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

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).
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PMID:The effect of hydroxychloroquine on alloreactivity and its potential use for graft-versus-host disease. 880 16

Hydroxychloroquine (HCQ), a lysosomotropic amine, is an immunosuppressive agent presently being evaluated in bone marrow transplant patients to treat graft-versus-host disease. While its immunosuppressive properties have been attributed primarily to its ability to interfere with antigen processing, recent reports demonstrate HCQ also blocks T-cell activation in vitro. To more precisely define the T-cell inhibitory effects of HCQ, the authors evaluated T-cell antigen receptor (TCR) signaling events in a T-cell line pretreated with HCQ. In a concentration-dependent manner, HCQ inhibited anti-TCR-induced up-regulation of CD69 expression, a distal TCR signaling event. Proximal TCR signals, including inductive protein tyrosine phosphorylation, tyrosine phosphorylation of phospholipase C gamma1, and total inositol phosphate production, were unaffected by HCQ. Strikingly, anti-TCR-crosslinking-induced calcium mobilization was significantly inhibited by HCQ, particularly at the highest concentrations tested (100 micromol/L) in both T-cell lines and primary T cells. HCQ, in a dose-dependent fashion, also reduced a B-cell antigen receptor calcium signal, indicating this effect may be a general property of HCQ. Inhibition of the calcium signal correlated directly with a reduction in the size of thapsigargin-sensitive intracellular calcium stores in HCQ-treated cells. Together, these findings suggest that disruption of TCR-crosslinking-dependent calcium signaling provides an additional mechanism to explain the immunomodulatory properties of HCQ.
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PMID:Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. 1082 29

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Both the disease and the medications used to treat it are associated with significant morbidity and mortality. The manifestations of chronic GVHD often resemble those of autoimmune disorders. Hydroxychloroquine (HCQ) is a 4-aminoquinoline antimalarial drug used for the treatment of autoimmune diseases. HCQ interferes with antigen processing and presentation, cytokine production, and cytotoxicity and is synergistic with cyclosporine and tacrolimus in vitro. Forty patients with steroid-resistant or steroid-dependent chronic GVHD were enrolled in a phase 2 trial of HCQ 800 mg (12 mg/kg) per day. Three complete responses and 14 partial responses were seen in 32 evaluable patients (53% response rate). All responders tolerated a >50% reduction in their steroid dose while receiving HCQ. Clinical response occurred at a median of 8 weeks (range, 4 to 24 weeks). No hematologic, hepatic, renal, or retinal toxicity was associated with HCQ. In light of its mechanisms of action, clinical activity for GVHD, and low toxicity profile, HCQ may be useful in a multiagent approach for the treatment of extensive chronic GVHD.
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PMID:Hydroxychloroquine for the treatment of chronic graft-versus-host disease. 1090 70

Hydroxychloroquine (HCQ) is an immunosuppressive agent that interferes with antigen presentation and with activity against graft-versus-host disease (GVHD). In a phase II trial assessing the GVHD prophylactic effects of HCQ, 51 consecutive unrelated donor transplant recipients received HCQ in addition to cyclosporin A, methylprednisolone, and methotrexate. HCQ was initiated on pretransplantation day -21 at 800 mg/d and continued until day +100 after transplantation. HCQ was extremely well tolerated and was not associated with side effects. Pharmacokinetic analyses demonstrated large inter- and intrapatient variability. The addition of HCQ did not affect posttransplantation immune recovery. Grade II to IV acute GVHD was observed in 56% of patients, and grade III and IV GVHD was observed in 17%. Day +100 mortality was 22%. When compared with a matched cohort of patients reported to the International Bone Marrow Transplant Registry, patients receiving HCQ had comparable cumulative incidences of grade II to IV acute GVHD. However, lower incidences of grades III and IV GVHD and better GVHD-free survival were observed in HCQ-treated patients (P =.01). We conclude that prophylactic HCQ is well tolerated and associated with a low incidence of severe acute GVHD. An ongoing placebo-controlled randomized trial will further determine what role HCQ plays in preventing GVHD after allografting.
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PMID:Hydroxychloroquine for the prevention of acute graft-versus-host disease after unrelated donor transplantation. 1465 55

Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). In a single-institution phase III trial, 95 recipients of allogeneic peripheral blood stem cell (PBSC) transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ, or placebo starting 21 days pretransplant and continued until day +365. HCQ was very well tolerated and not associated with side effects. Overall, the incidence of acute GVHD (aGVHD) was 59% in both arms, and severe aGVHD occurred in 11% (HCQ) and 14% (placebo) (P = .76). Sixty percent and 78% of patients developed chronic GVHD (cGVHD) in the HCQ and the placebo arms, respectively (P = .15). With a median follow-up of 18 months, relapse-free and overall survivals (OS) were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single-agent CSA had no effects on aGVHD or cGVHD or survival.
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PMID:A randomized double-blind trial of hydroxychloroquine for the prevention of chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation. 1788 57

Brief virologic news included the discovery of the virophage, a unique parasite of the giant mimivirus and the association of HHV-8 infection with a peculiar form of African diabetes. Secondly, this news focused on risk factors for arterial or venous thrombosis and therapy for auto-immune disorders. Only oral estrogen therapy increases the risk of venous thromboembolism in postmenopausal women. Despite significant homocysteine lowering, vitamin supplementation with folic acid, vitamins B6 and B12 did not reduce total cardiovascular events among high-risk patients. Patients with venous thromboembolism have a substantially increased long-term risk of subsequent cardiovascular events while obesity, systemic arterial hypertension, and diabetes are common risk factors for arterial and venous thrombosis. The non fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infection in all ethnic groups. Preventive anticoagulation of in-patients with risk of venous thromboembolism was inadequately prescribed in many hospitals of the world. Subcutaneous administration of methotrexate was more effective than the oral administration at the same dosage in patients suffering from active rheumatoid arthritis. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Anti-IL-5 and anti-IL-6 antibodies were effective for the treatment of respectively hypereosinophilic syndrome and rheumatoid arthritis. The efficacy of proteasome inhibitors and mesenchymal stems cells have been demonstrated in respectively two mouse strains with lupus-like disease and steroid-resistant severe acute graft-versus-host disease. These treatments may be useful for auto-immune disorders if their long term toxicity is acceptable. In conclusion, subcutaneous injections of physiological saline, used as placebo in two different trials, enhanced in vitro activation of immunocompetent cells in healthy individuals.
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PMID:[What's new in internal medicine?]. 1926 9