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Mark Larché

Publications and source records attributed to Mark Larché.

At least 19 recordsLinked to original sources
PubMed2006

The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses.

The IgE-facilitated allergen binding (IgE-FAB) assay represents an in vitro model of facilitated allergen presentation. Allergen-IgE complexes are incubated with an EBV-transformed B cell line and complexes bound to CD23 on the surface of cells are detected by flow cytometry. The addition of serum from patients who have received allergen-specific immunotherapy has been shown previously to inhibit allergen-IgE complex binding to CD23 on B cells. In this study, we describe the characterisation and analytical validation of the grass pollen-specific IgE-FAB assay according to guidelines from the International Conference on Harmonisation. We established the intra- and inter-assay variability of IgE-FAB and have defined the detection limits of this assay. We have also demonstrated assay linearity and robustness. Using the results from a randomised double-blind placebo-controlled trial of grass pollen immunotherapy (n=33), we have defined the clinical sensitivity and specificity of the IgE-FAB assay using ROC curve analysis. In conclusion, the IgE-FAB assay is reproducible, robust, sensitive and a specific method suitable as a tool for monitoring inhibitory antibody function from patients receiving allergen immunotherapy.

Allergens↗
PubMed2006

Immunoregulation by targeting T cells in the treatment of allergy and asthma.

T-cell responses to allergens are crucial in determining the choice between health and disease. Th2 responses drive synthesis of IgE and the recruitment, maturation, survival and effector function of accessory cells such as eosinophils, basophils and mast cells. Allergen-specific strategies for targeting T-cell responses in established allergic diseases have been employed with success for almost a century. Recently, new insight into the mechanism of action of such approaches has revealed modulation of the delicate and complex regulatory mechanisms including suppression of Th2 responses through antagonistic Th1 responses and regulation through IL-10 and TGFbeta production.

Allergens↗
PubMed2006

Peptide immunotherapy.

Synthetic peptides representing T-cell epitopes of allergens and autoantigens have been employed to induce antigen-specific tolerance in vivo in experimental models and the clinical setting. Delivery of peptides orally or by injection leads to reduced reactivity to antigen accompanied by the induction of T cells with a regulatory phenotype. Peptide therapy may provide a safe, effective, and economically viable approach for disease-modifying therapy in autoimmune and allergic diseases.

Allergens↗
PubMed2006

Immunological mechanisms of allergen-specific immunotherapy.

Allergen-specific immunotherapy has been carried out for almost a century and remains one of the few antigen-specific treatments for inflammatory diseases. The mechanisms by which allergen-specific immunotherapy exerts its effects include the modulation of both T-cell and B-cell responses to allergen. There is a strong rationale for improving the efficacy of allergen-specific immunotherapy by reducing the incidence and severity of adverse reactions mediated by IgE. Approaches to address this problem include the use of modified allergens, novel adjuvants and alternative routes of administration. This article reviews the development of allergen-specific immunotherapy, our current understanding of its mechanisms of action and its future prospects.

Allergens↗
PubMed2005

Peptide therapy for allergic diseases: basic mechanisms and new clinical approaches.

Desensitising allergen immunotherapy has been practised for many decades. Although time consuming, this form of therapy is antigen-specific and disease-modifying, in contrast to palliative pharmacotherapy. However, the use of allergen extracts containing native allergen molecules frequently results in allergic adverse reactions to treatment. Several strategies to reduce the allergenicity of therapeutic preparations, while maintaining their therapeutic benefit, are being developed. Peptide immunotherapy is one such approach. Short synthetic peptides, comprising T cell epitopes of major allergens, were unable to crosslink allergen-specific IgE molecules on basophils in vitro. Treatment of allergic volunteers with allergen peptides resulted in reduced skin, lung and nasal sensitivity to allergen challenge and improved their subjective ability to tolerate allergen exposure. Peptides reduced pro-inflammatory cytokine secretion from peripheral blood cells, whilst increasing the immunosuppressive cytokine IL-10. Furthermore, peptide therapy was associated with the induction of a population of CD4+ T cells with a suppressive functional phenotype. Thus, peptide therapy may be suitable for the antigen-specific treatment of allergic diseases.

Allergens↗
PubMed2005

T cell epitope immunotherapy induces a CD4+ T cell population with regulatory activity.

BACKGROUND: Synthetic peptides, representing CD4(+) T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. METHODS AND FINDINGS: In this study we address the mechanism of action of peptide immunotherapy (PIT) in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs) after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4(+) cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4(neg) PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4(+) and CD8(+) PBMCs. CONCLUSION: This study provides evidence for the induction of a population of CD4(+) T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.

Allergens↗
PubMed2005

Peptide-based therapeutic vaccines for allergic and autoimmune diseases.

Allergic and autoimmune diseases are forms of immune hypersensitivity that increasingly cause chronic ill health. Most current therapies treat symptoms rather than addressing underlying immunological mechanisms. The ability to modify antigen-specific pathogenic responses by therapeutic vaccination offers the prospect of targeted therapy resulting in long-term clinical improvement without nonspecific immune suppression. Examples of specific immune modulation can be found in nature and in established forms of immune desensitization. Understanding and exploiting common mechanisms such as the ability to induce antigen-specific regulatory cells should allow the development of effective therapeutic strategies for both forms of immunopathology. Targeting pathogenic T cells using vaccines consisting of synthetic peptides representing T cell epitopes is one such strategy that is currently being evaluated with encouraging results. Future challenges in the development of therapeutic vaccines include selection of appropriate antigens and peptides, optimization of peptide dose and route of administration and identifying strategies to induce bystander suppression.

Antigen-Presenting Cells↗
PubMed2005

Peptide-based vaccination: where do we stand?

PURPOSE OF REVIEW: Allergen-specific immunotherapy represents the only causative approach towards allergy treatment. Specific immunotherapy can, however, include allergic reactions and occasionally life-threatening anaphylaxis. Peptides have been evaluated as a potential therapeutic approach in atopic allergic disease because they have the potential to inhibit T-cell function but not induce anaphylaxis. RECENT FINDINGS: Data from early clinical trials of peptide vaccination revealed that therapy was associated with a modest improvement in allergic disease, and was accompanied by a high frequency of adverse reactions. More recent studies have demonstrated improved clinical outcomes, improved safety, and have defined the mechanisms of adverse events observed in earlier studies. Mechanisms of peptide vaccination include the hyporesponsiveness of allergen-specific responses and the induction of regulatory T cells and cytokines. Novel peptide design has allowed the generation of fragments that contain T-cell stimulatory epitopes, lack B cell epitopes, and can induce protective IgG responses in both mice and humans. Other approaches have focused on hypoallergenic B-cell epitopes that induce inhibitory IgG antibodies. Peptides that specifically induce regulatory cytokine production would also enhance peptide vaccines. Several recent studies have described immunodominant epitopes from major allergens that may form candidate peptides for use in peptide vaccination. SUMMARY: The manipulation of peptide epitopes may provide a strategy for the rational design of peptide allergy vaccines further improving safety and efficacy.

B-Lymphocytes↗
PubMed2005

Peptide-based immunotherapy: a novel strategy for allergic disease.

The T-cell component of the antigen-specific immune response is the target of various novel interventions to modify chronic immunologic disorders, such as allergic diseases. Recent clinical trials have evaluated the safety and efficacy of therapeutic vaccines consisting of short, synthetic, allergen-derived peptides, corresponding to T-cell epitopes from the eliciting antigen. The main advantage of such an approach is the reduction in systemic, immunoglobulin E-mediated adverse events compared with existing whole allergen immunotherapy, often referred to as 'allergy shots'. T-cell peptide epitopes, although capable of inducing immunologic tolerance, are short linear structures that have reduced ability to cross-link mast cell- and basophil-bound immunoglobulin E. The precise mechanism of tolerance induction remains incompletely defined. However, recent data indicate that peptide therapy induces/expands a population of antigen-specific regulatory T-cells. A novel form of treatment combining efficacy with a substantially decreased occurrence of adverse events is likely to have a major impact on the management and prevalence of allergic diseases. Furthermore, the principles of epitope-specific therapy hold promise for the development of therapeutic vaccines for the treatment of autoimmune diseases.

Allergens↗
PubMed2004

Investigating T cell activation and tolerance in vivo: peptide challenge in allergic asthmatics.

In the atopic allergic individual, challenge with allergen elicits manifestations of both the humoral (IgE-mediated or early-phase reaction) and the cell-mediated immune response (late-phase reaction). Detailed study of late-phase cell-mediated events is confounded by the effects of the earlier IgE-mediated response which results in mast cell and basophil activation. Thus the relative contributions to allergic inflammation of individual cell types, such as T cells and eosinophils, are difficult to define. In this review we describe experiments, largely from our own group, in which we have attempted to dissociate early and late allergic reactions. To this end, cell-mediated responses were induced in the absence of preceding IgE-mediated events, by the delivery of synthetic peptides representing T cell epitopes of the allergen. Activation of T cells resulted in airway narrowing and an increase in airway reactivity to non-specific stimuli. Furthermore, we describe the induction of antigen-specific hyporesponsiveness or "tolerance" following intradermal, but not mucosal, peptide delivery. The induction of peptide-induced hyporesponsiveness could be temporally dissociated from the initial T cell activation resulting in bronchoconstriction and likely occurred through a different mechanism. Analysis of in vitro allergen responses of peripheral blood cells revealed that hyporesponsiveness was associated with reductions in both Th1 and Th2 cytokines, together with a concomitant increase in the regulatory cytokine IL-10. We conclude that activation of T cells in vivo may result in manifestations of chronic allergic inflammation including bronchoconstriction and hyperreactivity. Additionally, when administered systemically at low dose, peptides may induce long-lasting hyporesponsiveness in the T cell compartment, through a mechanism that is associated with induction of IL-10.

Allergens↗
PubMed2004

Tregs and allergic disease.

Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect up to 15% of populations in Westernized countries. The description of Tregs as T cells that prevent development of autoimmune disease led to considerable interest in whether these Tregs were also normally involved in prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for the therapy of allergic disease. Current data suggest that Th2 responses to allergens are normally suppressed by both CD4+CD25+ Tregs and IL-10 Tregs. Furthermore, suppression by these subsets is decreased in allergic individuals. In animal models, Tregs could be induced by high- or low-dose inhaled antigen, and prior induction of such Tregs prevented subsequent development of allergen sensitization and airway inflammation in inhaled challenge models. For many years, allergen-injection immunotherapy has been used for the therapy of allergic disease, and this treatment may induce IL-10 Tregs, leading to both suppression of Th2 responses and a switch from IgE to IgG4 antibody production. Improvements in allergen immunotherapy, such as peptide therapy, and greater understanding of the biology of Tregs hold great promise for the treatment and prevention of allergic disease.

Allergens↗
PubMed2003

Allergen immunotherapy with cat allergen peptides.

Desensitising therapy for allergic diseases has changed little over almost a century of practice. Administration of increasing doses of extracts of allergen source material has been shown to be reproducibly effective when patients are carefully selected and appropriate concentrations of allergen employed. However, specific immunotherapy is limited by the interaction of specific IgE with allergen, leading to a relatively high frequency of adverse events including anaphylaxis and death. Several strategies have been developed to tackle this issue. Most of these rely on reducing the allergenicity of the treatment, whilst maintaining the immunogenicity. The use of short, synthetic peptide sequences corresponding to T-cell epitopes from the allergen has been shown to modify surrogate markers of allergy including cutaneous responses to allergen challenge and ex vivo parameters of T-cell activation. This review discusses recent advances in our understanding of the mechanisms and potential efficacy of this form of therapy.

Allergens↗
PubMed2003

Late asthmatic reactions induced by inhalation of allergen-derived T cell peptides.

In individuals with atopy and asthma, allergen-derived T cell peptides injected intradermally induce isolated late asthmatic reactions (LARs) followed by bronchial hyporesponsiveness to peptide, inhibition of the allergen-induced cutaneous late-phase reaction, and altered T cell function in vitro. Laboratory animal data indicate that "activation" and "tolerance" also occur if peptides are inhaled. In this study, we show that inhalation of Fel d 1-derived peptides induced isolated LAR in individuals with asthma sensitive to cat allergen comparable with that previously demonstrated using intradermal injection. LARs were accompanied by eosinophilia and nonsignificant elevations of total cysteinyl leukotrienes in the sputum. Unlike the intradermal route, repeated inhalation of peptides was not associated with abrogation of the LAR and produced a sputum eosinophilia comparable with the first exposure. In addition, there was no inhibition of the cutaneous late-phase reaction to whole cat dander. Thus, isolated LAR induced by inhaled, allergen-derived peptides represent a novel model of provoked asthma and are not associated with the induction of hyporesponsiveness ("tolerance") in the skin or lung.

Administration, Inhalation↗
PubMed2003

The role of T lymphocytes in the pathogenesis of asthma.

There is considerable evidence to support a role for T cells in asthma, particularly the involvement of T(H)2 cells both in atopic allergic asthma and in nonatopic and occupational asthma. There might also be a minor contribution from T(C)2 CD8+ T cells. Several T(H)2 cytokines have the potential to modulate airway inflammation, particularly IL-13, which induces airway hyperresponsiveness independently of IgE and eosinophilia in animal models. The identification of transcription factors controlling T(H)1 and T(H)2 development further support the T(H)2 hypothesis because GATA3 is overexpressed and T-bet is underexpressed in the asthmatic airway. Specific T cell directed immunotherapy might allow induction, modulation, or both of T-cell responses, and elucidation of the mechanisms of regulatory T cells might allow further optimization of immunotherapy. Recent advances in our understanding of dendritic cell function in directing T-cell responses might uncover further therapeutic targets. The efficacy of cyclosporin A and anti-CD4 treatment in patients with chronic severe asthma argues for continued T-cell involvement, but whether remodeling contributes to pathology inaccessible to anti-inflammatory treatment or T-cell immunotherapy will be an important future question.

Adrenal Cortex Hormones↗
PubMed2003

Peptide immunotherapy for allergic disease.

The only disease-modifying treatment available for IgE-mediated disease is specific immunotherapy, but the retention of B cell epitopes in whole allergen preparations confers a risk of IgE-mediated systemic reactions to their administration. Compelling evidence for the central role of T cells in allergic disease suggests that IgE-binding epitopes could be removed from such therapy, improving safety without affecting efficacy. Short, allergen-derived peptides lack the conformational determinants required for IgE crosslinking and are, therefore, an attractive therapeutic possibility. However, human leukocyte antigen (HLA) polymorphism means that T cell peptide epitopes present a huge diversity, which makes the design of peptide-based vaccines problematic. Over the past 10 years, advances in our understanding of epitope selection and major histocompatibility complex (MHC)-peptide-T cell receptor interactions have taken this therapy forward to early clinical trials with human volunteers.

Animals↗