Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation and is characterized by the overproduction of proinflammatory cytokines. In this study, we have identified interleukin-6 (IL-6) as a critical inflammatory cytokine that alters the balance between the effector and regulatory arms of the immune system and drives a proinflammatory phenotype that is a defining characteristic of GVHD. Our results demonstrate that inhibition of the IL-6 signaling pathway by way of antibodymediated blockade of the IL-6 receptor (IL-6R) markedly reduces pathologic damage attributable to GVHD. This is accompanied by a significant increase in the absolute number of regulatory T cells (Tregs) that is due to augmentation of thymic-dependent and thymicindependent Treg production.

Key Points Ruxolitinib treatment lessens immunopathology and prolongs survival in murine models of hemophagocytic lymphohistiocytosis. In vivo exposure to ruxolitinib limits CD8+ T-cell expansion and proinflammatory cytokine production.

Summary Haemophagocytic lymphohistiocytosis (HLH) is a life threatening complication of Epstein-Barr virus (EBV) infection. The anti-CD20 antibody rituximab depletes B cells, leading to improved outcomes for patients with EBV-associated B-lymphoproliferative disorders. To gather data on the use of rituximab in EBV-HLH, we performed a retrospective investigation involving 42 EBV-HLH patients who had received treatment with rituximab-containing regimens. On average, patients received 3 rituximab infusions (range 1 – 10) at a median dose of 375 mg/m2. In all patients, rituximab was administered with other HLH-directed medications, including steroids, etoposide and/or ciclosporin. Rituximab-containing regimens appeared well tolerated and improved clinical status in 43% of patients. Examination of laboratory data obtained prior to and within 2 – 4 weeks after the first rituximab dose revealed significant reductions in EBV load (median load pre-rituximab: 114,200 copies/ml, median post-rituximab: 225 copies/ml, p=0.0001) and serum ferritin levels (median ferritin pre-rituximab: 4,260 μg/l, median post-rituximab: 1,149 μg/l, p=0.001). Thus, when combined with conventional HLH-directed therapies, rituximab improves symptoms, reduces viral load and diminishes inflammation. These data support the incorporation of rituximab into future prospective clinical trials for patients with EBV-HLH.

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SummaryInvariant natural killer T (iNKT) cells comprise a rare lymphocyte sublineage with phenotypic and functional properties similar to T and NK cells. Akin to conventional αβ T cells, their development occurs primarily in the thymus, where they originate from CD4 + CD8 + double positive (DP) progenitors. However, the selection of iNKT cells is unique in that it is mediated by homotypic interactions of DP cells and recognition of glycolipid antigen-CD1d complexes. Additionally, iNKT cells acquire an activated innate-like phenotype during development that allows them to release cytokines rapidly following antigen exposure. Given their hybrid features, it is not surprising that the developmental program of iNKT cells partially overlaps with that of T and NK cells. Several recent reports have provided new and exciting insights into the developmental mechanisms that direct NKT cell lineage commitment and maturation. In this review, we provide a discussion of the NKT cell developmental program with an emphasis on the signaling mechanisms and transcription factors that influence the ontogeny of this lineage. Continued investigations of the complex interplay of these transcription factors and their relationship with other extracellular and intracellular signaling molecules will undoubtedly provide important clues into the biology of this unusual T-cell lineage.

We conducted a review of the literature detailing the respiratory effects of chlorine, an extremely important but toxic halogen. Historically, the heaviest mass inhalational exposures to chlorine resulted from World War I gassing. Currently potential human exposure to chlorine inhalation occurs in a variety of settings in the workplace, as a result of inadvertent environmental releases, and even in the home due to household cleaning mishaps. Chlorine species are highly reactive; tissue injury results from exposure to chlorine, hydrochloric acid, hypochlorous acid, or chloramines. Acute, high level exposure to chlorine gas in occupational or environmental settings results in a variety of dose-related lung effects ranging from respiratory mucus membrane irritation to pulmonary edema. Pulmonary function testing can reveal either obstructive or restrictive deficits immediately following exposure, with resolution over time in the majority of cases. However, some of those exposed may demonstrate long-term persistent obstructive or restrictive pulmonary deficits or increased nonspecific airway reactivity after high level exposure to chlorine gas. Symptoms and signs following inhalation of mixtures of chlorine-containing cleaners in the home are similar to those after occupational exposures and environmental releases. Although generally less severe, these events may be extremely common. Controlled human exposure data suggest that some subjects may be more responsive to the effects of chlorine gas; epidemiologic data also indicate that certain subpopulations (e.g., smokers) may be at greater risk of adverse outcome after chlorine inhalation. Although these findings are intriguing, additional study is needed to better delineate the risk factors that predispose toward the development of long-term pulmonary sequelae following chlorine gas exposure.

Exposures to environmental pollutants in utero may increase the risk of adverse health effects. We measured the concentrations of 59 potentially harmful chemicals in 77 maternal and 65 paired umbilical cord blood samples collected in San Francisco during 2010-11, including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), and perfluorinated compounds (PFCs) in serum, and metals in whole blood. Consistent with previous studies, we found evidence that concentrations of mercury (Hg) and lower-brominated PBDEs were often higher in umbilical cord blood or serum than in maternal samples (median cord:maternal ratio > 1), while for most PFCs and lead (Pb), concentrations in cord blood or serum were generally equal to or lower than their maternal pair (median cord:maternal ratio ≤ 1). In contrast to the conclusions of a recent review, we found evidence that several PCBs and OCPs were also often higher in cord than maternal serum (median cord:maternal ratio > 1) when concentrations are assessed on a lipid-adjusted basis. Our findings suggest that for many chemicals, fetuses may experience higher exposures than their mothers, and highlight the need to characterize potential health risks and inform policies aimed at reducing sources of exposure.

Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUCl antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qβ carrier with MUC1 glycopeptides containing 20–22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qβ-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qβ-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.