Archivum Immunologiae et Therapiae Experimentalis最新文献

In particular conditions, inhibition of an immune response is required to prevent tissue damage. Among these conditions are diseases caused by an over-reactive immune response, such as autoimmune or allergic disorders, or imminent organ rejection after transplantation. To avoid tissue damage, drug-mediated systemic immune suppression is an option, but it comes with high costs in the form of susceptibility to viral and bacterial infections. Thus, the induction of antigen-specific tolerance is preferable. Extracellular vesicles (EVs) are capable of delivering antigen together with immunosuppressive signals and may be used to specifically induce antigen-specific tolerance. However, naturally occurring EVs are heterogeneous and not all of them show immunosuppressive character. In our trials to engineer cell culture derived EVs to increase their tolerogenic potential, we equipped them with immunosuppressive miRNA mimics. Small EVs (sEVs) were isolated and purified from the human monocytic THP-1 cell line or from healthy donor peripheral blood mononuclear cells, and electroporated with miR-494 and miR-146a mimics. The acquired immunosuppressive potential of the modified sEVs was demonstrated by their ability to alter the major histocompatibility complex molecules and co-stimulatory receptors present on dendritic cells (DCs). To avoid allogeneic responses, the same cells that produced the sEVs served also as recipient cells. In contrast to the treatment with unmodified sEVs, the tolerogenic sEVs impeded lipopolysaccharide-induced maturation and kept DCs in a more immature developmental stage. Our experiments show that simple manipulations of sEVs using immunosuppressive cargo can lead to the inhibition of DC maturation.

Recent decades have shed a new light on the pathomechanism of periodontal inflammation. While classic periodontology concentrates on biofilm control, oral hygiene improvement, professional tooth cleaning and surgical correction of damaged periodontal tissues, new aspects of the destruction mechanisms are being raised. Among them, the greatest attention is paid to the influence of host response on the clinical manifestations of the disease. Numerous studies have proved that the shift from gingivitis to periodontitis is not a simple progress of the disease, but an event occurring only in susceptible individuals. Susceptibility may result from appearance of local factors facilitating biofilm accumulation and/or maturation, or from systemic features, among which over-reaction and prolonged agitation of non-specific component of inflammatory response is crucial. The present paper summarizes the association between periodontology and immunology and updates the knowledge accrued mostly in the recent years. After a brief explanation of advances in understanding of the disease aetiology, the most studied and potentially viable immunological markers of periodontal disease are presented. Possible new therapeutic strategies, exploiting knowledge about the nature of host response—immunomodulation and reduction of chronic oxidative stress—are also presented.

Interleukin (IL)-35 plays an immunosuppressive role in infectious diseases, autoimmune disorders, and cancers. However, IL-35 expression and its regulation of CD8⁺ T cells in infectious mononucleosis (IM) are not fully understood. In this study, three groups of participants were compared, including twenty-three patients of IM without liver inflammation, twenty-eight patients of IM with liver inflammation, and twenty-one controls. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated. CD8⁺ T cells were purified. Plasma IL-35 was measured by ELISA. PBMCs and CD8⁺ T cells were stimulated with recombinant human IL-35 in vitro. Perforin and granzyme B secretion was assessed by ELISPOT. Immune checkpoint molecule expression was investigated by flow cytometry. CD8⁺ T cells were co-cultured with HepG2 cells in direct contact and indirect contact manner. The cytotoxicity of CD8⁺ T cells was calculated by measuring lactate dehydrogenase release and proinflammatory cytokine expression. There was no significant difference in plasma IL-35 levels between patients with IM without liver inflammation and the controls, but the IL-35 level was notably increased in patients with IM who presented with liver inflammation and negatively correlated with aminotransferase. CD8⁺ T cells in patients with IM with liver inflammation showed stronger cytotoxicity. IL-35 stimulation inhibited CD8⁺ T cell-induced target cell death in patients with IM, mainly through suppression of IFN-γ/TNF-α secretion and elevation of immune checkpoint molecule expression, but did not affect perforin or granzyme B secretion. The current data indicated that IL-35 dampened the cytotoxicity of CD8⁺ T cells in patients with IM probably via repression of cytokine secretion. Elevated IL-35 may protect against CD8⁺ T cell-induced liver inflammation in patients with IM.

Humans are exposed to a number of environmental pollutants every day. Among them, endocrine disruptors are particularly harmful to human health. Bisphenol A (BPA) is a xenoestrogen that has been shown to disrupt the endocrine system and cause reproductive toxicity. In this study, we aimed to verify the potential relationship between BPA and miscarriage involving the formation of neutrophil extracellular traps (NETs). Blood samples were collected from healthy women and women who had miscarriage in the first trimester of pregnancy. The serum levels of cytoplasmic anti-PR3 antibody and perinuclear anti-MPO antibody were determined using an immunoenzymatic method. The concentrations of key proinflammatory proteins TNF-α and MCP-1, as well as NADPH oxidase subunits NOX1 and NCF2, were also measured in the serum samples. The serum concentration of BPA was determined using gas chromatography. The results showed that the concentrations of BPA were significantly elevated in the serum of women who had miscarriage compared to the control group, with the highest concentration found in the “NETs-positive” group. The levels of MCP-1 and TNF-α were significantly higher in the “NETs-positive” group compared to the “NETs-negative” and control group. The levels of NOX1 and NCF2 were also higher in the “NETs-positive” group compared to the “NETs-negative” group. The study showed that BPA could play a role in the course of miscarriage through the formation of NETs. The results indicate the need to limit the exposure of women planning pregnancy to xenoestrogens, including BPA.

Angiotensin II type 1 receptor (AT1R) antibodies are considered non-HLA (human leukocyte antigen) antibodies connected with humoral rejection after kidney transplantation. The role of AT1R antibodies in the pathogenesis of glomerular diseases and systemic vasculitis is unknown. We assessed the level of AT1R antibodies in 136 patients with different types of glomerulonephritis and systemic vasculitis and we observed kidney function and proteinuria, serum albumin and total protein levels for 2 years. The mean levels of AT1R antibodies were the following: 6.00 ± 1.31 U/ml in patients with membranous nephropathy (n = 18), 5.67 ± 1.31 U/ml with focal and segmental glomerulosclerosis (n = 25), 6.26 ± 2.25 U/ml with lupus nephropathy (n = 17), 10.60 ± 6.72 U/ml with IgA nephropathy (n = 14), 6.69 ± 2.52 U/ml with mesangial proliferative (non IgA) glomerulonephritis (n = 6), 6.63 ± 1.38 U/ml with systemic vasculitis (n = 56), including c-ANCA (anti-neutrophil cytoplasmic antibodies) vasculitis: 11.22 ± 10.78 U/ml (n = 40) and p-ANCA vasculitis: 12.65 ± 14.59 U/ml (n = 16). The mean AT1R antibodies level was higher in patients with lupus nephropathy and systemic vasculitis compared to glomerulonephritis groups. An inverse statistically significant correlation between AT1R antibodies and serum albumin (r =  − 0.51) in membranous nephropathy group was also found. Prospective analysis of creatinine levels indicated an increase of creatinine levels during time among patients with higher AT1R antibodies levels in p-ANCA vasculitis. Lupus nephropathy and systemic vasculitis patients may have high levels of AT1R antibodies. AT1R antibodies may be associated with the severity of membranous nephropathy and the course of p-ANCA vasculitis, although influence of concomitant factors is difficult to exclude.

BAFF system plays an essential role in B cells homeostasis and tolerance, although it has widely not been tested in transplantation with doubtful results. The main purpose was to study the BAFF soluble forms and their correlation with acute rejection (AR) and donor-specific antibodies production. Serum levels of BAFF, APRIL, and soluble forms of their receptors were analyzed in renal recipients with and without acute rejection (AR/NAR) appearance. All molecules were evaluated at pre- and post-transplantation. sTACI showed a significant correlation with BAFF and sR-BAFF levels, and sBCMA also showed a positive correlation with sAPRIL levels. A significant increase in sAPRIL levels in patients suffering AR was also found, and ROC curves analysis showed an AUC = 0.724, a concentration of 6.05 ng/ml (sensitivity: 66.7%; specificity: 73.3%), the best cutoff point for predicting AR. In the post-transplant dynamics of sAPRIL levels in the longitudinal cohort, we observed a significant decrease at 3 and 6 month post-transplantation compared to pretransplantation status. We also observed that recipients with high pre-transplant levels of sAPRIL generated antibodies earlier than those with lower sAPRIL levels, although their long-term post-transplantation was not different. Our results show that elevated serum levels of APRIL may be helpful as a biomarker for the diagnosis of AR, although the longitudinal study shows that it is not helpful as a prognostic biomarker.

Duchenne muscular dystrophy (DMD) is a lethal disease caused by X-linked mutations in the dystrophin gene. Dystrophin deficiency results in progressive degeneration of cardiac, respiratory and skeletal muscles leading to premature death due to cardiopulmonary complications. Currently, no cure exists for DMD. Based on our previous reports confirming a protective effect of human dystrophin expressing chimeric (DEC) cell therapy on cardiac, respiratory, and skeletal muscle function after intraosseous administration, now we assessed long-term safety and biodistribution of human DEC therapy for potential clinical applications in DMD patients. Safety of different DEC doses (1 × 10⁶ and 5 × 10⁶) was assessed at 180 days after systemic-intraosseous administration to mdx/scid mice, a model of DMD. Assessments included: single cell gel electrophoresis assay (COMET assay) to confirm lack of genetic toxicology, magnetic resonance imaging (MRI) for tumorigenicity, and body, muscle and organ weights. Human DEC biodistribution to the target (heart, diaphragm, gastrocnemius muscle) and non-target (blood, bone marrow, lung, liver, spleen) organs was detected by flow cytometry assessment of HLA-ABC markers. Human origin of dystrophin was verified by co-localization of dystrophin and human spectrin by immunofluorescence. No complications were observed after intraosseous transplant of human DEC. COMET assay of donors and fused DEC cells confirmed lack of DNA damage. Biodistribution analysis of HLA-ABC expression revealed dose-dependent presence of human DEC cells in target organs, whereas negligible presence was detected in non-target organs. Human origin of dystrophin in the heart, diaphragm and gastrocnemius muscle was confirmed by co-localization of dystrophin expression with human spectrin. MRI revealed no evidence of tumor formation. Body mass and muscle and organ weights were stable and comparable to vehicle controls, further confirming DEC safety at 180 days post- transplant. This preclinical study confirmed long-term local and systemic safety of human DEC therapy at 180 days after intraosseous administration. Thus, DEC can be considered as a novel myoblast based advanced therapy medicinal product for DMD patients.

Despite advances in surgery and chemotherapy, ovarian cancer remains one of the most lethal malignancies. Hence, the implementation of novel treatment approaches is required to improve the outcomes of the disease. Immunotherapy has been proven to be effective in many tumors and has already been incorporated into clinical practice. In this review, we describe key strategies in immunotherapy of ovarian cancer and summarize data from clinical studies assessing immunological prospects which could improve ovarian cancer treatment approaches in the future. The most notable current strategies include checkpoint blockade agents, the use of vaccines, adoptive cell transfer, as well as various combinations of these methods. While several of these options are promising, large controlled randomized studies are still needed to implement new immunotherapeutic options into clinical practice.

To evaluate soluble CD147 levels in COVID-19 and identify whether these are associated with hyperinflammation and disease severity. One-hundred and nine COVID-19 patients and 72 healthy blood donors were studied. Levels of CD147, matrix metalloproteases (MMP) and inflammatory markers were measured on hospital arrival, while the need for mechanical ventilation and the occurrence of death during hospitalization were recorded. CD147 levels were higher in COVID-19 (1.6, 1.0–2.3 vs 1.3, 1.0–1.6 ng/ml; P = 0.003) than controls. MMP-2 (9.2, 4.5–12.9 vs 4.2, 3.7–4.6 ng/ml; P < 0.001), MMP-3 (1.1, 0.9–1.3 vs 0.9, 0.7–1.0 ng/ml; P < 0.001) and MMP-9 (0.9, 0.5–1.2 vs 0.4, 0.2–0.6 ng/ml; P < 0.001) were also higher in COVID-19, while MMP-1 (0.6, 0–1.4 vs 0.6, 0.3–0.7 ng/ml; P = 0.711) was not different. Significant correlations were found between CD147 and MMP-2 (ρ = 0.34), MMP-3 (ρ = 0.21), interleukin 6 (ρ = 0.21), and the neutrophil/lymphocyte ratio (ρ = 0.26). Furthermore, CD147 levels were higher in patients who required mechanical ventilation (1.8, 1.4–2.4 vs 1.2, 0.8–1.9 ng/ml; P < 0.001) and in those who ultimately died (1.9, 1.4–2.7 vs 1.4, 0.9–1.9 ng/ml; P = 0.009). CD147 is elevated in COVID-19 and appears to contribute to hyperinflammation and disease severity.