Archivum Immunologiae et Therapiae Experimentalis最新文献

Sole nanomaterials or nanomaterials bound to specific biomolecules have been proposed to regulate the immune system. These materials have now emerged as new tools for eliciting immune-based therapies to treat various cancers. Graphene, graphene oxide (GO) and reduced GO (rGO) are the latest nanomaterials among other carbon nanotubes that have attracted wide interest among medical industry players due to their extraordinary properties, inert-state, non-toxic and stable dispersion in a various solvent. Currently, GO and rGO are utilized in various biomedical application including cancer immunotherapy. This review will highlight studies that have been carried out in elucidating the stimulation of GO and rGO on selected innate and adaptive immune cells and their effect on cancer progression to shed some insights for researchers in the development of various GO- and rGO-based immune therapies against various cancers.

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by dysfunction of immune regulation, overproduction of inflammatory cytokines and attack on normal tissues by self-reactive cells and antibodies. The main role in the pathogenesis plays the autoreactive tandem of B-T cells, responsible for lupus progression and acceleration. Both activated B and T cells express a phospholipid binding protein Annexin A1 and abnormal levels of the protein were found in murine and human autoimmune syndromes, potentiating its role as a therapeutic target. Here, using anti-annexin A1 antibody we explore its property to modulate the autoimmune response in MRL/lpr mouse model of lupus. Anti-ANX A1 antibody was tested in vitro using spleen cells from MRL/lpr mice to determine the effect on lymphocyte activation, plasma cells differentiation, apoptosis and proliferation by flow cytometry and ELISpot assays. Subsequently, several groups of young (disease-free) and old (sick) MRL/lpr mice were treated with the antibody to determine the levels of panel auto-antibodies and cytokines, T cell arrest and migration. Treatment of splenocytes with anti-ANX A1 antibody inhibited T-cell activation and proliferation, suppressed anti-dsDNA antibody-producing plasma cells and affected B cell apoptosis. Administration of the antibody to MRL/lpr mice resulted to decreased autoantibody levels to various lupus antigens, suppressed T cell migration from lymph nodes and increased the levels of IL4 mRNA compared to the control group. Anti-ANX A1 antibody therapy suppresses B and T cell over-activation and down- modulates disease activity.

The role of γδT cells in ulcerative colitis (UC) is well confirmed in experimental animals and demonstrated in many clinical observations. Recent investigations have indicated that UC is associated with several forms of immune imbalance, such as an imbalance between effector T cells and regulatory T cells. However, little is known about the cellular aspect of clinical colitis exacerbations. We observed 140 patients with histologically confirmed UC over the course of 8 years. We investigated the percentage of γδT and αβT cells in peripheral blood of patients and also the expression of various surface markers (CD25, CD54, CD62L). Patients were assembled into stable colitis and exacerbated colitis groups. The percentage of γδT and αβT cells was evaluated by Ortho Cytorone Absolute flow cytometer. In patients with exacerbated colitis we observed a decrease of γδT cells in peripheral blood and an increased ratio of αβT/γδT. Additionally, we found that exacerbation results in a significant increase of percentage of γδTCD25, γδTCD54 and γδTCD62L lymphocytes in peripheral blood when compared to patients with stable colitis. Exacerbation of ulcerative colitis results in a decreased percentage of γδT cells in peripheral blood with increase of CD25, CD54 and CD62L expressing γδT cells. This may represent the effect of cell activation and migration, similar to that observed after the surgical trauma. We hope that this observation may help to predict exacerbations in colitis patients.

Experimental allergic encephalomyelitis (EAE) is the animal model of multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (AHSCT) has recently been recognized as the standard treatment for MS. The aim of our experiment was to investigate the effect of AHSCT with the addition of low-dose post-transplantation cyclophosphamide (Cy) on EAE in rats. Low dose post-transplantation Cy is used in haploidentical HSCT to reduce the risk of graft versus host disease. We hypothesized that it could bring additional benefit in autologous HSCT in autoimmune diseases. Rats with evoked EAE were treated with high dose (125 mg/kg) Cy, followed by AHSCT or high dose (125 mg/kg) Cy followed by AHSCT followed by low dose (20 mg/kg) Cy in two-time schedules—with the therapy applied during the pre-symptomatic or symptomatic phase of the disease. Both AHSCT and AHSCT with post-transplantation Cy in accordance with both time schedules reduce the intensity of the inflammatory response in the CNS, in comparison with non-treated EAE rats. The reduction of clinical symptoms was present in all AHSCT treatment protocols, however, it was significantly stronger when post-transplantation Cy was given during the symptomatic phase of the disease. AHSCT with the addition of post HSCT low dose Cy improved the results of AHSCT by not only reducing the intensity of inflammation in the CNS but also by significantly reducing the clinical symptoms in treated animals when compared to AHSCT alone. We provide an experimental rationale that the addition of post-transplantation Cy may improve the outcome of HSCT in MS.

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Breast cancer is the leading cause of women’s death among all cancers. The main reason associated with this is the development of metastasis and therapy-resistant breast carcinoma (BC), which pose the main challenge of oncology nowadays. Evidence suggest that these tumors seem to have inhibitory mechanisms that may favor their progression and surveillance. Cancer cells can evade antitumor T cell responses by expressing some immune inhibitory molecules such as the cytotoxic T-lymphocyte antigen-4 (CTLA-4), whose clinical meaning has emerged in the last few years and is poorly understood in the BC context. This systematic literature review aims at identifying studies on CTLA-4 expression in BC, and address what is known about its clinical meaning. A literature search was performed in PubMed and LILACS databases, using the MESH terms “breast cancer”; “CTLA-4 Antigen/antagonists and inhibitors”; and “Lymphocytes, Tumor-Infiltrating/immunology”, published in the last 10 years. In total, 12 studies were included in this review. Systematic review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Despite the small number of eligible studies, the literature reports some associations between CTLA-4 expression in the tumor microenvironment and worse BC outcomes, regardless of its molecular subtype. CTLA-4 expression in BC is a putative marker of clinical significance and a rationale therapeutic target in the emerging field of immunotherapy.

Organ transplantation represents the optimal therapeutic tool for patients with end-stage organ failure. Hematopoietic stem cell transplantation (HSCT) is likewise an effective therapy for a wide range of malignant and non-malignant diseases. Better understanding of transplantation immunology and the use of multi-modal immunosuppression protocols, can decrease the risk of graft failure and graft-versus-host disease (GVHD) after HSCT. Nevertheless, a major challenge of modern transplantology still seems to be finding non-invasive biomarkers for recipients selection, monitoring of allograft function, and diagnosis of rejection. Since proinflammatory cytokine osteopontin (OPN) is closely involved in regulating both adaptive and innate immune responses, as well as the pathogenesis of inflammatory and autoimmune diseases, it is likely to play an important role in organ and HSC transplantation. This review is to summarize recent advances in our knowledge about OPN function in the kidney, heart, liver, lung, and HSC transplantation. Most studies found that elevated OPN is associated with poorer graft function in kidney, heart, liver and lung recipients. Moreover, some reports suggested that this protein can play role in GVHD pathogenesis. However, due to relatively small number of similar studies, as well as some inconclusive results, future investigation in this field is needed to verify if OPN can serve as a biomarker of organ and HSC transplantation. The knowledge about such markers will promote our understanding of the mechanisms underlying graft dysfunction and posttransplant mortality. In addition, such knowledge may be helpful in the development of new treatment strategies and identification of recipients with increased risk of allograft failure.

The effects of HIV infection and antiretroviral therapy (ART) on the gut microbiome are poorly understood and the literature data are inconsistent. The aim of this study was to assess the alpha and beta diversity of the fecal microbiota in HIV-infected patients on successful antiretroviral therapy with regard to sexual preferences and CD4 nadir. Thirty-six HIV-infected ART-treated patients with HIV viremia below 20 copies/ml and CD4 > 500 cells/μl were divided into two subgroups based on CD4 nadir. The composition of the intestinal microbiota was assessed by 16SrRNA sequencing (MiSeq Illumina). The alpha and beta diversity were analyzed according to CD4 nadir count and sexual preference. Several alpha diversity indexes were significantly higher in the MSM group than in heterosexual patients. The alpha diversity did not differ significantly between patients with CD4 nadir > 500 cells/μl and CD4 nadir < 200 cells/μl. Beta diversity was also associated with sexual preference. A significant difference in Weighted Unifrac was observed between all MSM and all non-MSM participants (p = 0.001). The MSM group was more diverse and demonstrated greater distances in Weighted Unifrac than the non-MSM group. The relative abundance of the Prevotella enterotype was higher in the MSM than the non-MSM group. Sexual preferences demonstrated a stronger influence on alpha and beta diversity in HIV-infected patients following successful antiretroviral treatment than HIV infection itself. The observed lack of association between CD4 nadir and alpha and beta diversity may be caused by the restoration of the faecal microbiota following antiretroviral treatment.

This study evaluated the efficacy of donor recipient chimeric cell (DRCC) therapy created by fusion of donor and recipient derived bone marrow cells (BMC) in chimerism and tolerance induction in a rat vascularized composite allograft (VCA) model. Twenty-four VCA (groin flaps) from MHC-mismatched ACI (RT1^a) donors were transplanted to Lewis (RT1^l) recipients. Rats were randomly divided into (n = 6/group): Group 1—untreated controls, Groups 2—7-day immunosuppression controls, Group 3—DRCC, and Group 4—DRCC with 7-day anti-αβTCR monoclonal antibody and cyclosporine A protocol. DRCC created by polyethylene glycol-mediated fusion of ACI and Lewis BMC were cultured and transplanted (2–4 × 10⁶) to VCA recipients via intraosseous delivery route. Flow cytometry assessed peripheral blood chimerism while fluorescent microscopy and PCR tested the presence of DRCC in the recipient’s blood, bone marrow (BM), and lymphoid organs at the study endpoint (VCA rejection). No complications were observed after DRCC intraosseous delivery. Group 4 presented the longest average VCA survival (79.3 ± 30.9 days) followed by Group 2 (53.3 ± 13.6 days), Group 3 (18 ± 7.5 days), and Group 1 (8.5 ± 1 days). The highest chimerism level was detected in Group 4 (57.9 ± 6.2%) at day 7 post-transplant. The chimerism declined at day 21 post-transplant and remained at 10% level during the entire follow-up period. Single dose of DRCC therapy induced long-term multilineage chimerism and extended VCA survival. DRCC introduces a novel concept of customized donor-recipient cell-based therapy supporting solid organ and VCA transplants.

In this communication, we will analyze some important factors and immunological phenomena related to neoantigen cancer vaccines, with particular emphasis on recently published Phase I clinical trials. Several obstacles and issues are addressed that challenge the current paradigm and inquire if neoantigens, which are essentially single-use vaccine candidates, are legitimate targets to induce protective immune responses with regard to the evolving mutational landscape. We also share insights into the striking similarities between cancer and antigenically variable pathogens and suggest that any successful vaccine against either should demonstrate a similar property: efficient induction of a diverse pool of immune cells equipped to prevent immune escape. Hence, to confront antigenic variability directly, we have employed our innovative vaccine concept, Variable Epitope Libraries, composed of large combinatorial libraries of heavily mutated epitopes, as a “universal” vaccine platform. Collectively, we offer critical analyses on key issues, which ultimately reflect on the prospective clinical relevance of personalized neoantigen vaccines which is still undefined.

Visfatin is a multifunctional protein involved in inflammatory immune stress. The aim of current study was to explore the role of visfatin in lipopolysaccharide (LPS)-induced intestinal mucosal inflammation and to confirm its cellular effect in inflammatory immune response through silencing of Toll-like receptors (TLRs). We divided Kunming mice into three groups: Saline group, LPS group, and LPS + visfatin group and performed hematoxylin and eosin staining, immunohistochemistry, quantitative polymerase chain reaction, Western blot, enzyme linked immunosorbent assay and RNA-seq analysis. Pretreatment of visfatin improves LPS-stimulated reduction of tight junction protein 1 (ZO-1) and secretory immunoglobulin A, inhibits overexpression of Claudin-1 and vascular endothelial growth factor, and reduces intestinal mucosal damage and inflammation. RNA-seq analysis of cellular transcriptomes indicated that visfatin is involved in down-regulation of mRNA level of TLR4 as well as attenuation of protein levels of TLR8 and nucleotide-binding oligomerization domain-containing protein 2, revealing that visfatin could reduce intestinal mucosal inflammation through TLR signaling pathway in mice ileum. In RAW264.7 cells, the genes silencing of Toll/IL-1R family, such as TLR4, TLR2, and IL-1R1, was accompanied by decreased expressions of inflammatory factors (TNF-α, IL-1β, IL-6 and MCP-1) along with lower cellular visfatin levels. Hence, visfatin maintains the intestinal mucosal barrier structure and attenuates the intestinal mucosal inflammation through the TLR signaling pathway. Likewise, the Toll/IL-1R family regulates the release of visfatin, which can participate in the inflammatory reaction through the regulation of inflammatory factors.