Sublingual allergen immunotherapy prevents house dust mite inhalant type 2 immunity through dendritic cell-mediated induction of Foxp3 regulatory T cells.

Sublingual allergen immunotherapy (SLIT) is an emerging treatment option for allergic asthma and a potential disease-modifying strategy for asthma prevention. The key cellular events leading to such long-term tolerance remain to be fully elucidated. We administered prophylactic SLIT in a mouse model of house dust mite (HDM)-driven allergic asthma.

Modulation of immune responses using adjuvants to facilitate therapeutic vaccination.

Therapeutic vaccination offers great promise as an intervention for a diversity of infectious and non-infectious conditions. Given that most chronic health conditions are thought to have an immune component, vaccination can at least in principle be proposed as a therapeutic strategy. Understanding the nature of protective immunity is of vital importance, and the progress made in recent years in defining the nature of pathological and protective immunity for a range of diseases has provided an impetus to devise strategies to promote such responses in a targeted manner.

Subcutaneous immunotherapy suppresses Th2 inflammation and induces neutralizing antibodies, but sublingual immunotherapy suppresses airway hyperresponsiveness in grass pollen mouse models for allergic asthma.

Background: Both subcutaneous and sublingual allergen immunotherapy (SCIT and SLIT) have been shown to effectively suppress allergic manifestations upon allergen exposure, providing long-term relief from symptoms in allergic disorders including allergic asthma. Clinical studies directly comparing SCIT and SLIT report a different kinetics and magnitude of immunological changes induced during treatment. Comparative studies into the mechanisms underlying immune suppression in SCIT and SLIT are lacking.

Enhanced efficacy of sublingual immunotherapy by liposome-mediated delivery of allergen.

Immunotherapy by sublingual administration of allergens provides high patient compliance and has emerged as an alternative to subcutaneous immunotherapy for the treatment of IgE-associated allergic diseases. However, sublingual immunotherapy (SLIT) can cause adverse events. Development of allergen delivery systems enabling more efficient delivery and hence lower allergen load might reduce the adverse events.

House Dust Mite-Specific Sublingual Immunotherapy Prevents the Development of Allergic Inflammation in a Mouse Model of Experimental Asthma.

Background: Evidence regarding sublingual immunotherapy (SLIT) efficacy and its good safety profile has been demonstrated with pollen and house dust mite (HDM) allergens in the treatment of airway allergies. In addition, the use of grass pollen presents a SLIT disease-modifying treatment for respiratory allergies.

Objectives: The aim of this study was to demonstrate the efficacy of HDM-based SLIT in mouse models of allergic airway inflammation and to gain insights into the involved local immunological mechanisms.

Glycoproteomic analysis of seven major allergenic proteins reveals novel post-translational modifications.

Allergenic proteins such as grass pollen and house dust mite (HDM) proteins are known to trigger hypersensitivity reactions of the immune system, leading to what is commonly known as allergy. Key allergenic proteins including sequence variants have been identified but characterization of their post-translational modifications (PTMs) is still limited. Here, we present a detailed PTM(1) characterization of a series of the main and clinically relevant allergens used in allergy tests and vaccines.

Shorter dosing intervals of sublingual immunotherapy lead to more efficacious treatment in a mouse model of allergic inflammation.

Current day practice of sublingual immunotherapy (SLIT) includes varying modalities of treatment that differ with regard to formulation, dosing and administration regimens. The aim of this study was to explore the importance of the dosing intervals in SLIT. The immunological effect of increased SLIT dosing frequency was tested in a mouse model of allergic inflammation.

Sublingual immunotherapy in sensitized mice.

Background: Many studies have demonstrated immunologic changes induced by sublingual immunotherapy (SLIT), but the definitive mechanism of action needs further investigation.

Objective: To study the immunologic response induced by SLIT in sensitized mice.

Methods: Timothy grass (Phleum pratense)-sensitized mice received SLIT for 2, 4, or 6 weeks at 3 different concentrations, including a buffer control.

Sublingual immunotherapy reduces allergic symptoms in a mouse model of rhinitis.

Background: Sublingual immunotherapy (SLIT) is a clinically effective treatment in both pollen and house dust mite-induced rhinitis and asthma. However, the mechanisms by which this is accomplished are not clear.

Objective: The objective of the current study was to establish a mouse model of rhinitis in order to study the effect and mechanisms of SLIT.

Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-gamma.

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation.

Enhanced oral tolerance in transgenic mice with hepatocyte secretion of IL-10.

Several cytokines derived from Th3 and Tr1 cells, including IL-10, are believed to regulate oral tolerance, but direct evidence is lacking. We have explored the potential role of IL-10 by generating transgenic (TG) mice with sustained hepatocyte-specific expression of rat IL-10. TG mice expressed rat IL-10 downstream of a transthyretin promoter, which led to serum levels that were increased 10- to 100-fold compared with normal animals.

Induction of mucosal tolerance in Peyer's patch-deficient, ligated small bowel loops.

To explore the requirement for M cells and the Peyer's patch (PP) in induction of oral tolerance and address the potential in vivo role of intestinal epithelial cells as nonprofessional APCs, we have attempted to induce tolerance in mice with ligated small bowel loops without M cells and Peyer's patches. A 2-centimeter section of vascularized small bowel was spliced away from the gut without disruption of the mesenteric attachments. We introduced OVA directly into the lumen of the loop prior to footpad immunization.

Defects in CD8+ regulatory T cells in the lamina propria of patients with inflammatory bowel disease.

Mucosal tolerance is believed to be partly mediated by regulatory T cells. Intestinal epithelial cells (IECs) may play an important role in the generation of such regulatory cells, because they are able to process and present Ag to T cells. Furthermore, we have previously demonstrated that IECs are able to generate regulatory CD8(+) T cells in vitro.

Activation of a unique population of CD8(+) T cells by intestinal epithelial cells.

Intestinal epithelial cells may play a role in the regulation of immune responses toward luminal antigens. We show that a subset of CD8(+) T cells undergoes oligoclonal expansion in the intestinal mucosa, probably through interaction with a unique complex expressed on epithelial cells, formed by a CEA subfamily member (gp180) and CD1d. This subset, which is regulatory in vitro, may play a role in the control of intestinal immune responses toward luminal antigens.

The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells.

Background & Aims: Previous studies have suggested that intestinal epithelial cells (IECs) may function as antigen-presenting cells for CD4+ and CD8+ T cells. However, these cells fail to express conventional costimulatory molecules (CD80, CD86), leading to the possibility that antigen presented by normal IECs could result in anergy. Other members of the B7 family have recently been identified.

Ca2+ response in neutrophils after exposure to bacterial N-formyl-methionyl-leucyl-phenylalanine: delayed response in ulcerative colitis.

Objective: In acute stages of ulcerative colitis (UC), neutrophils migrate from the circulation into inflamed colonic tissue, initiated by yet unknown stimuli. The bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a component of the surface membrane of colonic bacteria such as Escherichia coli and stimulates Ca2+ influx into neutrophils, reflecting the fact that ionized calcium is an important secondary messenger for several neutrophil functions, including locomotion, phagocytosis and free oxygen radical production. Recent studies have revealed that Ca2+ dependent ICAM-1/beta 2-integrin mediated neutrophil migration is impaired in UC patients.

CD4+ T regulatory cells from the colonic lamina propria of normal mice inhibit proliferation of enterobacteria-reactive, disease-inducing Th1-cells from scid mice with colitis.

Adoptive transfer of CD4+ T cells into scid mice leads to a chronic colitis in the recipients. The transferred CD4+ T cells accumulate in the intestinal lamina propria (LP), express an activated Th1 phenotype and proliferate vigorously when exposed ex vivo to enteric bacterial antigens. As LP CD4+ T cells from normal BALB/c mice do not respond to enteric bacterial antigens, we have investigated whether colonic LP-derived CD4+ T cells from normal mice suppress the antibacterial response of CD4+ T cells from scid mice with colitis.

Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells.

Background & Aims: Regulatory T cells play a role in the control of immune responses in the intestinal mucosa and their absence may predispose to inflammatory bowel disease (IBD). We have previously shown that T cells activated by intestinal epithelial cells (IECs) are suppressive in function. Our goal was to characterize the phenotype and function of T cells proliferating after interaction with IECs.

Impaired sensitivity to beta 2 integrin-blocking in ICAM-1-mediated neutrophil migration in ulcerative colitis.

Background: Factors influencing the directed migration of neutrophils into colonic tissue in ulcerative colitis (UC) are poorly described. ICAM-1 has recently been shown to possess chemotactic properties, and the aim of this study was to evaluate the involvement of beta 2 integrins in this ICAM-1-mediated migration.

Methods: The chemotactic effect of ICAM-1 on neutrophils isolated from 13 UC patients and 17 healthy volunteers was studied in microchemotaxis chambers.

Distinct differences in autoantigen specificity of anti-neutrophil cytoplasm antibodies in systemic vasculitides and other inflammatory diseases.

Background: Anti-neutrophil cytoplasm antibodies in necrotizing vasculitides need to be distinguished from ANCAs in other inflammatory conditions to avoid clinical misinterpretation.

Objectives: To help clinicians and laboratory scientists recognize and utilize vasculitis-related ANCAs as an aid in diagnostic workup and patient follow-up, and be aware that ANCAs with different characteristics are commonly found in other chronic inflammatory conditions that persistently engage neutrophils in the inflammatory process.

Methods: Indirect immunofluorescence and enzyme immunoassay methods were used to detect ANCAs with both known and unknown neutrophil autoantigenic targets.

Enteric bacterial antigens activate CD4(+) T cells from scid mice with inflammatory bowel disease.

Scid mice transplanted with CD4(+) T cells from congenic donor mice develop a chronic and lethal inflammatory bowel disease (IBD) 2-3 months post-transplantation. In the present study we have investigated the response of CD4(+) T cells from scid mice with colitis against fecal extracts. Our results show that in contrast to CD4(+) T cells from normal BALB/c mice, CD4(+) T cells from scid mice with colitis proliferate strongly in response to antigen-presenting cells (APC) pulsed with fecal extracts.

Immunoglobulin leakiness in scid mice with CD4(+) T-cell-induced chronic colitis.

Inflammatory bowel disease in scid mice is initiated by transplantation of CD4(+) T-cells from immunocompetent syngenic donor mice. As the disease progresses, immunoglobulin (Ig)-containing cells appear in the gut lamina propria, suggesting that locally accumulating Ig may play a role in disease development. In the present work we have investigated the relationship between disease progression and patterns or levels of Ig isotypes in the feces of scid mice suffering from an ongoing colitis.

In vitro activated CD4+ T cells from interferon-gamma (IFN-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts.

To investigate the role of IFN-gamma in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4+ T cells from either wild-type (WT) or IFN-gamma-deficient (IFN-gammaKO) BALB/c mice. In vitro, the two types of T cells displayed comparable proliferation rates and production of tumour necrosis factor-alpha (TNF-alpha), IL-2, IL-4 and IL-10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4+ blasts induced a lethal IBD, whereas IFN-gammaKO blasts induced a less severe intestinal inflammation with moderate weight loss.

Reactions of N-N and N-O compounds with horseradish peroxidase and peroxidases from Mycobacterium tuberculosis.

Several N-N-and N-O-containing compounds were analysed for their ability to act as substrates for horseradish peroxidase and peroxidases in Mycobacterium tuberculosis extracts. Aminoguanidine, diaminoguanidine, isoniazid, hydroxylamine and hydrazine were found to be weak substrates for horseradish peroxidase in reaction I and to inhibit the reaction of horseradish peroxidase with hydrogen peroxide. The same compounds inhibited the reaction of Mycobacterium tuberculosis peroxidase-catalase with hydrogen peroxide, and hydroxylamine was found to be a weak substrate for this enzyme.