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Serum N-glycan patterns from 50 Crohn's disease (CD) patients and 50 healthy controls were acquired using a carbon matrix, from which eight N-glycans with significant difference were screened out to reveal remarkale performance for CD diagnosis. This research is expected to help future glycan-based disease detection not limited to CD.

The IL-12 family of heterodimeric cytokines, consisting of IL-12, IL-23, IL-27, and IL-35, has important roles in regulating the immune response. IL-12 family members are comprised of a heterodimer consisting of α and β chains: IL-12 (p40 and p35), IL-23 (p40 and p19), IL-27 (Ebi3 and p28), and IL-35 (Ebi3 and p35). Given the combinatorial nature of the IL-12 family, we generated adenoviral vectors expressing two putative IL-12 family members not yet found naturally, termed IL-X (Ebi3 and p19) and IL-Y (p40 and p28), as single-chain molecules. scIL-Y, but not scIL-X, was able to stimulate significantly a unique cytokine/chemokine expression profile as well as activate STAT3 in mice, in part, through a pathway involving IL-27Rα in splenocytes. Adenoviral-mediated, intra-tumoral delivery of scIL-Y increased tumor growth in contrast to the anti-tumor effects of scIL-12 and scIL-23. Similarly, treatment of pre-diabetic non-obese diabetic (NOD) mice by intravenous injection of Ad.scIL-Y prevented the onset of hyperglycemia. Analysis of cells from Ad.scIL-Y-treated NOD mice demonstrated that scIL-Y reduced expression of inflammatory mediators such as IFN-γ. Our data demonstrates that a novel, synthetic member of the IL-12 family, termed IL-Y, confers unique immunosuppressive effects in two different disease models and thus could have therapeutic applications.

This study evaluated the cholesterol-lowering property of lactic acid bacteria (LAB) isolated from mink. Two strains, Enterococcus faecium MDF1104 and Lactobacillus plantarum MDL1118, were shown to remove cholesterol from broths of natural hen egg yolk and skimmed milk. The cholesterol in hen egg yolk was reduced by 58.15% and 38% by L. plantarum and E. faecium, respectively. When the bacteria were used in combination, 48.95% (p < 0.01) of cholesterol was removed from skimmed milk. Experimental mice remained healthy when fed different doses of the LAB, and the total serum cholesterol concentration was the lowest (0.90 mmol/L) (p < 0.01) when a combination of L. plantarum and E. faecium was used. Based on our results, we suggest that L. plantarum MDL1118, E. faecium MDF1104, or a combination of the 2 strains could be considered as promising cholesterol-lowering probiotics.

Tumor-specific immunosuppression is frequently observed in tumor-bearing hosts. Exosomes are nano-sized, endosomal-derived membrane vesicles secreted by most tumor and hematopoietic cells and have been shown to actively participate in immune regulation. We previously demonstrated that antigen-specific immunosuppressive exosomes could be isolated from the blood plasma of antigen-immunized mice. Here, we demonstrate that plasma-derived exosomes isolated from mice bearing OVA-expressing tumors were able to suppress OVA-specific immune responses in a mouse delayed-type hypersensitivity model. Enrichment of tumor-derived exosomes in the plasma of mice bearing subcutaneous melanoma was not detected using an exosome-tagging approach. Instead, depletion of MHC class II(+) vesicles from plasma-derived exosomes or using plasma-derived exosomes isolated from MHC class II-deficient mice resulted in significant abrogation of the suppressive effect. These results demonstrate that circulating host-derived, MHC class II(+) exosomes in tumor-bearing hosts are able to suppress the immune response specific to tumor antigens.

Rheumatoid arthritis (RA) is a chronic autoimmune disease and one of the leading causes of disability in the USA. Although certain biological therapies, including protein and antibodies targeting inflammatory factors such as the tumor necrosis factor, are effective in reducing symptoms of RA, these treatments do not reverse disease. Also, although novel gene therapy approaches have shown promise in preclinical and clinical studies to treat RA, it is still unclear whether gene therapy can be readily and safely applied to treat the large number of RA patients. Recently, nanosized, endocytic-derived membrane vesicles “exosomes” were demonstrated to function in cell-to-cell communication and to possess potent immunoregulatory properties. In particular, immunosuppressive DC-derived exosomes and blood plasma- or serum-derived exosomes have shown potent therapeutic effects in animal models of inflammatory and autoimmune disease including RA. This paper discusses the current knowledge on the production, efficacy, mechanism of action, and potential therapeutic use of immunosuppressive exosomes for arthritis therapy.

Mycoplasmas cause numerous human diseases and are common opportunistic pathogens in cancer patients and immunocompromised individuals. Mycoplasma infection elicits various host immune responses. Here we demonstrate that mycoplasma-infected tumor cells release exosomes (myco+ exosomes) that specifically activate splenic B cells and induce splenocytes cytokine production. Induction of cytokines, including the proinflammatory IFN-γ and the anti-inflammatory IL-10, was largely dependent on the presence of B cells. B cells were the major IL-10 producers. In splenocytes from B cell deficient μMT mice, induction of IFN-γ+ T cells by myco+ exosomes was greatly increased compared with wild type splenocytes. In addition, anti-CD3-stimulated T cell proliferation was greatly inhibited in the presence of myco+ exosome-treated B cells. Also, anti-CD3-stimulated T cell signaling was impaired by myco+ exosome treatment. Proteomic analysis identified mycoplasma proteins in exosomes that potentially contribute to the effects. Our results demonstrate that mycoplasma-infected tumor cells release exosomes carrying mycoplasma components that preferentially activate B cells, which in turn, are able to inhibit T cell activity. These results suggest that mycoplasmas infecting tumor cells can exploit the exosome pathway to disseminate their own components and modulate the activity of immune cells, in particular, activate B cells with inhibitory activity.

Exosomes are endosome-derived, 30–100 nm small membrane vesicles released by most cell types including tumor cells. They are enriched in a selective repertoire of proteins and nucleic acids from parental cells and are thought to be actively involved in conferring intercellular signals. Tumor-derived exosomes have been viewed as a source of tumor antigens that can be used to induce antitumor immune responses. However, tumor-derived exosomes also have been found to possess immunosuppressive properties and are able to facilitate tumor growth, metastasis, and the development of drug resistance. These different effects of tumor-derived exosomes contribute to the pathogenesis of cancer. This review will discuss the roles of tumor-derived exosomes in cancer pathogenesis, therapy, and diagnostics.

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs.

Tumor cells usually express specific antigens that are potentially immunogenic; however, established tumors primarily induce immune tolerance. In the last decade, a population of small membrane vesicles, termed "exosomes", has gained increasing attention for their potential role in tumor immune regulation. Exosomes are formed in the late endocytic compartments and are released upon their fusion with the plasma membrane. They are secreted by various cell types, especially tumor cells and cells in the hematopoietic system. Although tumor-derived exosomes usually contain tumor antigens, they have been shown to exert diverse immunosuppressive effects. However, the ability of tumor-derived exosomes to induce antigen-specific immunosuppression has not been well examined. Also, the immunoregulatory effect of exosome-like vesicles in the blood circulation of tumor-bearing hosts remains unclear. In this thesis, we first investigate the role of tumor-derived exosomes in mediating antigen-specific immune suppression using ovalbumin (OVA) as a model tumor antigen. We demonstrate that exosomes derived from OVA-expressing tumor cell lines potently suppress OVA-specific delayed-type hypersensitivity (DTH) response. We also show that exosomes are mostly taken up by dendritic cells (DCs) after local administration, and the mRNA levels of TGF-beta1 and IL-4 in the draining lymph node were significantly elevated in correlation with suppression of the DTH response. Furthermore, tumor-derived exosomes affect the function of DCs in vitro by inhibiting their maturation and inducing TGF-beta1 production. These results suggest that tumor-derived exosomes are able to confer antigen-specific immune suppression possibly by DC-mediated mechanism. We further investigate the immunoregulatory effect of plasma-derived exosomes and demonstrate that plasma-derived exosomes isolated from mice bearing OVA-expressing tumors are able to suppress the OVA-specific DTH response. However, enrichment of tumor-derived exosomes in blood plasma was not identified and the suppressive effect is partially mediated by the MHC class II+ vesicle portion. The third part of the thesis discusses the B cell stimulatory and the consequent T cell inhibitory effect of exosomes derived from tumor cells with mycoplasma infection. The work presented in this thesis increases our understanding of the immunoregulatory role of tumor-derived exosomes, circulating exosomes in tumor-bearing hosts as well as exosomes derived from pathogen-infected tumor cells.