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Biomedical subjects

H Renz

Publications and source records attributed to H Renz.

At least 109 records · Page 6Linked to original sources
PubMed1997

Modulation of the allergic immune response in BALB/c mice by subcutaneous injection of high doses of the dominant T cell epitope from the major birch pollen allergen Bet v 1.

Several in vitro and in vivo studies indicate that application of high doses of dominant T cell epitopes can induce a state of antigen-specific non-responsiveness (anergy). In the present study, we developed a murine model of an allergic immune response to Bet v 1, the major birch pollen allergen. Mice were sensitized by injection of rBet v 1 and the allergic state was proven by the presence of allergen-specific IgE and positive immediate-type skin tests to Bet v 1. In epitope mapping experiments, an immunodominant T cell epitope of Bet v 1 in BALB/c mice was identified by the use of overlapping peptides. This peptide (BV 139) was subsequently employed for treatment. Two tolerization protocols were used: in one approach, the peptide was administered to naive mice before immunization (group BV139-S), in the second, already sensitized mice were treated (S-BV139). The results demonstrated that administering high doses of the dominant T cell epitope of Bet v 1 profoundly diminished T cell proliferation to the peptide in the BV139-S group, and to the peptide as well as to the whole protein in the S-BV139 group. Skin test reactivity to Bet v 1 was reduced in the BV139-S group. However, no differences in terms of specific antibody production between treated and untreated mice could be observed. This study provides evidence that administration of dominant T cell epitopes can down-regulate the allergen-specific T cell response. Proceeding on the assumption that the T lymphocyte response to allergens is crucial for the induction and maintenance of the allergic disease, a modulation of the immune response to allergens by treatment with T cell epitope peptides could represent a promising concept for immunotherapy in the future.

Adjuvants, Immunologic↗
PubMed1997

Incremental lines in root cementum of human teeth: an approach to their ultrastructural nature by microscopy.

In ground sections of human teeth, root cementum shows under the light microscope as alternating, almost concentric, dark and light rings. In paleontology and forensic medicine, the number of these incremental lines or annulations is used to derive the age-at-death of the individual. To find the ultrastructural features underlying these cemental annulations, we used bright-field light microscopy (LM), confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), and electron-dispersive x-radiation (EDX) in a scanning electron microscope (SEM). Annulations visible in ground sections of about 100-micron thickness were no longer visible in semi-thin sections (thickness, 1-2 microns) of the same specimen in the same area. The assumption that annulations could be caused by super-imposing structures in the depth of field of the light microscope's objective lens was not verified by CLSM. Fiber bundles of higher density than the surrounding matrix in TEM micrographs could not be connected unambiguously with annulations in LM micrographs. After all, the ultrastructural nature of cemental annulations remains an open question.

Age Determination by Teeth↗
PubMed1997

Effects of powder on infection risks and associated mechanisms.

This paper examines the release of Tumour necrosis factor alpha, (TNFa) interleukin 1, eicosanoids, and hydrogen peroxide from macrophages exposed to glove starch particles. Studies are described which show that T-cell responses are potently activated by glove powder products leading to the release and formation of high amounts of pro-inflammatory mediators, ultimately resulting in adverse clinical consequences such as starch peritonitis or adhesions.

Animals↗
PubMed1996

Nebulized IFN-gamma inhibits the development of secondary allergic responses in mice.

The effects of nebulized IFN-gamma on primary and secondary IgE production and development of airway hyper-responsiveness (AHR) were investigated. BALB/c mice received primary exposure to aerosolized OVA daily for 10 days and developed anti-OVA IgE responses, immediate cutaneous reactivity to OVA, and altered airway function when assayed on day 12. After secondary exposure to OVA challenges on days 30 and 31, these mice developed an amplified IgE response, heightened cutaneous reactivity to OVA and AHR when measured on day 37. Administration of IFN-gamma for 13 days, beginning 3 days prior to and during primary OVA sensitization, resulted in a decrease in anti-OVA IgE, increases in serum anti-OVA IgG2a levels, a decrease in cutaneous reactivity to OVA, and normal airway function when assessed on day 12 after primary sensitization. This treatment also prevented the development of secondary anti-OVA IgE responses and altered airway responsiveness but did not induce a secondary rise in anti-OVA IgG2a in the serum measured on day 37. Treatment with IFN-gamma on days 26 to 30, well after primary responses were established but just prior to secondary OVA challenge, abolished the development of secondary anti-OVA IgE responses, resulted in an increase in anti-OVA IgG2a in the serum, and prevented the development of AHR. In vitro, CD4+ T cells obtained from OVA-sensitized mice treated with either "early" or "late" IFN-gamma inhibited IgE production. Delivery of IFN-gamma to the airways can prevent secondary allergen sensitization even after primary sensitization has been achieved and this effect is mediated by CD4+ T cells.

Administration, Inhalation↗
PubMed1996

Stimulation of IgE and IgA production by CD45RA T helper cells in atopic patients.

The role of CD45RA T cells on allergen-dependent lymphocyte functions was analyzed in atopic patients. As compared with age-matched nonatopic controls, atopic patients exhibited a significantly (p < 0.01) increased frequency of CD45RA T cells in peripheral blood. Concentration of serum IgE correlated with increases in this T cell subset. In contrast to nonatopic controls, not only CD45RO but also CD45RA T cells from atopic patients provide help for allergen-stimulated IgE and IgA production, and they act in a synergistic fashion. Transwell coculture experiments revealed that optimal production of IgE and IgA required physical contact of CD45RA T cells with B cells. Freshly prepared and in vitro-activated CD45RO and CD45RA T cells from atopic patients showed an increased expression of CD40 ligand when compared with nonatopic individuals. In addition, CD45RA (and CD45RO) T cells from atopic individuals produced IL-4, IL-5, and IFN-gamma when stimulated with mitogens. Whereas stimulation of normal lymphocytes with tetanus Ag was followed by conversion of the CD45RA to the CD45RO phenotype, T cells from atopic donors did not acquire the CD45RO isoform to the same degree despite T cell activation. In atopic patients, addition of IL-4 to anti-CD3/anti-TCR stimulated CD45RA T cell prevented the shift towards the CD45RO phenotype. These data indicate that a subset of CD45RA T cells plays a unique role as effector T cells regulating IgE and IgA production in atopic patients.

Allergens↗
PubMed1996

Nerve growth-factor and anti-CD40 provide opposite signals for the production of IgE in interleukin-4-treated lymphocytes.

Nerve growth factor (NGF) is a well-known neurotrophic factor acting on both the peripheral and the central nervous systems. In addition, it has been shown to play a role in the function of the immune system through specific receptors. Both high-affinity and low-affinity NGF receptors (NGFR) are expressed on human B lymphocytes. The low-affinity NGFR has been shown to have structural homology with another specific B cell surface molecule, CD40, which plays an important role in IgE production. In view of the structural similarities of the p75 NGFR and CD40 we examined whether NGF may also be involved in the regulation of IgE production. We found that NGF and anti-CD40 exerted opposite effects on the induction of IgE by IL-4 in peripheral blood mononuclear cells. NGF inhibited the induction of IgE by IL-4 and this inhibition was not mediated through blocking of the induction of CD23 nor through inhibition of IL-4R expression. The inhibition of IL-4-dependent IgE production was observed on surface (s)IgE+ and sIgE-/sIgM+ B lymphocytes. Anti-CD40 on the other hand, exerted an enhancing effect on IgE production and its addition to IL-4 provided a signal that was resistant to the inhibitory effect of NGF. Antagonistic effects of NGF and IL-4 were also observed for other Ig isotypes since IL-4 prevented the increase in IgA and IgM production induced by NGF. These data indicate that although NGFR and CD40 belong to the same receptor superfamily and exert similar proliferative effects on B lymphocytes, they interact differently with IL-4 in the regulation of IgE production.

Antibodies, Monoclonal↗
PubMed1996

Effects of interferon-alpha on cytokine profile, T cell receptor repertoire and peptide reactivity of human allergen-specific T cells.

A large panel of T cell clones (TCC) specific for the recombinant form of Poa pratensis allergen (rKBG7.2 or Poa p9) were established from the peripheral blood of grass pollen-sensitive donor in the absence or presence of recombinant interferon-alpha (IFN-alpha) in bulk culture and their pattern of cytokine secretion, peptide reactivity and TCR V beta repertoire was examined. The majority of allergen-specific TCC derived in absence of IFN-alpha produced high amounts of interleukin-4 (IL-4) and IL-5 but not IFN-gamma (Th2 cells), while most of TCC derived in presence of IFN-alpha produced IFN-gamma but not, or limited amounts of, IL-4 and IL-5 (Th1 or Th0 cells). Of 24 TCC established in the presence of IFN-alpha, 22 were able to recognize a single allergen peptide, p26, while none of the clones established in the absence of IFN-alpha showed a similar specificity. The majority of both clones expressed the V beta 2 element regardless of whether they were established in the presence of INF-alpha, but the presence of IFN-alpha favored the expansion of V beta 2+, V beta 17+ and V beta 22+ Poa p9-specific T cells, whereas in the absence of IFN-alpha, other TCR V beta-bearing T cells (V beta 5, and V beta 6.7, and V beta 14) were expanded in addition to V beta 2+ T cells. None of V beta 2+ clones established in the absence of IFN-alpha reacted with p26, whereas all the V beta 2+ clones established in its presence in the absence of interferon-alpha reacted with p26, whereas all the V beta 2+ clones established in its presence reacted to this peptide. IFN-alpha also shifted the TCR V beta repertoire of both Poa p9- and Lolium perenne group 1 (Lol p1)-specific T cell lines generated from the same patient and from a different grass-sensitive individual. These data demonstrate that IFN-alpha modulates the development of allergen-specific T cells in vitro, and suggest that IFN-alpha may represent a useful tool for novel immunotherapeutic approaches in allergic disorders.

Allergens↗
PubMed1996

Murine animal models to study the central role of T cells in immediate-type hypersensitivity responses.

The development of allergic sensitization and inflammation is dependent on activation and stimulation of T cells that exhibit pro-allergic functions. A mouse model system was developed to study the role of T cells in allergic sensitization in more detail. Local sensitization of mice stimulates an allergen specific IgE/IgG1 response that is associated with the development of immediate type skin test responses and increased airway responsiveness (AR). Strains of mice are identified that are high or low responder animals for allergens including ovalbumin and house dust mite. Each allergen stimulates a different pattern of T-cell receptor V beta expressing T cells in local draining lymph nodes. To induce a state of increased AR, at least two separate events are required. The first event is the presence of allergen specific IgE/IgG1. The second event is characterized as a local allergen challenge at the site of the response. These T cells play a critical role in the regulation of the allergic immune response including IgE production and increased AR. Based on these results intervention strategies can be developed which specifically target the development and function of these allergen specific T-cell populations and modify their pro-allergic activities.

Allergens↗
PubMed1996

The relevance of murine animal models to study the development of allergic bronchial asthma.

Bronchial asthma (BA) develops on the basis of a genetic predisposition and involves a characteristic sequence of changes in immune functions. In the immunopathogenesis, several phases can be distinguished: the initial stage is defined as the development of allergic sensitization. This step is dependent on: (i) T cell activation; (ii) IL-4 production; (ii) IgE synthesis; and (iv) mediator release by effector cells. The second phase of allergic inflammation as a consequence of the T cell dependent sensitization is characterized by IL-5 production and eosinophil activation and recruitment. Airway mucosa remodelling is the consequence of chronic inflammatory processes and represents the final stage of BA. In this article animal models will be discussed with regard to their relevance for these different phases in development of chronic allergic BA.

Animals↗
PubMed1996

Allergen specificity of skin-infiltrating T cells is not restricted to a type-2 cytokine pattern in chronic skin lesions of atopic dermatitis.

The majority of allergen-specific T cells derived from inhalant allergen patch test lesions in patients with atopic dermatitis were previously found to produce a restricted type-2 cytokine pattern. Recent studies, however, have revealed that in chronic eczematous skin lesions of patients with atopic dermatitis, expression of the type-1 cytokine interferon-gamma predominates. To evaluate cytokine production by allergen-specific T cells in chronic atopic dermatitis, we established house dust mite (Dermatophagoides pteronyssinus)-specific T-cell clones from the dermis of chronic skin lesions of sensitized adult patients with atopic dermatitis. Frequencies of skin-derived T cells proliferating in the presence of Dermatophagoides pteronyssinus were between one in 138 and one in 4255, indicating that only a minority of skin-infiltrating T cells are allergen specific. When these cells were analyzed for their capacity to produce interferon-gamma, the majority (71%) of these cells were found to express interferon-gamma mRNA and to secrete interferon-gamma protein, either alone or in combination with interleukin-4. Phenotypic analysis revealed that 15% of skin-infiltrating allergen-specific T cells were CD8+. No selection of Vbeta elements was detected in Dermatophagoides pteronyssinus-specific T-cell clones. These studies demonstrate that allergen specificity of skin-infiltrating T cells is not restricted to a type-2 cytokine pattern in lesional atopic dermatitis. The notion that the majority of allergen-specific, skin-infiltrating T cells are capable of producing interferon-gamma further supports the concept that interferon-gamma expression has major pathogenetic relevance for the chronic phase of atopic dermatitis.

Adult↗
PubMed1996

Prevention of the development of immediate hypersensitivity and airway hyperresponsiveness following in vivo treatment with soluble IL-4 receptor.

The effects of local versus systemic treatment with soluble IL-4 receptors (sIL-4R) were tested in a model of allergen-induced immediate hypersensitivity responses in BALB/c mice. Mice sensitized through the airways to ovalbumin (OVA) by ultrasonic nebulization once a week for 4 weeks developed increased serum anti-OVA IgE and IgG1 antibody titers and these were accompanied by immediate-type skin test responses to the allergen. These responses were also associated with the development of increased airway responsiveness (AR) as monitored by electrical field stimulation of tracheal smooth muscle preparations in vitro. Sensitized mice, treated by intraperitoneal injections of sIL-4R (150 micrograms/injection) administered in parallel to the sensitization protocol, developed significant suppression of anti-OVA IgE, anti-OVA IgG1 antibody production and of immediate cutaneous hypersensitivity responses. Airway responsiveness was normalized to some extent. Total IgE production was only slightly reduced. These effects were comparable to the findings following intraperitoneal injection of monoclonal anti-IL-4 antibody. Administration of sIL-4R via the airways was also effective in inhibiting the development of immediate hypersensitivity responses, including IgE production, and was more potent in normalizing airway responsiveness. These effects were achieved at lower concentrations than needed for systemic treatment. These data suggest that delivery of sIL-4R via the airways can effectively modulate the development of immediate hypersensitivity and airway hyperresponsiveness in response to aerosolized allergen.

Aerosols↗
PubMed1996

Pretreatment with allergen prevents immediate hypersensitivity and airway hyperresponsiveness.

The ability of subcutaneous pretreatment with an immunogenic peptide derived from Fel d I, the major cat protein, to suppress the development of allergic responses was examined in a mouse model of antigen-induced sensitization. BALB/c mice exposed to aerosolized Fel d I chain 1 peptide developed antigen-specific IgE responses, immediate cutaneous reactivity to the peptide, and increased airway responsiveness (AR). Both subcutaneous and intraperitoneal administration of the peptide prior to sensitization caused a 50% reduction in cutaneous reactivity which was associated with a decrease in serum anti-Fel d I chain 1 IgE and IgG1 antibody responses and an increase in specific IgG. Pretreatment with the peptide also suppressed spleen and lymph node proliferative responses to the peptide. However, only subcutaneous peptide injections could prevent the development of increased AR. Transfer of spleen cells from subcutaneously peptide-treated mice to sensitized recipients reduced serum antigen-specific IgE and IgG1 antibody responses and skin test reactivity, and prevented alterations in AR. These data suggest that IgE (and IgG1) responses and airway hyperresponsiveness induced by allergen sensitization via the airways can be modulated by subcutaneous administration of peptide. Further, the results define a model for investigating the modulatory effects of subcutaneous administration of immunogenic peptides or protein on an ongoing allergic response.

Aerosols↗
PubMed1996

Production of interleukin-4 and interferon-gamma by TCR-V beta-expressing T-cell subsets in allergen-sensitized mice.

Sensitization of BALB/c mice to ovalbumin (OVA) through the airways stimulated allergen-specific immediate hypersensitivity responses and these effects were related to the expansion of V beta 8.1/8.2+ T cells. In contrast, splenic V beta 2+ T cells from sensitized animals inhibited V beta 8.1/8.2+ T-cell induction of anti-OVA IgE production in vivo. To examine whether such differences in T-cell function were associated with differences in cytokine production, CD4+ T cells and CD4+ T cells depleted of V beta 8.1/8.2+ T cells were analyzed for interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) production. In nonsensitized animals, no differences in IL-4 and IFN-gamma production were found in mRNA levels as well as in protein levels in these two populations of cells. In contrast, CD4+ T cells from sensitized mice showed higher IL-4 and lower IFN-gamma production than CD4+ cells depleted of V beta 8+ lymphocytes. Similar results were obtained after stimulation of CD4+ T cells from OVA-sensitized animals with anti-V beta 2 and anti-V beta 8.1/8.2 antibodies. Stimulation of V beta 8.1/8.2+ T cells from sensitized mice with OVA or OVA peptide 323-339 also resulted in increased production of IL-4. These data indicate that allergen sensitization via the airways stimulates the selective expansion of certain V beta-expressing T cells and that these T-cell subsets exhibit different functional activities in terms of cytokine production.

Allergens↗
PubMed1995

Modulatory effects of staphylococcal superantigen TSST-1 on IgE synthesis in atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin disorder associated with elevated serum IgE and colonization of the skin by Staphylococi which secrete toxins with superantigenic activity. The present study examined the immunomodulatory effects of toxic shock syndrome toxin (TSST)-1, a prototypic superantigen, on IgE synthesis by interleukin (IL)-4-stimulated peripheral blood mononuclear cells (PBMC) from five patients with AD and five normal subjects. TSST-1 inhibited IL-4-induced IgE synthesis by AD and normal PBMC (P < 0.05). In contrast, IgG synthesis was not similarly affected (P > 0.30). Inhibition of IL-4-induced IgE production was associated with induction of interferon (IFN)-gamma synthesis by TSST-1 (P < 0.02). Normal PBMC synthesized significantly more (P < 0.005) IFN-gamma than AD PBMC. A neutralizing antibody to IFN-gamma reversed TSST-1-induced suppression of IgE synthesis by the normal PBMC (P < 0.03), but not the AD PBMC. In AD, but not normal, PBMC anti-IFN-alpha antibody reversed the suppression of IgE synthesis induced by TSST-1. These results demonstrate that TSST-1 uses different mechanisms for modulation of IgE synthesis in AD versus normal PBMC. Furthermore, the reversal of TSST-1-induced suppression of IgE synthesis in AD PBMC by anti-IFN-alpha, but not anti-IFN-gamma, is consistent with the concept that AD is associated with defective Th1 cell function and enhanced monocyte activity.

Adult↗
PubMed1995

Role and modulation of T-cell cytokines in allergy.

Allergic sensitization and the development of effector functions are controlled by IL-4-secreting and IL-5-secreting type 2 T cells. Recent studies have provided new insights into the events triggering the development of type 1 and type 2 T cells, the discrimination of type 1 and type 2 effector T cells from various T-cell subsets, and the improvement of established and new therapeutic strategies, which are aimed at modulating such T-cell functions in the allergic patient.

Adjuvants, Immunologic↗
PubMed1995

Decreased frequency of interferon-gamma- and interleukin-2-producing cells in patients with atopic diseases measured at the single cell level.

BACKGROUND: Recently, diminished interferon-gamma (IFN-gamma) and increased interleukin (IL-4 production in peripheral blood mononuclear cells (PBMCs) from atopic patients have been described by several groups, measured as total cytokine content in culture supernatants. These studies suggested a predominance of TH2-like cells producing large amounts of IL-4 in atopic patients. It is not clear whether the reported cytokine imbalances are the result of an alteration in the distribution of specific T-cell subsets or whether intrinsic dysregulation in cytokine production is a characteristic of atopic individuals. OBJECTIVE: This study examined the production of IFN-gamma, and IL-2 in PBMCs from atopic patients at the single cell level with the use of freshly isolated lymphocytes. METHODS: We recently described a flow cytometric assay in which three-color analysis was used to study the production of a cytokine of interest in a T-cell subpopulation defined by two cell surface markers. PBMCs from 23 atopic patients and 14 control subjects were stimulated with phorbol ester and ionomycin for 5 hours. PBMCs from seven patients and seven control subjects were also cultured with immobilized anti-CD3 antibodies for 24 hours. Cells were fixed, made permeable, and stained for intracellular cytokines in combination with cell surface markers CD3, CD8, and CD45RO. Cytokine-producing cells were analyzed by gating on T-cell subsets. RESULTS: IFN-gamma-producing cells were significantly decreased (p < 0.05) in CD4+ T cells but not in CD8+ T cells of atopic patients. CD45R0+ and CD45R0-T cells showed a decreased proportion of IFN-gamma-producing cells (p < 0.05 and p < 0.01, respectively). IL-2 production was diminished in all T-cell subsets (p < 0.01). The number of IL-4-producing cells was not elevated, and such cells were exclusively found in the CD45RO+ T cells. Analysis of culture supernatants of sorted CD45RO+ T cells for IL-4 and IFN-gamma production confirmed these results. CONCLUSION: Our findings provide evidence that a reduced IFN-gamma production in atopic patients is due to an intrinsic defect selectively found in the CD4+ T cells. Because IL-2 production was markedly decreased but IL-4 production was unchanged, our data demonstrate a deficiency in the ability of atopic T cells to produce TH1-like cytokines on stimulation with phorbol ester, ionomycin, or anti-CD3 monoclonal antibodies.

Adolescent↗
PubMed1995

T cell receptor-V beta repertoire in allergen-specific sensitization and increased airway responsiveness.

An animal model system was developed to study the mechanisms resulting in allergic sensitization. Local allergen exposure via the airways and the lung stimulated an allergen-specific immunoglobulin E (IgE) response that was paralleled by the development of increased airway responsiveness (AR). It was found that CD4+ T cells of local draining lymph nodes played an important role in the regulation of these events. Stimulation of allergen-specific T cells requires interaction between major histocompatibility complex (MHC) class II molecules (expressed on antigen-presenting cells), peptide (presented on MHC) and the T cell receptor. Allergen sensitization stimulated T cells that expressed a restricted T cell receptor V beta (TCR-V beta) elements. Each allergen stimulated different V beta elements, and sensitization to the same allergen resulted in a different pattern of TCR-V beta stimulation in different lymphoid tissues. Some of these T cells had pro-allergenic effects, whereas others were able to inhibit the development of the allergic response, including the development of increased AR. These data indicate that the local T cell response regulates the type of immune response that evolves following local allergen sensitization.

Allergens↗