompatibility complex (MHC) class II presentation of antigen in vitro by affecting invariant chain dissociation from MHC class II. The goal of this study was to evaluate the role of chloroquine in abrogating T-cell priming to MiHC and GVHD in mice after transplantation of an MiHC incompatible donor. C57BL/6 mice were treated with phosphate-buffered saline or chloroquine at 400 micrograms intraperitoneally every day for 5 days before priming with BALB.B cells (MiHC-incompatible) followed by weekly injections of chloroquine at 400 micrograms for 4 to 8 weeks. Chloroquine treatment decreased the proliferative T-cell response to MiHC by 67% and the cytolytic T-cell activation by greater than 50%. After bone marrow transplantation (LP/J into C57BL/6; MiHC-incompatible), GVHD was significantly decreased in chloroquine-treated mice (17% with GVHD) as compared with that in controls (92% with GVHD). Chloroquine treatment did not have other effects in vivo on the normal T- and B-cell mitogenic responses, T-cell allogeneic responses, and MHC class II and I surface expression. Chloroquine treatment does decrease the ability of C57BL/6 antigen-presenting cells to stimulate C3H.SW T cells reactive with MiHC expressed on C57BL/6 cells, suggesting an effect on MHC class II presentation of MiHC in vivo. Treatment with chloroquine in vivo appears to result in decreased CD4+ T-cell priming to MiHC and GVHD by decreased class II MHC antigen presentation. Thus, chloroquine treatment may represent an alternative approach to control GVHD.
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PMID:Chloroquine treatment affects T-cell priming to minor histocompatibility antigens and graft-versus-host disease. 749 96

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.
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PMID: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. 1252 76