Larssonmack4289

This review mainly focuses on tumor immune checkpoints, immune checkpoint inhibitors and their application in the treatment of malignant tumors.The innate immune system uses pattern recognition receptors (PRRs) or other molecular receptors to recognize pathogenic microorganisms such as the invading bacteria, and prevents the spread of infection by triggering an inflammatory response, which plays a vital role in antimicrobial defense. Toll-like receptor-4 (TLR4) is the core of innate immune system in mammals and plays a key role in bacterial endotoxin-mediated inflammation. TLR4 recognizes lipopolysaccharide (LPS) on the cell wall of Gram-negative bacteria, thereby activating the TLR4 signaling pathway, releasing pro-inflammatory factors and chemokines, and inducing inflammation. Currently, drugs targeting the TLR4 signaling pathway mainly act on LPS and its receptor LPS binding protein (LBP), CD14, myeloid differentiation protein 2 (MD2), and TLR4, such as lipid A analogs and natural products as well as their derivatives, and natural and synthetic peptides and proteins, etc. They have potential therapeutic effects in the treatment of autoimmune diseases, acute and chronic inflammation, cardiovascular diseases, and neurological diseases.Hypoxia is a key characteristic of solid malignant tumor microenvironment. Exosomes secreted by tumor cells as well as stromal cells are important components of the tumor microenvironment. Hypoxia regulates the formation, contents loading, release and biological functions of exosomes. In the hypoxic microenvironment, tumor cell-derived exosomes can deliver important differentially-expressed molecular cargoes to a variety of immune cells and regulate these cells activity to facilitate the growth of tumors by inducing M2 polarization of macrophages, expansion of regulatory T cells, activation of myeloid-derived suppressor cells, and inhibition of cytotoxicity in natural killer cells. To elucidate the interaction mediated by exosomes between tumor cells and immune cells under hypoxia tumor microenvironment and the underlying mechanisms by which exosomes regulate anti-tumor immunity will provide reference for the application of exosomes in tumor vaccines, anti-cancer drug delivery and combined immunotherapy.Objective To prepare a neutralizing monoclonal antibody (mAb) that can simultaneously block enterovirus 71 (EV71) and coxsackievirus A16 (CV-A16) infections. Methods BALB/c mice were immunized with 163-177 amino acids (SP55) of the C-terminal of EV71 virion particle 1 (VP1) protein, and the mAbs were prepared by hybridoma technology. Neutralization antigenic epitope SP55 of EV71 and the highly homologous CV-A16 VP1 protein C-terminal 163-177 amino acids (PEP55) were applied to detect the mAbs that cross-reacted with EV71 and CV-A16 at the same time, and an in vitro neutralization test was conducted to detect the neutralization effect of EV71 and CV-A16, and to analyze the biological characteristics of the mAb. Results A mAb 6E5 with IgG1 subclass heavy chain and Kappa light chain was prepared, 6E5 mAb can cross-neutralize both EV71 and CV-A16. The mAb 6E5 could neutralize EV71 with a titer of 1128, and CV-A16 with a titer of 132. Conclusion We have prepared a mAb 6E5 with a pan-spectrum neutralizing activity that can neutralize EV71 and CV-A16 at the same time.Objective To detect and analyze the plasma levels and immunoactivities of different forms of circulating-free DNA (cfDNA) in systemic lupus erythematosus (SLE) patients. TGFbeta inhibitor Methods The study enrolled 58 patients with SLE, 66 patients with other autoimmune diseases (non-SLE) and 60 healthy individuals. Total cfDNA, exosome cfDNA and immune complex cfDNA were extracted from the plasma and detected using a fluorescence method. Overall methylation levels of cfDNA were measured. Macrophages and dendritic cells induced in vitro were co-cultured with exosomes or immune complexes derived from SLE patients pre-treated with deoxyribonuclease 1-like 3(DNASE1L3) or immunoglobulin G (IgG) specific degradation enzyme or none. Then, cytokines and cell surface activation markers were detected by the multiple fluorescent microsphere assay. Results Among the three groups, SLE patients had the highest levels of exosomes and immune complex cfDNA, followed by non-SLE patients, and no significant differences were found in the simple o difference in the two types of cells stimulated with exosomes and immune complexes pre-treated with IgG enzymes or none, but an overall downward trend existed indeed. Conclusion Exosomes and immune complex cfDNA increase significantly in the plasma of SLE patients, and they can stimulate strong responses of macrophages and dendritic cells.Objective To investigate the mechanism underlying the immunosuppressive effect and its reverse of γδ1 T cells derived from breast cancer tissues by inducing immunosenescence. Methods After γδ1 T cells isolated from breast cancer tissues were co-cultured with peripheral blood-derived naive CD4+ T cells, the proliferation of treated CD4+ T cells was detected by CCK-8 assay, and the activity of senescence-associated β-galactosidase (SA-β-Gal) in treated CD4+ T cells was detected by SA-β-Gal staining. After the induced senescent CD4+ T cells were co-cultured with the naive CD4+ T cells, the proliferation, apoptosis, activity of the treated CD4+ T cells were examined by CCK-8 assay, flow cytometry and SA-β-Gal staining, respectively; the expression of cell cycle-associated proteins P53, P21 and P16 in the treated CD4+ T cells was detected by Western blot analysis in order to verify the immunosuppressive effect of the senescent CD4+ T cells. The expression levels of inhibitory cytokines interleukin 17D (IL-17D), ILγδ1 T cells from breast cancer tissues. The inhibitory effect of γδ1 T cells on the proliferation of CD4+ T cells could be reduced by anti-IL-17D monoclonal antibody. TLR8 ligand ssRNA40 inhibited the secretion of IL-17D, and then partially reversed the proliferating inhibition on the naive CD4+ T cells and immunosenescent induction by γδ1 T cells. Conclusion The γδ1 T cells derived from breast cancer tissues exert immunosuppressive effect by producing IL-17D to induce the immunosenescence of the naive CD4+ T cells. TLR8 ligand ssRNA40 can partially reduce the level of IL-17D secreted by γδ1 T cells, which can partially reverse the senescence and immunosuppression effect of γδ1 T cells on naive CD4+ T cells.