Cancer cells are poorly immunogenic and have a wide range of mutations, which makes them unsuitable for use in vaccination treatment. Here, we show that elimination of CD47, a ligand for the myeloid ...cell inhibitory receptor SIRPα, from tumor cells by genetic deletion or antibody blocking, significantly improves the effectiveness of the immune response to tumour cells. In both solid and hematopoietic mouse tumor models, vaccination with tumor cells or tumor antigen-expressing cells, that lack CD47 or were pre-coated with anti-CD47 antibodies, achieved an antitumor immune response. The efficacy of this approach was synergistically enhanced when used in combination with anti-PD-1 antibodies. The induction of antitumor responses depends on SIRPα
CD11c
DCs, which exhibit rapid expansion following introduction of CD47-deficient tumor cells. Our results indicate that CD47-deficient whole tumor cells can induce antitumor responses.
CXCR4 is expressed on leukaemia cells and haematopoietic stem cells (HSCs), and its ligand stromal‐derived factor 1 (SDF‐1) is produced abundantly by stromal cells in the bone marrow (BM). The ...SDF‐1/CXCR4 axis plays important roles in homing to and retention in the protective BM microenvironment of malignant leukaemia cells and normal HSCs. CXCR4 expression is regulated by multiple mechanisms and the level of CXCR4 expression on leukaemia cells has prognostic indications in patients with acute leukaemia. CXCR4 antagonists can mobilize leukaemia cells from BM to circulation, which render them effectively eradicated by chemotherapeutic agents, small molecular inhibitors or hypomethylating agents. Therefore, such combinational therapies have been tested in clinical trials. However, new evidence emerged that drug‐resistant leukaemia cells were not affected by CXCR4 antagonists, and the migration of certain leukaemia cells to the leukaemia niche was independent of SDF‐1/CXCR4 axis. In this review, we summarize the role of CXCR4 in progression and treatment of acute leukaemia, with a focus on the potential of CXCR4 as a therapeutic target for acute leukaemia. We also discuss the potential value of using CXCR4 antagonists as chemosensitizer for conditioning regimens and immunosensitizer for graft‐vs‐leukaemia effects of allogeneic haematopoietic stem cell transplantation.
CXCR4 is expressed on leukaemia cells and its ligand stromal‐derived factor 1 (SDF‐1) is produced by stromal cells in the bone marrow. The SDF‐1/CXCR4 axis plays an important role in homing to and retention in bone marrow of leukaemia cells. During the last three decades, CXCR4 has been studied as a potential target for treatment of acute leukaemia.
CD47 serves as a ligand for signaling regulatory protein α (SIRPα) and as a receptor for thrombospondin‐1 (TSP‐1). Although CD47, TSP‐1, and SIRPα are thought to be involved in the clearance of aged ...red blood cells (RBCs), aging‐associated changes in the expression and interaction of these molecules on RBCs have been elusive. Using direct stochastic optical reconstruction microscopy (dSTORM)‐based imaging and quantitative analysis, we can report that CD47 molecules on young RBCs reside as nanoclusters with little binding to TSP‐1, suggesting a minimal role for TSP‐1/CD47 signaling in normal RBCs. On aged RBCs, CD47 molecules decreased in number but formed bigger and denser clusters, with increased ability to bind TSP‐1. Exposure of aged RBCs to TSP‐1 resulted in a further increase in the size of CD47 clusters via a lipid raft‐dependent mechanism. Furthermore, CD47 cluster formation was dramatically inhibited on thbs1−/− mouse RBCs and associated with a significantly prolonged RBC lifespan. These results indicate that the strength of CD47 binding to its ligand TSP‐1 is predominantly determined by the distribution pattern and not the amount of CD47 molecules on RBCs, and offer direct evidence for the role of TSP‐1 in phagocytosis of aged RBCs. This study provides clear nanoscale pictures of aging‐associated changes in CD47 distribution and TSP‐1/CD47 interaction on the cell surface, and insights into the molecular basis for how these molecules coordinate to remove aged RBCs.
On young RBCs (Top), CD47 molecules reside as nanoclusters with minimal binding to TSP‐1 trimmers. On aged RBCs (Bottom), CD47 proteins form bigger and denser clusters and gain increased ability to bind TSP‐1, thus promoting phagocytosis of aged RBCs.
Thrombospondin‐1 (TSP‐1) is a key mediator of renal ischemia‐reperfusion injury (IRI), a major cause of kidney dysfunction under various disease conditions and a risk factor of renal allograft ...rejection. In this study, we developed a nanotechnology‐based therapy targeting TSP‐1 to prevent renal IRI. A biocompatible nanoparticle (NP) capable of specific binding to TSP‐1 was prepared by conjugating NPs with TSP‐1‐binding (LSKL) peptides. LSKL/NPs not only effectively adsorbed recombinant TSP‐1 proteins in vitro, but also efficiently neutralized TSP‐1 in mice undergoing renal IRI. IRI‐induced elevation of TSP‐1 in the kidney was significantly inhibited by post‐IR treatment with LSKL/NPs, but not free LSKL or NPs. Furthermore, TSP‐1 proteins adsorbed on LSKL/NPs were functionally inactive and unable to induce apoptosis in renal tubular epithelial cells. Importantly, LSKL/NPs induced strong protection against renal IRI, as shown by markedly diminished serum creatinine levels and improved histological lesions of the kidney. Thus, LSKL/NPs provide a useful means of depleting and inactivating TSP‐1 and a potential therapy for renal IRI.
In mice, biocompatible nanoparticles targeting thrombospondin‐1 prevent renal ischemia reperfusion injury and improve renal function and histology.
Xenotransplantation using pigs as the transplant source has the potential to resolve the severe shortage of human organ donors. Although the development of relatively non-toxic immunosuppressive or ...tolerance-inducing regimens will be required to justify clinical trials using pig organs, recent advances in our understanding of the biology of xenograft rejection and zoonotic infections, and the generation of alpha1,3-galactosyltransferase-deficient pigs have moved this approach closer to clinical application. This Review highlights the major obstacles impeding the translation of xenotransplantation into clinical therapies and the potential solutions, providing a perspective on the future of clinical xenotransplantation.
The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) would have applications in regenerative medicine, modeling of lung disease, drug screening and ...studies of human lung development. We have established, based on developmental paradigms, a highly efficient method for directed differentiation of hPSCs into lung and airway epithelial cells. Long-term differentiation of hPSCs in vivo and in vitro yielded basal, goblet, Clara, ciliated, type I and type II alveolar epithelial cells. The type II alveolar epithelial cells were capable of surfactant protein-B uptake and stimulated surfactant release, providing evidence of specific function. Inhibiting or removing retinoic acid, Wnt and BMP-agonists to signaling pathways critical for early lung development in the mouse-recapitulated defects in corresponding genetic mouse knockouts. As this protocol generates most cell types of the respiratory system, it may be useful for deriving patient-specific therapeutic cells.
There is an urgent need for animal models of coronavirus disease 2019 to study immunopathogenesis and test therapeutic intervenes. In this study, we showed that NOD/SCID IL2rg–/– (NSG) mice engrafted ...with human lung (HL) tissue (NSG‐L mice) could be infected efficiently by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), and that live virus capable of infecting Vero cells was found in the HL grafts and multiple organs from infected NSG‐L mice. RNA‐Sequencing identified a series of differentially expressed genes, which are enriched in viral defense responses, chemotaxis, IFN stimulation and pulmonary fibrosis, between HL grafts from infected and control NSG‐L mice. Furthermore, when infected with SARS‐CoV‐2, humanized mice with both human immune system (HIS) and autologous HL grafts (HISL mice) had bodyweight loss and hemorrhage and immune cell infiltration in HL grafts, which were not observed in immunodeficient NSG‐L mice, indicating the development of anti‐viral immune responses in these mice. In support of this possibility, the infected HISL mice showed bodyweight recovery and lack of detectable live virus at the later time. These results demonstrate that NSG‐L and HISL mice are susceptible to SARS‐CoV‐2 infection, offering a useful in vivo model for studying SARS‐CoV‐2 infection and the associated immune response and immunopathology, and testing anti‐SARS‐CoV‐2 therapies.
We established a humanized mouse model carrying human lung tissue and autologous immune system. We found that these humanized mice are susceptible to infection by SARS‐CoV‐2 and develop disease‐associated lung injury, offering a convenient and useful animal model to investigate COVID‐19 pathogenesis and test anti‐SARS‐CoV‐2 interventions.
Polysaccharides were extracted from jujube fruit using an efficient, optimized subcritical water extraction process. A maximum crude polysaccharide yield of 7.9% was obtained at an extraction ...temperature of 140 °C and a time of 60 min. The crude polysaccharides extracted under these conditions were purified. Three polysaccharide fractions, ZP1, ZP2 and ZP3, were obtained and their structures were investigated. The three fractions were mainly composed of arabinose, galactose, glucose, mannose, rhamnose, and galacturonic acid. ZP3 was further investigated using methylation and NMR spectroscopy, and ZP3 comprised a main chain of (1 → 4)-α-D-GalAp, (1 → 2,4)-α-L-Rhap, with a (1 → 4,6)-α-D-Galp branch. Assays of antioxidant activity showed that ZP3 exhibited a remarkable DPPH capacity and moderate hydroxyl radical scavenging ability, suggesting that it has potential applications as a natural antioxidant in foods and pharmaceuticals.
•Subcritical water was used for polysaccharides extraction from Jujube.•Three polysaccharide fractions were isolated by anion-exchange chromatography.•The structural features and bioactivities were investigated.•Among those, ZP3 fraction showed strong scavenging activities on DPPH.
Expansion of myeloid-derived suppressor cells (MDSCs) has been documented in some murine models and patients with autoimmune diseases, but the exact role of MDSCs in this process remains largely ...unknown. The current study investigates this question in patients with systemic lupus erythematosus (SLE). Patients with active SLE showed a significant increase in HLA-DR(-)CD11b(+)CD33(+)MDSCs, including both CD14(+)CD66b(-)monocytic and CD14(-)CD66b(+)granulocytic MDSCs, in the peripheral blood compared to healthy controls (HCs). The frequency of MDSCs was positively correlated with the levels of serum arginase-1 (Arg-1) activity, T helper 17 (TH17) responses, and disease severity in SLE patients. Consistently, in comparison with MDSCs from HCs, MDSCs from SLE patients exhibited significantly elevated Arg-1 production and increased potential to promote TH17 differentiation in vitro in an Arg-1-dependent manner. Moreover, in a humanized SLE model, MDSCs were essential for the induction of TH17 responses and the associated renal injuries, and the effect of MDSCs was Arg-1-dependent. Our data provide direct evidence demonstrating a pathogenic role for MDSCs in human SLE. This study also provides a molecular mechanism of the pathogenesis of SLE by demonstrating an Arg-1-dependent effect of MDSCs in the development of TH17 cell-associated autoimmunity, and suggests that targeting MDSCs or Arg-1 may offer potential therapeutic strategies for the treatment of SLE and other TH17 cell-mediated autoimmune diseases.
Human embryonic stem cells (hESCs) hold great promise for cell therapy as a source of diverse differentiated cell types. One key bottleneck to realizing such potential is allogenic immune rejection ...of hESC-derived cells by recipients. Here, we optimized humanized mice (Hu-mice) reconstituted with a functional human immune system that mounts a vigorous rejection of hESCs and their derivatives. We established knockin hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, denoted CP hESCs. We then demonstrated that allogenic CP hESC-derived teratomas, fibroblasts, and cardiomyocytes are immune protected in Hu-mice, while cells derived from parental hESCs are effectively rejected. Expression of both CTLA4-Ig, which disrupts T cell costimulatory pathways, and PD-L1, which activates T cell inhibitory pathway, is required to confer immune protection, as neither was sufficient on their own. These findings are instrumental for developing a strategy to protect hESC-derived cells from allogenic immune responses without requiring systemic immune suppression.
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•Optimized Hu-mice for studying human immune responses to hESC-derived allografts•CTLA4-Ig/PD-L1 were knocked into hESCs and provided localized immune protection•Allografts from modified hESCs did not induce systemic immunosuppression•CTLA4-Ig and PD-L1 are both required for immune protection of allografts
A strategy for localized immune suppression developed by Rong et al. protects hESC-derived cells from an allogenic immune response in an optimized humanized mouse model, without inducing systemic immune suppression.
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