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Introduction: Individualized response to the immune triggers influences the course of immune-mediated diseases and the response to immunotherapies. Both inter- and intra-subject variations occur in time-dependent dynamics of biological systems. The present study aimed to establish a model for inherent personalized-time-dependent variability in response to immune triggers. Methods: Male C57BL/6 mice were administered concanavalin A (ConA) and followed every 2 h for 10 h and at 24 h for serum alanine aminotransferase (ALT) levels. Results: A marked intragroup variability was noted for both the timing of the effect of ConA, the magnitude of the increase in ALT levels, and the time to peak. While in some mice, a peak level was achieved, whereas a continuous increase in liver damage was noted in others. Four mice died at different time points during the study irrespective of their liver damage, further supporting the individualized-based response to the trigger. Conclusions: This feasibility study established a model for determining the personalized-inherent variability in a time-dependent response to the immune triggers. These results highlight the importance of considering both the time and the wide range of individualized variability in immune responses while designing personalized-based immunotherapies. [ABSTRACT FROM AUTHOR]

• Microtubules (MTs) are tubular polymers of tubulin that are highly dynamic and found throughout the cytoplasm and play a role in the innate and adaptive immune systems. • Studies suggest an essential role for MTs in the gut. • Here, we propose a model that represents gut MTs as potential targets for immunotherapy. Microtubules (MTs) are tubular polymers of tubulin that are highly dynamic and found throughout the cytoplasm. MTs are involved in maintaining cell structure and, together with microfilaments and intermediate filaments, form the cytoskeleton. Recent findings on MT structure and function contributed to the understanding of their potential role as players in the innate and adaptive immune systems. Additionally, studies suggest an essential role for these cellular structures in the gut. Here, we review recent data on interactions between MT and various arms of the immune system and propose a model that represents gut MTs as potential targets for immunotherapy, and specifically for oral immunotherapy. [ABSTRACT FROM AUTHOR]

Plasticity in biological systems is attributed to the combination of multiple parameters which determine function. These include genotypic, phenotypic, and environmental factors. While biological processes can be viewed as ordered and sequential, biological randomness was suggested to underline part of them. The present review looks into the concept of randomness in biological systems by exploring the glycosphingolipids-NKT cells example. NKT cells are a unique subset of regulatory lymphocytes which play a role in both inflammation and tolerance. Glycosphingolipids promote an immune balance by changing different arms of the immune system in opposing environments. Traditional immunology looks at skewing the immune system into different directions by different types of activation of the same cell stimulation of different cells subsets, use of different ligands, or different the effect of different immune environments. While these may explain some of the effects, the lack of consistency and opposing results under similar settings may involve randomness which may also be part of real life effects of immunomodulatory agents. It means that several of the biological processes, cannot be explained by simple linear models, and may involve more complex concepts. The application for these concepts for improving therapies to patients with Gaucher disease are discussed. SUMMARY The use of different ligands that target a variety of cell subsets in different immune environments may underlie differences in the functionality of NKT cells and their variability in response to NKT-based therapies. The novel concept of randomness in biology means that several biological processes cannot be solely explained by simple linear models and may instead involve much more complicated schemes of random disorder. These may have implications on future design of therapeutic regimens for improving the response to current treatments. [ABSTRACT FROM AUTHOR]

Background: It has been shown that the proportion of natural killer T cells is markedly elevated during liver regeneration and their activation under different conditions can modulate this process. As natural killer T cells and liver injury are central in liver regeneration, elucidating their role is important.Methods: The aim of the current study is to explore the role of natural killer T cells in impaired liver regeneration. Concanvalin A was injected 4 days before partial hepatectomy to natural killer T cells- deficient mice or to anti CD1d1-treated mice. Ki-67 and proliferating cell nuclear antigen were used to measure hepatocytes proliferation. Expression of hepatic cyclin B1 and proliferating cell nuclear antigen were evaluated by Western Blot and liver injury was assessed by ALT and histology.Results: Natural killer T cells- deficient or mice injected with anti CD1d antibodies exhibited reduced liver regeneration. These mice were considerably resistant to ConA-induced liver injury. In the absence of NKT cells hepatic proliferating cell nuclear antigen and cyclin B1 decreased in mice injected with Concanvalin A before partial hepatectomy. This was accompanied with reduced serum interleukin-6 levels.Conclusions: Natural killer T cells play an important role in liver regeneration, which is associated with cyclin B1 and interleukin-6. [ABSTRACT FROM AUTHOR]

Abstract: Mucosal tolerance remains an attractive approach for the treatment of autoimmune and inflammatory diseases. The agents used in these treatments lack toxicity, can be easily administered, and enable the promotion of antigen-specific immune responses. The limited success of clinical trials over the past 2 decades has led to the fear that the beneficial effect observed in animal models cannot be repeated in humans. Successful application of mucosal tolerance for the treatment of human diseases will depend on strategies that target the correct cells in the gut–liver axis, improve antigen presentation, alter the administered dose and formulations, utilize potent mucosal adjuvants, develop immune biomarkers enabling follow-up of the effect, utilize combination therapies with other immune modulatory agents, and target the right patient populations. Here, we discuss 12 of the major questions related to oral tolerance and its clinical application to humans with immune-mediated disorders. [Copyright &y& Elsevier]

β-Glycosphingolipids have emerged as a family of potential ligands for natural killer T (NKT)- regulatory lymphocytes. This subset of regulatory lymphocytes has been implicated in the regulation of autoimmune processes. The major histocompatibility complex (MHC) Class I-like CD1d glycoprotein is a member of the CD1 family of antigen-presenting molecules and is responsible for selection of NKT cells. β-Glycolipids have been shown to alter immune responses in the opposing settings of autoimmune diseases or cancer. In this review, we discuss the potential use of β-glycoshpingolipids for NKT-based immunotherapy. [ABSTRACT FROM AUTHOR]

β-glucosylceramide (GC) is a naturally occurring glycosphingolipid that was shown to improve hepatic steatosis, steatohepatitis, and insulin resistance in animal models of nonalcoholic fatty liver disease. In this study, we evaluated the safety and efficacy of oral administration of GC in subjects with nonalcoholic steatohepatitis (NASH). Twenty-three patients with biopsy proven NASH were enrolled in a double-blind, placebo-controlled trial. Patients were orally administered daily with 7.5 mg of GC. Patients were followed for safety, liver enzymes, HbA1c, insulin sensitivity, lipid profile, hepatic fat content as measured by magnetic resonance imaging (MRI), and NASH score on liver biopsy. No treatment-related adverse events were observed during treatment. In a per protocol analysis of data, oral administration of GC decreased the hepatic fat content as measured by MRI in GC-treated compared with placebo. HbA1C decreased in patients treated with GC. GC treatment was associated with a milder decrease in the high-density lipoprotein serum levels. The beneficial effects were associated with a decrease in CD4 and NKT cell subsets of lymphocytes. Due to the small number of subjects enrolled, differences did reach statistical significance. Oral administration of GC is safe and biologically active in patients with NASH and insulin resistance. [ABSTRACT FROM AUTHOR]

Abstract: The integrity of lipid rafts in cell membranes is important for signal transduction. Aim: To determine the distinct effects of β-glycolipids on the composition of lipid rafts in natural killer T (NKT) cells and on the level of expression of flotillin-2, leukocyte-specific protein tyrosine kinase (Lck), and STAT1-associated pathways. Methods: The effects of glycolipids were determined by composition analysis of the raft domains, FACS analysis of the distribution patterns for the raft ganglioside, GM1, and fluorescence microscopy of raft patching. To evaluate the effects of the immune environment on glycolipid-associated alteration of lipid rafts, hepatitis was induced by an intravenous injection of concanavalin A (ConA) in mice treated with various glycolipids. Results: The administration of β-glucosylceramide, β-lactosylceramide, and a combination of both significantly altered GM1 content in lymphocyte membranes in an environment-dependent manner. These effects were associated with altered expression levels of flotillin-2, Lck, and STAT1, and with a significant decrease in intrahepatic CD8+ lymphocyte trapping and the alleviation of ConA-induced hepatitis. The administration of α-glycolipids failed to induce similar effects. Conclusions: The alteration in the expression levels of flotillin-2, Lck, and STAT1 that occurs concomitantly with changes in lipid raft composition and structure following the administration of β-glycolipids in ConA-induced hepatitis is microenvironment-dependent and is associated with decreased intrahepatic CD8+ T lymphocyte trapping and amelioration of immune-mediated hepatitis. [Copyright &y& Elsevier]

Abstract: T lymphocytes expressing NK1.1 marker (NKT) have been suggested to play crucial roles in immune modulation. Aim.– To determine the role of NK1.1+ cells in induction and maintenance of pro-inflammatory and/or tolerizing responses. Methods.– Colitis was induced in C57/B6 donor mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Donor mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Depletion of NK1.1+ lymphocytes was performed before lymphocyte harvesting. Splenocytes were harvested and separated into T-cell subpopulations, and transplanted into recipient mice before intracolonic instillation of TNBS. Standard clinical, macroscopic, and microscopic scores, and intracellular staining, flow cytometry, and cytotoxicity assays were performed. Results.– The adoptive transfer of CD4+ and NK1.1+ cells harvested from tolerized mice markedly ameliorated the colitis in recipient mice. In contrast, the adoptive transfer of CD8+ and double negative lymphocytes failed to transfer the tolerance. Recipients of splenocytes from tolerized mice exhibited an increase in CD4+IL4+/CD4+IFNγ+ ratio. In contrast, recipients of splenocytes from NK1.1-depleted-tolerized mice exhibited severe colitis with a significant decrease of the CD4+IL4+/CD4+IFNγ+ ratio. However adoptive transfer of splenocytes from non-tolerized NKT-depleted mice led to an alleviation of colitis with a relative increase of the CD4+IL4+/CD4+IFNγ+ ratio. Conclusions: NK1.1+ lymphocytes play a critical role in immune regulation. They may be accountable for an alteration of the inflammatory response and the CD4+IL4+/CD4+IFNγ ratio immune-mediated colitis and in peripheral tolerance induction. [Copyright &y& Elsevier]

• Structure provide insight into the functions of beta-glycosphingolipids. • We determined the effects of GSL structures on their immune modulatory functions. • A saturated C8 chain, and a trans double bond at C-2 in the C8 chain, suppressed liver inflammation. • A structure-dependent apoptosis suppression and altered NKT distribution were shown. Structure-activity relationships provide insight into the binding interactions of beta-glycosphingolipids (GSLs) with both the TCR and the CD1d molecules, as well as the subsequent immunologic response of regulatory NKT cells. To determine the effects of synthetic GSL structures on their immune modulatory functions. GSLs of various structures were tested in vitro and in an animal model of Concanavalin A (ConA) immune-mediated hepatitis. In vitro , using SV40 binding to live monkey CV1 cells, the l - threo stereoisomer of C8-β-LacCer inhibits caveolar internalization, reducing viral binding to the cell surface. In vivo , in the ConA model, LR172, which has a saturated C8 chain, and LR178, which has a trans double bond at C-2 in the C8 chain, suppressed the immune-mediated liver inflammation and reduced IFNγ levels in a dose dependent manner. The beneficial effects of LR172 and of LR178 are associated with suppression of liver apoptosis, increased phosphorylated STAT3 expression in the liver, and an increase in the NKT liver/spleen ratio. The assembly of GSLs determines their immunomodulatory effect and can serve as a method for structure-based design of immunotherapy. [ABSTRACT FROM AUTHOR]