...phenotypic and cytokine profile analyses of peanut-pulsed BMDCs revealed no classical activation by raw or DR peanut preparations compared with LPS (Fig 2, D and E, and see Fig E7 in this ...article's Online Repository at www.jacionline.org). ...by contrast with direct AGE-relevant modification of HEL that showed increased presentation to an HEL-specific T-cell hybridoma, DR PPE-pulsed dendritic cells (DCs) did not enhance the presentation of unmodified HEL, reinforcing the absence of DR PPE-elicited DC costimulation (Fig 2, F, and see Fig E8 in this article's Online Repository at www.jacionline.org).
Summary Background Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We ...aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD. Methods We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18–65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin 5 mg/kg per day on days −1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140–300 ng/mL) for 100 days plus methotrexate 15 mg/m2 on day 1, then 10 mg/m2 on days 3, 6, and 11). The primary endpoint was incidence of grade 2–4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853. Findings Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2–4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5–24), and the incidence of grade 3–4 acute GVHD was 4% (1–13). Grade 2–4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2–4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% 95% CI 2–34) and fludarabine and melphalan reduced-intensity conditioning (12% 4–27). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. Interpretation Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted. Funding National Health and Medical Research Council and Queensland Health.
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