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Biomedical subjects

G F Hoyne

Publications and source records attributed to G F Hoyne.

At least 19 recordsLinked to original sources
PubMed1998

Induction of tolerance via the respiratory mucosa.

Immunological tolerance is defined as a state of specific non-responsiveness to a particular antigen induced by previous exposure to that same antigen. The mucosal surfaces comprise the upper and lower respiratory tracts, the gastrointestinal tract and the urogenitary tract, and are a major site of antigenic challenge. The immune system associated with the mucosa has the extraordinary potential to discriminate between antigens that are harmless (e.g. inhaled and dietary antigens) and those that are associated with pathogens. Normally soluble proteins delivered through the mucosal surfaces do not elicit a strong systemic immune response but instead induce a transient local immune response that is replaced by long-term peripheral unresponsiveness this is termed mucosal tolerance. The phenomenon of oral tolerance is well established and considerable attention has focussed on defining the underlying mechanisms. However, only comparatively recently was the induction of tolerance via the respiratory mucosa described, and it is this form of mucosal tolerance which forms the basis of this review.

Humans↗
PubMed1997

Regulation of T cell function in mucosal tolerance.

Administering antigens through mucosal surfaces leads to the induction of antigen-specific T cell unresponsiveness. This property of the mucosal immune system is now beginning to be exploited in the design of immunotherapeutic strategies aimed at targeting disease-inducing T cell populations. The induction of high dose mucosal tolerance leads to the induction of T cell anergy. Recent studies have suggested that the induction of anergy in vivo may not necessarily be due to a lack of costimulation by APC. Instead, recognition of mucosal antigen leads to transient T cell activation which eventually gives rise to a population of regulatory T cells whose function is to modulate, rather than promote antigen-specific immune responses. These regulatory T cells mediate linked suppression in vivo thus enabling T cell responses directed to a multideterminant protein to be effectively controlled. The manner in which T cell responses to mucosally delivered antigens are regulated are examined herein.

Animals↗
PubMed1997

Prediction of murine MHC class I epitopes in a major house dust mite allergen and induction of T1-type CD8+ T cell responses.

The group I (Der p 1) allergen of Dermatophagoides pteronyssinus (house dust mite, HDM) contains several T helper (Th) epitopes recognized by C57BL/6 mice, with the peptide (111-139) containing a dominant MHC class II-restricted epitope (113-127). Since CD8+ T cells are thought to play a role in the regulation of allergic disease, we examined the Der p 1 sequence for potential MHC class I-binding motifs and observed that residues 111-119 (FGISNYCQI) contain motifs for H-2Db and Kb. Furthermore, immunization of C57BL/6 mice with unadjuvanted Ty virus-like particles (VLP) carrying Der p 1 (111-139), a method known to induce murine cytotoxic T lymphocyte (CTL) responses, primed Der p 1 (111-119)-specific Db-restricted CTL which produce high levels of IFN-gamma and low levels of IL-5 and IL-6 in vitro (T1-type CTL). VLP carrying the minimal epitope (FGISNYCQI) also induced a CTL response following immunization without adjuvant by various routes. Der p 1 (111-139)-VLP adjuvanted with alum did not prime CTL in C57BL/6 mice but were found to prime Th1-type CD4+ T cells that recognize the overlapping peptide (113-127) and native protein. The ability to successfully predict allergen-specific CD8+ T cell epitopes and prime CD8+ and/or CD4+ T cell responses provides an opportunity to dissect the relative roles of these T cells in the regulation of allergic responses and may offer therapeutic potential for reprogramming Th2-type allergic responses.

Administration, Intranasal↗
PubMed1997

Characterization of the specificity and duration of T cell tolerance to intranasally administered peptides in mice: a role for intramolecular epitope suppression.

Mucosal administration of antigens in experimental animals leads to the induction of peripheral T cell tolerance. We have previously reported that in H-2b mice, intranasal (i.n.) or oral administration of a peptide containing the immunodominant T cell epitope will down-regulate the function of CD4+ T cells reactive with Der P 1, a major target antigen in both B and T cell responses to house dust mite. In the present study we have investigated the tolerogenicity of peptides containing both dominant and subdominant determinants when given i.n. to nalve mice. Induction of tolerance by the nasally administered immunodominant peptide leads to a diminution in all T cell-derived cytokines and modulation of delayed-type hypersensitivity responses, but IgE production did not seem to be affected, furthermore the induction of T cell tolerance was stable, lasting beyond 6 months. We have also examined the specificity of intramolecular epitope suppression which is a feature of mucosal tolerance induced by nasally administered peptides and demonstrate that regulatory CD4+ T cells may exert their suppressive effect by linked recognition of epitopes on the same or neighbouring antigen-presenting cells.

Administration, Intranasal↗
PubMed1996

Peptide-mediated regulation of the allergic immune response.

A major key to successful immunotherapy may depend on altering the qualitative nature of the immune response in allergic patients. In this review we examine how immune responses to environmental allergens are regulated, and the mechanisms used by the immune system to prevent allergic sensitization. We also discuss future prospects of using allergen-derived peptides in immunotherapy and the possibility of 'reprogramming' the immune responses by immunizing under conditions that promote Th1 responses instead of Th2 responses.

Animals↗
PubMed1996

Regulation of house dust mite responses by intranasally administered peptide: transient activation of CD4+ T cells precedes the development of tolerance in vivo.

We have previously demonstrated that intranasal (i.n.) administration of an immunodominant peptide (p1-111-139) derived from the house dust mite (HDM) allergen Der p 1 inhibits antigen-specific CD4+ T cell responses in H-2b mice. Here we report that i.n. peptide induced a rapid but transient activation of MHC class II restricted CD4+ T cells that peaked 4 days after peptide treatment and was of similar magnitude to that induced by parenteral immunization with antigen in adjuvant. During the early phase of the response lymph node and splenic T cells secreted a range of lymphokines when re-stimulated in vitro with p1 111-139; however, by day 14 IL-2 and IFN-gamma secretion by T cells were down-regulated. Mice deficient in CD8+ T cells became tolerant by i.n. treatment with peptide, suggesting that CD8+ T cells are not involved in down-regulating the CD4+ T cell response. Rechallenging mice with a single dose of p1 111-139 21 days after the initial treatment elicited a further transient T cell response, which was subsequently down-regulated over time. Although the i.n. peptide induced a strong transient CD4+ T cell response, only low levels of peptide-specific antibodies were detected either after the initial or subsequent i.n. exposures to p1 111-139. Our findings address the mechanisms underlying peripheral T cell tolerance following i.n. administration of a high dose of immunogenic peptide and have implications for understanding the consequences of peptide immunothearapy.

Animals↗
PubMed1996

Induction of T cell responses to the invariant chain derived peptide CLIP in mice immunized with the group 1 allergen of house dust mite.

In this study we demonstrate that immunization of H-2(b) mice with the allergen Der p 1 induces MHC class II restricted T cells that proliferate to residues 15-29 of Der p 1 (p15-29) and to the murine MHC class II-associated invariant chain derived peptide (CLIP). T cells from naive H-2(b) mice and those immunized with murine CLIP fail to respond to either CLIP or p15-29. T cell lines and clones reactive with p15-29 strongly proliferate in response to splenic antigen-presenting cells (APC) from normal H-2(b) mice but show reduced proliferation to APC from invariant chain deficient mice. Furthermore, T cells isolated from Der p 1 primed mice and expanded on H-2(b) spleen cells in the absence of the p15-29 epitope retained specificity for both p15-29 and CLIP, suggesting that naturally presented self components can act as mimetic peptides and may maintain T cell memory to foreign antigens.

Allergens↗
PubMed1995

Peptide modulation of allergen-specific immune responses.

In vitro peptide stimulation of allergen-reactive T-helper type 1 and type 0 cells, in the absence of costimulatory signals, induces anergy that is accompanied by the modulation of cell surface phenotype and changes in cytokine production. In experimental animal models, the administration of allergen-derived peptides may result in the downregulation of cytokine and antibody production, which is preceded by transient activation of CD4+ T cells, without the induction of effector immunity. Preliminary results of clinical trials using allergen-derived peptides for desensitization are becoming available and should provide some insight into the efficacy of peptide therapy in man.

Antigenic Modulation↗
PubMed1995

T-cell responses to orally administered antigens. Study of the kinetics of lymphokine production after single and multiple feeding.

Mice fed a protein antigen develop a phenomenon called oral tolerance which is defined classically by the inability to respond to a parenteral challenge with the same antigen. In a recent report we showed that antigen-reactive T cells are not depleted following the development of oral tolerance to the soluble antigen ovalbumin (OVA). Instead mice remain highly sensitized so OVA-reactive T cells can be detected in the mesenteric lymph nodes (MLN), Peyer's patches and spleen. In the present study we show that OVA-specific T cells become sensitized in the MLN within 24 hr of feeding and that lymphokine responses peak 48-96 hr after feeding. T cells produced large amounts of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma) but no interleukin-2 (IL-2) following activation in vitro. Responsiveness as measured by GM-CSF declined by days 8-11 while the ability to stimulate IFN-gamma secretion was more persistent. It was found in experiments with repeated feeding, 1 week apart, that the T-cell responsiveness was restimulated after each feed and that the magnitude and duration of the IFN-gamma or GM-CSF responses were almost identical to primary, even after 10 feeds.

Animals↗
PubMed1994

Differences in epitopes recognized by T cells during oral tolerance and priming.

Feeding protein antigens to mice normally leads to the development of oral tolerance but under some circumstances, feeding can lead to immunity, for example, following pretreatment of mice with cyclophosphamide (CY). In both cases, however, it is possible to detect sensitized T cells in the spleen and mesenteric lymph nodes (MLN) by in vitro lymphokine release for granulocyte-macrophage-CSF (GM-CSF) and IFN-gamma. This study examines the recognition of the immunodominant T cell epitope on ovalbumin (OVA) following intragastric priming and tolerance. T cells from CY/OVA treated mice and cells from mice injected subcutaneously with OVA in CFA responded well to both OVA and the H2d restricted peptide epitope pOVA323-339 releasing GM-CSF. On the other hand MLN or spleen T cells from tolerized mice which responded to the protein in vitro did not recognize the immunodominant determinant. The cells responding from tolerized mice were restricted by the class II MHC so these results show there can be differential recognition of T cell epitopes between oral priming and tolerance.

Administration, Oral↗
PubMed1994

Inhibition of T-cell responses by feeding peptides containing major and cryptic epitopes: studies with the Der p I allergen.

H-2b mice respond to the 222 residue allergen Der p I by producing T cells sensitized to the dominant epitopes encompassed in peptides 21-49, 78-100, 110-131 and 197-212. Immunization with the synthetic peptides 120-143 and 144-169, however, revealed cryptic epitopes which could sensitize T cells for responses to the respective peptides and, providing splenic adherent cells were added to lymph node cultures, to the whole allergen. It is shown that feeding recombinant fusion peptides can markedly inhibit the ability of the whole antigen to immunize mice, as measured by the in vitro interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-3 release on stimulation with protein or peptides, although inhibition measured by IL-2 release was more marked. The inhibition extended to epitopes other than those in the fusion peptides used for feeding. Thus feeding peptide 101-154 inhibited responses to 110-131 and 78-100. Fusion peptides 1-14 and 188-222 did not inhibit responses, although 188-222 did contain an epitope. Inhibition was also obtained when mice were fed a fusion containing the cryptic epitope 144-169. The ability of peptides containing the cryptic epitopes to inhibit responses has significant implications for peptide-based immunotherapy.

Administration, Oral↗
PubMed1993

Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice.

Antigen-specific CD4+ T cells play an important role in the allergic immune response to house dust mite (HDM) allergens in humans. The group 1 allergen of Dermatophagoides spp. is a major target antigen in both B and T cell recognition of HDM. In vitro studies have shown that the presentation of peptides to human T cells under appropriate conditions may lead to a state of specific nonresponsiveness. Therefore, to determine if peptides are able to modulate the function of allergen-reactive T cells in vivo, we have used a murine model of T cell recognition of the HDM allergen Der p 1. The results demonstrate that inhalation of low concentrations of peptide containing the major T cell epitope of Der p 1 (residues 111-139), induces tolerance in naive C57BL/6J mice such that they become profoundly unresponsive to an immunogenic challenge with the intact allergen. When restimulated in vitro with antigen, lymph node T cells isolated from tolerant mice secrete very low levels of interleukin 2, proliferative poorly, and are unable to provide cognate help to stimulate specific antibody production. Furthermore, intranasal peptide therapy was able to inhibit an ongoing immune response to the allergen in mice and this has potential implications in the development of allergen-based immunotherapy.

Administration, Inhalation↗
PubMed1993

House dust mite allergy: from T-cell epitopes to immunotherapy.

CD4+ T-lymphocytes induce and regulate allergic inflammatory responses to common environmental aeroallergens derived from Dermatophagoides spp. (house dust mite, HDM), which cause clinical symptoms in approximately 10% of the population. Definition of the molecular structure of HDM proteins combined with the ability to isolate monoclonal populations of human CD4+ T-cells representative of the 'interleukin-4 (IL-4) dominant' functional phenotype, which support immunoglobulin E (IgE) synthesis, has allowed T-cell recognition of HDM to be examined in detail. The results of these investigations demonstrated extensive heterogeneity in both the antigen and HLA class II restriction specificity of the HDM reactive T-cell repertoire. Furthermore, long-lived clones of T-cells with oligoclonality in T-cell antigen receptor (TcR) usage, driven by chronic stimulation with HDM, have been identified in human peripheral blood. The presentation of specific peptides and superantigens under conditions that induce T-cell non-responsiveness has provided an in vitro model for analysing the mechanisms of CD4+ T-cell targeted immunotherapy. It appears that the mechanisms underlying T-cell anergy are accompanied by a transient downregulation of TcR and CD28 and mediated by a shift in the cytokine profile from that of the 'IL-4 dominant' to the 'interferon-gamma (IFN-gamma) dominant' functional phenotype of CD4+ T-cells. In parallel, using a murine model, it has been demonstrated that administration of an immunodominant peptide via the mucosal surfaces of the respiratory and alimentary tracts may tolerize an established response to intact HDM proteins. The potential application of these models in the development of novel approaches to immunotherapy is discussed.

Allergens↗
PubMed1993

Characterization of T-cell responses to the house dust mite allergen Der p II in mice. Evidence for major and cryptic epitopes.

Major histocompatibility complex (MHC) congenic strains can be defined as high and low responders to the major house dust mite allergen Der p II on the basis of the ability to sensitize T cells for in vitro lymphokine release. Mice of the H-2b haplotype were high responders, H-2k were intermediate and H-2d low responders. Like responses to other proteins, only a limited number of epitopes could be located by the response of T cells from mice immunized with allergen to a series of overlapping peptides. The epitopes for H-2b mice were 11-35, 78-104 and 105-129, 36-50 and 78-104 for H-2k mice and 36-60 for H-2d. Immunization with the peptides however revealed that spleen-adherent cells were required for lymph node cells to recall responses to the whole protein and in addition that mice could be sensitized by cryptic epitopes defined by peptides 22-50 and 1-20 for H-2b mice. Peptides containing these cryptic epitopes did not normally induce responses in mice primed with the allergen, but when they were used for immunizing they could prime mice for responses to the peptide and the whole allergen. The results both help to define a model for studying the presentation of allergens and have significant implications for peptide-based immunotherapy.

Allergens↗
PubMed1993

Presentation of peptides and proteins by intestinal epithelial cells.

Murine intestinal epithelial cells (IEC) constitutively express major histocompatibility complex (MHC) class II molecules, which enable them to present foreign antigens to T cells in vitro. In this study we have compared the ability of freshly isolated IEC and spleen adherent cells to present both protein and peptide antigens to T cells in vitro. Consistently IEC were unable to present protein but could readily present immunogenic peptides in an MHC-dependent fashion to stimulate lymphokine release from T cells. Consistent with their inability to process protein antigens, IEC were also unable to present a synthetic peptide which requires intracellular processing, whereas spleen antigen-presenting cells (APC) could readily present the same peptide. These findings indicate that IEC may lack the necessary intracellular machinery to process exogenous antigens but they raise the possibility that IEC may play an important immunological role in vivo by presenting processed peptides to T cells.

Animals↗
PubMed1993

Comparison of antigen presentation by lymph node cells from protein and peptide-primed mice.

Lymph node cells from mice primed with peptides from the allergens Der p I and Der p II (the group I and II allergens of Dermatophagoides pteronyssinus) were unable to recall responses to the protein antigen when cultured in vitro despite being able to mount large responses to the peptides. The T cells could however recall responses to the protein when spleen-adherent cells were added into culture. Treating the spleen accessory cells with the monoclonal antibody (mAb) 33D1 and complement largely abrogated the protein response of peptide-primed T cells which indicates that dendritic cells were mainly responsible for the antigen-presenting function. If mice were primed with two injections of peptide the lymph node cells obtained could respond to both protein and peptides in vitro without the need for exogenous accessory cells. Using either negative depletion with the J11D mAb or positive purification, it was found that the presentation of protein antigen to lymph node T cells primed with either protein or peptide was limited to antigen-specific B cells. Peptide antigens could however be presented by both B and non-B populations. In one case the peptide 105-129 from Der p II which contains a T-cell epitope could not be shown to induce T-cell responses in the lymph node unless presentation was mediated by spleen-adherent or B-specific cells. These results are important for peptide-based immunomodulation and in interpreting results obtained from lymph node cultures.

Allergens↗