Δευτέρα, 13 Μαΐου 2019

Archivum Immunologiae et Therapiae Experimentalis

Natural Killer and Natural Killer T Cells in Juvenile Systemic Lupus Erythematosus: Relation to Disease Activity and Progression


The contribution of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, in systemic lupus erythematosus (SLE) is still unclear. Herein, we examined the frequency of peripheral NK cells, CD56dimand CD56bright NK cells, and NKT cells in patients with juvenile SLE and their potential relations to SLE-related clinical and laboratory parameters. The study included 35 SLE children and 20 apparently healthy controls. After baseline clinical and lab work, SLE Disease Activity Index (SLEDAI-2K) and Pediatric Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (Ped-SDI) scores were assessed. The frequency of peripheral NK cells, CD56dim and CD56bright NK cells, and NKT cells was examined using flow cytometry. SLE patients showed significantly lower frequency of NK cells and NKT cells and higher frequency of CD56bright NK cells compared to controls. Disease activity, urea, and creatinine correlated negatively with NK, but positively with CD56bright NK cells. NK and NKT cells exhibited inverse correlation with the renal biopsy activity index; however, CD56bright NK cells showed direct correlations with both activity and chronicity indices. Regarding Ped-SDI, renal, neuropsychiatry disorders, and growth failure correlated inversely with NK but directly with CD56bright NK cells. NKT cell inversely correlated with renal damage and delayed puberty. In conclusion, low frequency of NK and NKT and expansion of CD56bright NK cells are marked in juvenile SLE, particularly with activity. These changes have direct effect on renal impairment and growth failure, reflecting their potential influence on disease progression.

Heterogeneous Mixture of Amniotic Cells is Likely a Better Source of Stem Cells than Adipose Tissue


Stem cells are increasingly being used in the course of burn treatment. As several different types of stem cells are available for the purposes, it is important to chose the most efficient and the most practicable stem cell type. The aim of this study was to compare the potential of heterogeneous amnion cell mixture with the presently used standard therapy, the adipose tissue-derived stem cells. The placenta was collected during a Cesarean section procedure. Adipose tissue tissue-derived cells were isolated using the Cytori's Celution® System. Cells were tested for fulfillment of the minimum criteria for stem cells. The efficiency of cell cultures was tested by an analysis of population doubling, cell proliferation, cell cycle and cell migration. Amniotic cells presented a higher ability for differentiation to chondrocytes and osteocytes than adipose-derived regenerative cells but a lower ability for differentiation toward adipocytes. Additionally, in vitro experiments have demonstrated a higher applicability of amniotic cells than adipose tissue-derived stem cells. Amniotic cells show several advantages: easy access to placenta, low costs and a lack of ethical dilemmas related to stem cell harvesting. The main disadvantage is, however, their availability, as isogenic treatment would only be possible for women around children-bearing age, unless personalized banks for amniotic cells would be established.

Significance and Role of Pattern Recognition Receptors in Malignancy


Pattern recognition receptors (PRRs) are members of innate immunity, playing pivotal role in several immunological reactions. They are known to act as a bridge between innate and adaptive immunity. They are expressed on several normal cell types but have been shown with increasing frequency on/in tumor cells. Significance of this phenomenon is largely unknown, but it has been shown by several authors that they, predominantly Toll-like receptors (TLRs), act in the interest of tumor, by promotion of its growth and spreading. Preparation of artificial of TLRs ligands (agonists) paved the way to use them as a therapeutic agents for cancer, so far in a limited scale. Agonists may be combined with conventional anti-cancer modalities with apparently promising results. PRRs recognizing nucleic acids such as RIG-1 like receptors (sensing RNA) and STING (sensing DNA) constitute a novel promising approach for cancer immunotherapy.

Theaflavin-3, 3′-Digallate Attenuates Rheumatoid Inflammation in Mice Through the Nuclear Factor-κB and MAPK Pathways


Rheumatoid arthritis (RA) is a common autoimmune disease which impacts a large number of patients worldwide, and new drugs are required for lower the disease burden. Theaflavin-3, 3′-digallate (TFDG) is polyphenol exhibiting inhibition on inflammatory factors. This study aimed to explore the attenuation of TFDG on RA. The collagen-induced arthritis (CIA) mouse model was established and administered with TFDG. The arthritis score and incidence was recorded to assess the amelioration of TFDG on arthritis. Histopathological change of the mouse joint tissues was evaluated by haemotoxylin and eosin staining. The expression of pro-inflammatory mediators including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 was quantified by ELISA. The activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways in the synovium were determined by Western blotting. In comparison with the control, administration of TFDG significantly reduced arthritis score and incidence in the CIA mouse model. TFDG significantly suppressed the expression of IL-1β, TNF-α, and IL-6, as well as the levels of MMP-1, MMP-2, and MMP-3 in the synovium. TFDG also showed remarkable inhibition on the activation of NF-κB and the phosphorylation of P38, JNK2, and ERK. This study puts up evidence that TFDG exerts protection on RA via inhibiting the activation of NF-κB- and MAPK-signaling pathways.

The Influence of Antidepressants on the Immune System


Depression is one of the most frequently diagnosed condition in psychiatry. Despite the availability of many preparations, over 30% of treated patients do not achieve remission. Recently the emphasis is put on the contribution of the body's inflammatory response as one of the causes of depression. The interactions between nervous and immune systems are the main issue addressed by psychoneuroimmunology. In patients suffering from depression changes in the plasma concentrations of cytokines and in the number and level of activation of immune cells has been found. Attention is paid to the high levels of pro-inflammatory cytokines, the prevalence of Th1 responses to Th2, weakening of NK cell cytotoxicity and changes in lymphocyte proliferation and apoptosis. A number of studies focus on influence of antidepressants and non-standard methods of depression treatment, such as ketamine infusion, on patients' immunology. Many of them seem to regulate the immune responses. The study results encourage to look for new ways to treat depression with immunomodulatory drugs. In this article authors present the current knowledge about immune system changes accompanying depression as well as the study results showing the influence of drugs on the immune system, especially in the context of reducing the symptoms of depression.

PD-L1 Ameliorates Murine Acute Graft-Versus-Host Disease by Suppressing Effector But Not Regulatory T Cells Function


There is increasing evidence that interaction between programmed death 1 (PD-1) and its ligands PD-1 (PD-L1) plays a critical role in the pathology of acute graft-versus-host disease (aGVHD). However, the role of PD-L1 in the development of aGVHD has been controversial in recent mouse studies. In this study, we carried out studies in a murine aGVHD model to clarify the role of PD-L1 in aGVHD pathogenesis. We found that systemic overexpression of PD-L1 by hydrodynamic gene transfer (HGT) method in vivo ameliorates aGVHD-induced lethality in mice. Systemic overexpression of PD-L1 inhibits the donor T cells activation, effector memory status, as well as Th1 and Th17 cells responses in vivo. In addition, PD-L1 Ig treatment significantly suppressed T cells' proliferation, promoted T cells' apoptosis, and reduced pro-inflammatory cytokines expression by effector T cells in vitro in the stimulation of anti-CD3/CD28 and allogeneic dendritic cells. However, we found that PD-L1 overexpression did not affect Treg cells' differentiation in vivo and in vitro, depletion of Treg cells in PD-L1 HGT recipients did not aggravate aGVHD mortality. Therefore, our results demonstrated that systemic treatment with PD-L1 protein ameliorates aGVHD by suppressing effector but not regulatory T cell function. Our findings suggest that systemic treatment with PD-L1 may be a potential strategy to prevent or ameliorate aGVHD.

Post-transplant Alternative Complement Pathway Activation Influences Kidney Allograft Function


The complement system is one of the crucial pathophysiological mechanisms that directly influence the function of a transplanted kidney. Since the complement pathways' activation potential can be easily determined via their functional activity measurement, we focused on fluctuation in the cascade activity in the early post-transplant period. The aim of the study was to relate the kidney transplantation-induced complement system response to allograft outcome. Forty-two kidney recipients (aged: 53.5 [37–52], 17 females/25 males) and 24 healthy controls (aged: 40.5 [34–51], 13 females/11 males) were enrolled in the study. The functional activities of alternative, classical, and lectin pathways were determined before and in the first week after transplantation using Wielisa®-kit. We observed that the baseline functional activity of the alternative pathway (AP) was higher in chronic kidney disease patients awaiting transplantation compared to healthy controls and that its level depended on the type of dialysis. AP-functional activity was decreased following transplantation procedure and its post-transplant level was related to allograft function. The baseline and transplantation-induced functional activities of the classical and lectin pathways were not influenced by dialysis type and were not associated with transplant outcome. Moreover, our study showed that intraoperative graft surface cooling had a protective effect on AP activation. Our study confirms the influence of dialysis modality on persistent AP complement activation and supports the role of AP in an early phase after kidney transplantation and allograft outcome.

IgG from Non-atopic Individuals Induces In Vitro IFN-γ and IL-10 Production by Human Intra-thymic γδT Cells: A Comparison with Atopic IgG and IVIg


Matured in the thymus, γδT cells can modulate the development of allergy in humans. The main γδT cell subsets have been described as interleukin (IL)-17A or interferon (IFN)-γ producers, but these cells can also produce other modulatory cytokines, such as IL-4 and IL-10. Here, we aimed to evaluate whether IgG can modulate the profile of cytokine production by γδT cells during their maturation in the thymus and after its migration to peripheral tissues. Thymic tissues were obtained from 12 infants, and peripheral blood mononuclear cells (PBMCs) were obtained from adults (both groups without an atopic background). IgG was purified from atopic and non-atopic volunteers. Thymocytes and PBMCs were cultured with purified atopic or non-atopic IgG, and intracellular cytokine production and phenotype were assessed. Mock and IVIg conditions were used as controls. IgG from non-atopic individuals induced IFN-γ and IL-10 production by thymic γδT cells, and no effect was observed on peripheral γδT cells. IL-17 production was inhibited by non-atopic IgG on thymic γδT cells and augmented by atopic IgG on peripheral γδT cells. Modulated thymic γδT cells did not produce IFN-γ and IL-10 simultaneously. We additionally evaluated the phenotype of intrathymic γδT cells and observed that IgG from all groups could induce CD25 expression and could not influence the CD28 expression of these cells. This report describes evidence revealing that IgG may influence the production of IFN-γ and IL-10 by intrathymic γδT cells depending on the donor atopic state. This observation is unprecedented and needs to be considered in further studies in the IgG immunotherapy field.

Conjugation of Meningococcal Lipooligosaccharides Through Their Non-Reducing Terminus Results in Improved Induction a Protective Immune Response


The present studies prove that conjugation of meningococcal lipooligosaccharides through their non-reducing terminus conserves their inner epitopes resulting in conjugates potent to induce a protective immune response. Four different oligosaccharides were obtained by specific degradations of the same L7 lipooligosaccharide (L7-LOS), and each was linked to tetanus toxoid by direct reductive amination. Two were truncated oligosaccharides with incomplete inner epitopes and were obtained by mild acid hydrolysis of lipooligosaccharide. The terminal galactose of one oligosaccharide was additionally enzymatically oxidized. These oligosaccharides were conjugated through a newly exposed terminal Kdo in reducing end or through oxidized galactose localized at non-reducing end of the core, respectively. The third was a full-length oligosaccharide obtained by O-deacylation of the L7-LOS and subsequent enzymatic removal of phosphate substituents from its lipid A moiety. The fourth one was also a full-length O-deacylated lipooligosaccharide, but treated with galactose oxidase. This allowed direct conjugation to tetanus toxoid through terminal 2-N-acyl-2-deoxy-d-glucopyranose or through oxidized galactose, respectively. Comparison of the immune performance of four conjugates in mice revealed, that while each was able to induce significant level of L7-LOS-specific IgG antibody, the conjugates made with the full-length saccharides were able to induce antibodies with increased bactericidal activity against homologous meningococci. Only full-length oligosaccharides were good inhibitors of the binding of L7-LOS to the bactericidal antiserum. Moreover, induction of the significant level of the L7-LOS-specific antibody by full-length lipooligosaccharide conjugated from non-reducing end, provided also the direct evidence that internal core epitopes are fully responsible for the immunorecognition and immunoreactivity.

The Effect of Fucoidan, a Potential New, Natural, Anti-Neoplastic Agent on Uterine Sarcomas and Carcinosarcoma Cell Lines: ENITEC Collaborative Study


The aim of the study was to assess the activity of fucoidan on the uterine sarcomas (MES-SA and ESS-1) and carcinosarcoma cell lines (SK-UT-1 and SK-UT-1B) and its toxicity on the human skin fibroblasts (HSF). Two uterine sarcomas and two carcinosarcoma cell lines were examined, as a control HSF were used. Cell viability was assessed with MTT test, apoptosis with caspase-3 activity and cell cycle by assessment of DNA synthesis. Fucoidan significantly decreases cell viability in SK-UT-1, SK-UT-1B, and ESS-1 cell lines, such effect was not observed in MES-SA. Fucoidan was not substantially affecting proliferation among normal cells. The tested agent induced apoptosis in all cell cultures used in the experiment. Fucoidan affects cell cycle of all tested cell lines except MES-SA by increasing percentage of cells in G0/sub-G1/G1 phase. Fucoidan do not only affect proliferation but induces apoptosis in selected uterine sarcoma and carcinosarcoma cell lines, so it has potential to be used as cytotoxic agent. Fucoidan seems to be promising anti-cancer agent for endometrial stromal sarcoma and carcinosarcoma.

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