Immunotherapy has been successfully used in the treatment of multiple malignancies, but clinical studies revealed low response rates. Thus, the development of new effective immunotherapeutic ...modalities is urgently needed. Successfully inducing tumor cell death with enhanced antigenicity is important for the expansion and differentiation of tumor-specific CD8+ cytotoxic T lymphocytes. Cationic liposome/DNA complexes (CLN/DNA), which usually have obvious cytotoxic effects, may improve the antitumor immunity through enhancing the immunogenicity of dying tumor cells. Herein, we report that a plasmid DNA-encapsulated cationic lipid nanoparticle formulated with cholesterol, DOTAP, and DSPE-mPEG2000 significantly increases the tumor cell death with high antigenicity in vitro. Furthermore, the cationic liposome/DNA complex (CLN/DNA) treatment promotes the activation of dendritic cells (DCs). We also find that the intratumorally injected CLN/DNA successfully promoted the activation of DCs in the tumor-draining lymph node. Importantly, both local tumor growth and distant tumor formation were significantly inhibited by T cell-dependent antitumor immune responses after intratumoral injection of CLN/DNA. This study presents a simple and effective strategy for improving the cancer immunotherapy.
CD47 is a ubiquitously expressed transmembrane glycoprotein that plays a complex role in regulation of cell survival and function. We have previously shown that the interspecies incompatibility of ...CD47 plays an important role in triggering rejection of cellular xenografts by macrophages. However, the role of CD47 in solid organ transplantation remains undetermined. Here, we explored this question in mouse models of heart allotransplantation. We observed that the lack of CD47 in donor hearts had no deleterious effect on graft survival in syngeneic or single MHC class I‐mismatched recipients, in which both wild‐type (WT) and CD47 knockout (CD47 KO) mouse hearts survived long term with no sign of rejection. Paradoxically, elimination of donor CD47 was beneficial for graft survival in signal MHC class II‐ and class I‐ plus class II‐mismatched combinations, in which CD47 KO donor hearts showed significantly improved survival compared to WT donor hearts. Similarly, CD47 KO donor hearts were more resistant than WT hearts to humoral rejection in α1,3‐galactosyltransferase‐deficient mice. Moreover, a significant prolongation of WT allografts was observed in recipient mice treated with antibodies against a CD47 ligand thrombospondin‐1 (TSP1) or with TSP1 deficiency, indicating that TSP1‐CD47 signaling may stimulate vascularized allograft rejection. Thus, unlike cellular transplantation, donor CD47 expression may accelerate the rejection of vascularized allografts.
The breakthrough of induced pluripotent stem cell (iPSC) technology has raised the possibility that patient-specific iPSCs may become a renewable source of autologous cells for cell therapy without ...the concern of immune rejection. However, the immunogenicity of autologous human iPSC (hiPSC)-derived cells is not well understood. Using a humanized mouse model (denoted Hu-mice) reconstituted with a functional human immune system, we demonstrate that most teratomas formed by autologous integration-free hiPSCs exhibit local infiltration of antigen-specific T cells and associated tissue necrosis, indicating immune rejection of certain hiPSC-derived cells. In this context, autologous hiPSC-derived smooth muscle cells (SMCs) appear to be highly immunogenic, while autologous hiPSC-derived retinal pigment epithelial (RPE) cells are immune tolerated even in non-ocular locations. This differential immunogenicity is due in part to abnormal expression of immunogenic antigens in hiPSC-derived SMCs, but not in hiPSC-derived RPEs. These findings support the feasibility of developing hiPSC-derived RPEs for treating macular degeneration.
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•Hu-mice offer a model to study immune responses to autologous hiPSC derivatives•Hu-mice reveal differential immune responses to hiPSC-derived SMCs and RPEs•Misexpression of immunogenic antigens in hiPSC-derived SMCs leads to T cell response•hiPSC-RPEs are tolerated even in non-ocular sites, supporting their clinical use
Patient iPSCs have potential as a renewable source for autologous cell therapy that avoids immune rejection. Using a humanized mouse model with a functional human immune system, Zhao et al. observe differential immune responses to various autologous hiPSC derivatives, including rejection of smooth muscle cells and tolerance to retinal pigmented epithelium.
Hemophagocytic lymphohistiocytosis (HLH) has recently been increasingly reported as an important complication after stem cell transplantation, in line with the increase in the number of ...HLA-mismatched transplantation. Although previous clinical studies have shown an elevation of inflammatory cytokines in patients with HLH after hematopoietic stem cell transplantation, as well as those after viral infection or autoimmune disease, the disease pathogenesis remains poorly understood. Here we explored this issue in humanized mice with functional human lymphohematopoietic systems, which were constructed by transplantation of human CD34
cells alone, or along with human fetal thymus into NOD/SCID/γc
(NSG) or NSG mice carrying human SCF/GM-CSF/IL-3 transgenes (SGM3). In comparison with humanized NSG (huNSG) mice, huSGM3 mice had higher human myeloid reconstitution and aggressive expansion of human CD4
memory T cells, particularly in the absence of human thymus. Although all huNSG mice appeared healthy throughout the observation period of over 20 weeks, huSGM3 mice developed fatal disease characterized by severe human T cell and macrophage infiltrations to systemic organs. HuSGM3 mice also showed severe anemia and thrombocytopenia with hypoplastic bone marrow, but increased reticulocyte counts in blood. In addition, huSGM3 mice showed a significant elevation in human inflammatory cytokines including IL-6, IL-18, IFN-α, and TNF-γ, faithfully reproducing HLH in clinical situations. Our study suggests that posttransplant HLH is triggered by alloresponses (or xenoresponses in our model), driven by myeloid cytokines, and exacerbated by vicious cycles of T-cell and macrophage activation.
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•Vascular permeability is increased upon in-vivo exposure of PM2.5.•The damaged endothelial integrity mediates the disorder of vascular permeability.•PM2.5 exposure activates VEGFR 2 ...and MAPK/ERK signaling, causing VEC shedding.•PM2.5 exposure initiates the ROS production and cell membrane damage.
Although in-vivo exposure of PM2.5 has been suggested to initiate a disorder on vascular permeability, the effects and related mechanism has not been well defined. In this work, an obvious increase on vascular permeability has been confirmed in vivo by vein injection of PM2.5 into Balb/c mouse. Human umbilical vein vascular endothelial cells and the consisted ex-vivo vascular endothelium were used as model to investigate the effects of PM2.5 on the vascular permeability and the underlying molecular mechanism. Upon PM2.5 exposure, the vascular endothelial growth factor receptor 2 on cell membrane phosphorylates and activates the downstream mitogen-activated protein kinase (MAPK)/ERK signaling. The adherens junction protein VE-cadherin sheds and the intercellular junction opens, damaging the integrity of vascular endothelium via paracellular pathway. Besides, PM2.5 induces the intracellular reactive oxygen species (ROS) production and triggers the oxidative stress including activity decrease of superoxide dismutase, lactate dehydrogenase release and permeability increase of cell membrane. Taken together, the paracellular and transcellular permeability enhancement jointly contributes to the significant increase of endothelium permeability and thus vascular permeability upon PM2.5 exposure. This work provides an insight into molecular mechanism of PM2.5 associated cardiovascular disease and offered a real-time screening method for the health risk of PM2.5.
•The validity of RDM method to simulate suspended sediment concentration is verified.•Integrated sediment diffusion coefficient Kz′=βKm is proposed to study the dispersion and diffusion.•Results show ...that β in flow with submerged canopy is larger than that in emergent canopy flow.
Based on the Lagrangian approach, this study proposes a random displacement model (RDM) to predict the concentration of suspended sediment in vegetated steady open channel flow. Validation of the method was conducted by comparing the simulated results by using the RDM with available experimental measurements for uniform open-channel flows. The method is further validated with the classical Rouse formula. To simulate the important vertical dispersion caused by vegetation in the sediment-laden open channel flow, a new integrated sediment diffusion coefficient is introduced in this study, which is equal to a coefficient β multiplying the turbulent diffusion coefficient. As such, the RDM approach for sandy flow with vegetation was established for predicting the suspended sediment concentration in low-sediment-concentration flow with both the emergent and submerged vegetation. The study shows that the value of β for submerged vegetation flow is larger than that for emergent vegetation flow. The simulated result using the RDM is in good agreement with the available experimental data, indicating that the proposed sediment diffusion coefficient model can be accurately used to investigate the sediment concentration in vegetated steady open channel flow.
An increasing number of experiments and clinical trials have demonstrated the safety, feasibility, and efficacy of mesenchymal stem cells (MSCs)‐based therapies for the treatment of various diseases. ...The main drawbacks of MSC therapy are the lack of specific homing after systemic infusion and early death of injected cells because of the injury micro‐environment. We pretreated bone mesenchymal stem cells (BMSCs) with erythropoietin (EPO) to investigate their positive effect on cyclosporine A (CsA)‐induced nephrotoxicity. BMSCs were incubated with different concentrations of EPO (10, 100, 500, and 1000 IU/mL) for 24 and 48 h, and their proliferation rate, cytoskeletal morphology, migration ability, and the expression of CXCR4 were evaluated to determine the optimal pretreatment conditions. To investigate the therapeutic effects of BMSCs pretreated with EPO in CsA‐induced nephrotoxicity, we established CsA‐induced in vitro and in vivo toxicity models. In our in vitro study, preconditioning of BMSCs with 500 IU/mL EPO for 48 h induced a marked increase in their proliferation rate, cytoskeletal rearrangement, migration in the scrape‐healing assay, and migration toward injured HK2 cells. In vivo, EPO‐BMSCs showed higher ability to improve renal function than BMSCs, and in CsA‐induced rats treated with EPO‐BMSCs, interstitial lymphocyte infiltration, tubular swelling, necrosis, and interstitial fibrosis decreased. We demonstrated that pretreatment with 500 IU/mL EPO before infusion markedly increased the homing ability of BMSCs, and obviously ameliorate CsA‐induced nephrotoxicity in rats.
We demonstrated that pretreatment with 500 IU/mL EPO before infusion markedly increased the homing ability of BMSCs, and obviously ameliorate CsA‐induced nephrotoxicity in rats.
The future of manufacturing applications in three-dimensional (3D) printing depends on the improvement and the development of materials suitable for 3D printing technology. This study aims to develop ...an applicable and convenient protocol for light-curing resin used in 3D industry, which could enhance antibacterial and mechanical properties of polymethyl methacrylate (PMMA) resin through the combination of nano-fillers of surface modified titanium dioxide (TiO2) and micro-fillers of polyetheretherketone (PEEK). PMMA-based composite resins with various additions of TiO2 and PEEK were prepared and submitted to characterizations including mechanical properties, distribution of the fillers (TiO2 or/and PEEK) on the fractured surface, cytotoxicity, antibacterial activity, and blood compatibility assessment. These results indicated that the reinforced composite resins of PMMA (TiO2-1%-PEEK-1%) possessed the most optimized properties compared to the other groups. In addition, we found the addition of 1% of TiO2 would be an effective amount to enhance both mechanical and antibacterial properties for PMMA composite resin. Furthermore, the model printed by PMMA (TiO2-1%-PEEK-1%) composite resin showed a smooth surface and a precise resolution, indicating this functional dental restoration material would be a suitable light-curing resin in 3D industry.
Cullin-RING ligases (CRLs) are the largest class of E3 ubiquitin ligases regulating the stability and subsequent activity of a large number of important proteins responsible for the development and ...progression of various diseases, including autoimmune diseases (AIDs). However, the detailed mechanisms of the pathogenesis of AIDs are complicated and involve multiple signaling pathways. An in-depth understanding of the underlying regulatory mechanisms of the initiation and progression of AIDs will aid in the development of effective therapeutic strategies. CRLs play critical roles in regulating AIDs, partially by affecting the key inflammation-associated pathways such as NF-κB, JAK/STAT, and TGF-β. In this review, we summarize and discuss the potential roles of CRLs in the inflammatory signaling pathways and pathogenesis of AIDs. Furthermore, advances in the development of novel therapeutic strategies for AIDs through targeting CRLs are also highlighted.
We have previously proven that human macrophages can phagocytose porcine cells even in the absence of Ab or complement opsonization, indicating that macrophages present a pivotal immunological ...obstacle to xenotransplantation. A recent report indicates that the signal regulatory protein (SIRP)α is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPα, prevents autologous phagocytosis. Considering the limited compatibility (73%) in amino acid sequences between pig and human CD47, we hypothesized that the interspecies incompatibility of CD47 may contribute to the rejection of xenogeneic cells by macrophages. In the present study, we have demonstrated that porcine CD47 does not induce SIRPα tyrosine phosphorylation in human macrophage-like cell line, and soluble human CD47-Fc fusion protein inhibits the phagocytic activity of human macrophages toward porcine cells. In addition, we have verified that manipulation of porcine cells for expression of human CD47 radically reduces the susceptibility of the cells to phagocytosis by human macrophages. These results indicate that the interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRPα on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection.
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