PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice.

Boosting T cell immune response posttransplant with checkpoint inhibitors increases graft-versus-lymphoma (GVL) effects at the cost of increasing acute graft-versus-host disease (aGVHD). A combined targeted therapy is needed to decrease checkpoint inhibitors-induced aGVHD without impairing GVL. We studied whether this competition could be avoided by giving concurrent anti-PD-1 antibody and ruxolitinib in allotransplant mouse models in which recipients were challenged with A20 or EL4 lymphoma cells. Given alone the PD-1 antibody increased GVL but did not improve survival of recipients challenged with A20 cells because of increased deaths from aGVHD. Adding ruxolitinib decreased levels of effector T cells and related cytokines. Tbx21- T cells had higher PD-1 levels compared with Tbx21+ T cells. Ruxolitinib increased PD-1 levels on donor T cells by suppressing Tbx21 expression. Ruxolitinib increased apoptosis of T cells which was reversed by the PD-1 antibody. PD-1 antibody preserved expression of granzyme B and cytotoxicity of T cells which were decreased by ruxolitinib. The net result of combined therapy was increased GVL, no increase in aGVHD and increased survival. The combined therapy improved survival of recipients challenged by A20 cells which expressed high level of PD-L1, but not EL4 cells which do not express PD-L1.

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants.

High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs), resulting in poor post-transplant immune recovery. IL-22 mediates recovery of TECs via a proregenerative effect, but the precise mechanism by which this occurs is unknown. In this study, we found IL-22 improved thymus recovery after damage from irradiation in association with increased number of TECs. This effect was blocked by ruxolitinib, a JAK1/JAK2 inhibitor. IL-22 increased the number of TECs via a Stat3-dependent signaling in the mTEC1 murine thymic epithelial cell line. This, in turn, upregulated transcription of myeloid cell leukemia sequence 1 (Mcl1), resulting in increased number of TECs. Similar effects were seen in irradiated mice given IL-22. Defects in IL-22 resulted in delayed thymus recovery in irradiated mice and had an impact on levels of thymus function-related genes such as Foxn1, Aire, and Kgf. In mice, post-transplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intrathymic levels of Aire, and increased the proportion of natural regulatory T cells, resulting in decreased severity of chronic graft-versus-host disease (GVHD). Our data highlight the critical role of the IL-22/Stat3/Mcl-1 pathway in the regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T cell function with IL-22 decreases GVHD after allotransplants.

Recipient-derived IL-22 alleviates murine acute graft-versus-host disease in association with reduced activation of antigen presenting cells.

Acute graft-versus-host disease (aGVHD) remains a major challenging complication of patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). CD4+ effector T cells and their related cytokines mediate pathogenesis of aGVHD, in which donor-T-cell derived interleukin-22 (IL-22) was recently indicated to play a role. The role of recipient-derived IL-22 in aGVHD remains to be elucidated. By applying IL-22 knock out (IL-22KO) mice as recipients of allotransplant, we found recipient derived IL-22 alleviated aGVHD and improved survival of allotransplant recipients. Knock out of IL-22 in recipient increased levels of T-helper (Th1) 1 cells but decreased levels of regulatory T cells (Tregs) in target tissues of aGVHD. Levels of IL-22 increased in aGVHD mice. Recipient antigen presenting cells (APCs) are important sources of IL-22. IL-22 reduced activation of APCs in vitro. Defect of IL-22 in APCs resulted in increased polarization of Th1 cells but decreased level of Tregs in an in vitro co-culture system. Our data highlight an immunoregulatory function of recipient-derived IL-22 in aGVHD.

Construction of Ni/In2O3 Integrated Nanocatalysts Based on MIL-68(In) Precursors for Efficient CO2 Hydrogenation to Methanol.

The efficient and economic conversion of CO2 and renewable H2 into methanol has received intensive attention due to growing concern for anthropogenic CO2 emissions, particularly from fossil fuel combustion. Herein, we have developed a novel method for preparing Ni/In2O3 nanocatalysts by using porous MIL-68(In) and nickel(II) acetylacetonate (Ni(acac)2) as the dual precursors of In2O3 and Ni components, respectively. Combined with in-depth characterization analysis, it was revealed that the utilization of MIL-68(In) as precursors favored the good distribution of Ni nanoparticles (∼6.2 nm) on the porous In2O3 support and inhibited the metal sintering at high temperatures. The varied catalyst fabrication parameters were explored, indicating that the designed Ni/In2O3 catalyst (Ni content of 5 wt %) exhibited better catalytic performance than the compared catalyst prepared using In(OH)3 as a precursor of In2O3. The obtained Ni/In2O3 catalyst also showed excellent durability in long-term tests (120 h). However, a high Ni loading (31 wt %) would result in the formation of the Ni-In alloy phase during the CO2 hydrogenation which favored CO formation with selectivity as high as 69%. This phenomenon is more obvious if Ni and In2O3 had a strong interaction, depending on the catalyst fabrication methods. In addition, with the aid of in situ diffuse reflectance infrared Fourier transform spectroscopy and density functional theory (DFT) calculations, the Ni/In2O3 catalyst predominantly follows the formate pathway in the CO2 hydrogenation to methanol, with HCOO* and *H3CO as the major intermediates, while the small size of Ni particles is beneficial to the formation of formate species based on DFT calculation. This study suggests that the Ni/In2O3 nanocatalyst fabricated using metal-organic frameworks as precursors can effectively promote CO2 thermal hydrogenation to methanol.

Efficient CO2 Electroreduction to Ethanol by Cu3 Sn Catalyst.

Electrochemical carbon dioxide reduction to ethanol suggests a potential strategy to reduce the CO2 level and generate valuable liquid fuels, while the development of low-cost catalysts with high activity and selectivity remains a major challenge. In this work, a bimetallic, low-entropy state Cu3 Sn catalyst featuring efficient electrocatalytic CO2  reduction to ethanol is developed. This low-entropy state Cu3 Sn catalyst allows a high Faradaic efficiency of 64% for ethanol production, distinctively from the high-entropy state Cu6 Sn5  catalyst with the main selectivity toward producing formate. At an industry-level current density of -900 mA cm-2 , the Cu3 Sn catalyst exhibited excellent stability for over 48 h in a membrane-electrode based electrolyzer. Theoretical calculations indicate that the high ethanol selectivity on Cu3 Sn is attributed to its enhanced adsorption of several key intermediates in the ethanol production pathway. Moreover, the life-cycle assessment reveals that using the Cu3 Sn electrocatalyst, an electrochemical CO2 -to-ethanol electrolysis system powered by wind electricity can lead to a global warming potential of 120 kgCO2-eq for producing 1 ton of ethanol, corresponding to a 55% reduction of carbon emissions compared to the conventional bio-ethanol process.

Dynamic of plasma IL-22 level is an indicator of thymic output after allogeneic hematopoietic cell transplantation.

AIMS: Interleukin-22 (IL-22) promotes thymus recovery and improves T-cell recovery in preclinical allogeneic hematopoietic cell transplant models. However, the correlation between IL-22 and thymus recovery is unknown in human transplant. MATERIALS AND METHODS: In this study, plasma IL-22 levels of transplanted humans were analyzed peri-transplant. Thymic output was assessed by detecting blood signal joint T-cell receptor excision circles (TRECs). Flow cytometry was applied to measure T-cell subsets. KEY FINDINGS: Plasma IL-22 level positively correlated with blood TRECs level at days 14 and 28 posttransplant. Multiple linear regression analysis showed plasma IL-22 level, occurrence of acute graft-versus-host disease (aGVHD) and age were significantly associated with blood TRECs level at day 28 after allotransplant. An increase of plasma IL-22 level during day 14 and day 28 correlated with faster recovery of blood TRECs and naïve T-cell levels in allotransplant recipients. Recipients with high TRECs levels at day 28 had lower incidence of aGVHD comparing with those who with low TRECs levels according to a median split of their TRECs levels, an effect also seen in the high IL-22 level and low IL-22 level cohorts. Other factors such as age and infection had impacts on plasma IL-22 level in allotransplants. SIGNIFICANCE: Our findings suggest that dynamic change of plasma IL-22 level is an indicator of thymic output and occurrence of aGVHD. Monitoring plasma IL-22 level might help to assess recovery of thymus function in human allotransplants.

Janus kinase inhibitor ruxolitinib blocks thymic regeneration after acute thymus injury.

Thymic epithelial cells (TECs) are crucial for the production of T-cells. Cancer therapies including cytotoxic drugs and ionizing radiations damage TECs resulting in abnormal T-cell production and function. Fortunately, TECs can regenerate after injury. The Janus kinase (Jak) pathway is important in supporting survival of TECs. Jak inhibitors are used to treat cancer and immune disorders. The impact of Jak inhibitors on recovery of TECs is unknown. We induced acute thymus injury in mice by using ionizing radiation and evaluated the impact of ruxolitinib on thymus regeneration. We also tested if ruxolitinib affected proliferation of TECs in vitro. An increase was observed in the recovery of thymus cells after acute injury in association with up-regulation of TEC-related growth factors including keratinocyte growth factor (Kgf), epidermal growth factor (Egf), insulin-like growth factor 1 (Igf1) and receptor activator of NF-κB ligand (Rankl). Giving ruxolitinib decreased levels of receptors of these growth factors on TECs and blocked growth factor-induced recovery of thymus cells in damaged thymii. Ruxolitinib also blocked growth factors-induced proliferation of TECs in vitro. Thymus regeneration was inhibited when ruxolitinib was given immediately after thymus injury but not when it was given 1 week later. These data may have implications for how ruxolitinib is used in clinical practices.

Selective inhibition of interleukin-1 receptor-associated kinase 1 ameliorates lipopolysaccharide-induced sepsis in mice.

Interleukin-1 receptor-associated kinases (IRAKs), particularly IRAK1 and IRAK4, are important in transducing signal from Toll-like receptor 4. We interrogated if a selective inhibition of IRAK1 could alleviate lipopolysaccharide (LPS)-induced sepsis. In this study, we tested the impact of a novel selective IRAK1 inhibitor Jh-X-119-01 on LPS-induced sepsis in mice. Survival at day 5 was 13.3% in control group where septic mice were treated by vehicle, while the values were 37.5% (p = 0.046, vs. control) and 56.3% (p = 0.003, vs. control) for 5 mg/kg and 10 mg/kg Jh-X-119-01-treated mice. Jh-X-119-01 alleviated lung injury and reduced production of TNFα and IFNγ in peritoneal macrophages. Jh-X-119-01 decreased phosphorylation of NF-κB and mRNA levels of IL-6 and TNFα in LPS-treated macrophages in vitro. Jh-X-119-01 selectively inhibited IRAK1 phosphorylation comparing with a non-selective IRAK1/4 inhibitor which simultaneously inhibited phosphorylation of IRAK1 and IRAK4. Both Jh-X-119-01 and IRAK1/4 inhibitor increased survival of septic mice, but Jh-X-119-01-treated mice had higher blood CD11b+ cell counts than IRAK1/4 inhibitor-treated ones [24 h: (1.18 ± 0.26) × 106/ml vs. (0.79 ± 0.20) × 106/ml, p = 0.001; 48 h: (1.00 ± 0.30) × 106/ml vs. (0.67 ± 0.23) × 106/ml, p = 0.042]. IRAK1/4 inhibitor induced more apoptosis of macrophages than Jh-X-119-01 did in vitro. IRAK1/4 inhibitor decreased protein levels of anti-apoptotic BCL-2 and MCL-1 in RAW 264.7 and THP-1 cells, an effect not seen in Jh-X-119-01-treated cells. In conclusion, Jh-X-119-01 selectively inhibited activation of IRAK1 and protected mice from LPS-induced sepsis. Jh-X-119-01 showed less toxicity on macrophages comparing with a non-selective IRAK1/4 inhibitor.

Selective carbon dioxide electroreduction to ethylene and ethanol by core-shell copper/cuprous oxide.

Developing an effective catalyst to reduce carbon dioxide (CO2) to value-added C2+ products is a key challenge for CO2 utilization. Here we report a core-shell copper with native oxide (Cu@Cu2O) catalyst featuring a thin native oxide layer on the surface grown under ambient conditions. The Cu(I) oxide species on Cu@Cu2O surface remained relatively stable against reduction under CO2 electroreduction condition, and the synergism between surface Cu+ and Cu0 in Cu@Cu2O contributed to boosting its efficiency and selectivity toward C2 products. This Cu@Cu2O catalyst achieved an excellent selectivity (∼50% at -1.0 V vs reversible hydrogen electrode) for C2 (ethylene and ethanol) production.

Electrochemical N2 fixation by Cu-modified iron oxide dendrites.

The electrochemical nitrogen reduction reaction (NRR) under mild conditions is significantly challenging, due to the extremely high stability of dinitrogen (N2) molecules. The NRR pathway also confronts the competitive water reduction reaction that takes places universally in an aqueous solution. Herein, a Fe2O3/Cu catalyst is demonstrated as an efficient NRR electrocatalyst. The electronic interactions elevate the d-state electron center, enabling strong back-bonding for N2 molecules. The altering of d-electron distribution promotes the adsorption of N2, leading to a high catalytic activity. As a result, the Fe2O3/Cu catalyst exhibits an outstanding ammonia production rate of 15.66 µg·h-1·mgcat.-1 at -0.1 V versus reversible hydrogen electrode (RHE), a Faradaic efficiency of 24.4%, and a good electrochemical stability.

Donor T-cell-derived interleukin-22 promotes thymus regeneration and alleviates chronic graft-versus-host disease in murine allogeneic hematopoietic cell transplant.

Defect of thymus results in poor posttransplant immune recovery and dysfunction of immune tolerance after allogeneic hematopoietic cell transplants (allo-HCT). Improving thymus regeneration represents a potential strategy to accelerate recovery of T-cell immunity. IL-22 was reported to mediate thymus regeneration after injury. In this study, we found donor T-cell is a major source of IL-22 in allotransplant recipient. Through applying IL-22 knock out (IL-22KO) mice in allo-HCT, we found donor T-cell derived IL-22 promotes thymus regeneration in association with increased level of intra-thymic IL-22. IL-22KO T-cell-transplanted recipients show deficient thymus recovery which is reversed by injection of exogenous IL-22. T-cell derived IL-22 promotes proliferation of thymic epithelial cells (TECs) in vitro. In addition, donor T-cell derived IL-22 increases expression level of Aire in the thymus and decreases skin chronic graft-versus-host disease (GVHD). Furthermore, short-term use of exogenous IL-22 posttransplant accelerates recovery of thymus without increasing severity of acute GVHD. Our data indicate that cross-talk between T-cell and TECs is an important mechanism to mediate reconstitution of T-cell immunity after allo-HCT.

Unconventional morphologies of CoO nanocrystals via controlled oxidation of cobalt oleate precursors.

We report an 'oxidation state' regulating method for the synthesis of anisotropic wurtzite CoO nanocrytals (NCs) with various shapes, including ultrathin nanosheets and a core-antenna structure for the first time. We show that the decomposition process of precursors was altered by their oxidation, which played a significant role in the unconventional growth.