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Biomedical subjects

M L Kapsenberg

Publications and source records attributed to M L Kapsenberg.

At least 55 records · Page 3Linked to original sources
PubMed1996

T-cell responses to allergens: epitope-specificity and clinical relevance.

Allergen-specific T cells play an important role in the pathophysiology of atopic allergies. Recently, cDNAs that encode many important allergens have been cloned and their amino acid sequences deduced, thus allowing the elucidation of the epitope-specificity of allergen-specific T cells. Here, Joost van Neerven and colleagues discuss the results of these studies, and the implications for the development of efficient strategies for specific immunotherapy.

Allergens↗
PubMed1996

Chemicals and proteins as allergens and adjuvants.

Small molecular weight chemicals may irritate tissues via the induction of the production of various proinflammatory and chemotactic molecules. The structure of these irritants is heterogenous, as is the pattern of their effects. Chemicals are potentially allergenic (i.e. haptens) when they are able to bind proteins such as immune response molecules. Sensitization will occur when these haptens additionally induce irritation resulting from an intrinsic adjuvant's activity of the chemical. In most cases haptens induce the activation of hapten-specific T cells with a type 1 cytokine profile mediating delayed hypersensitivity. A limited number of haptens induce the production of type 2 cytokines in T cells and, consequently, allergic reactions after inhalation. Similarly, inhaled proteins become allergenic when they activate protein allergen-specific T cells producing type 2 cytokines. In many individuals this cytokine profile is associated with atopy. It must be expected, however, that a type 2 cytokine profile can also be inflicted by the action of various adjuvants types, such as biologically active small molecular weight chemicals and proteins (i.e. enzymes) and microorganisms, thereby promoting allergic reactions.

Adjuvants, Immunologic↗
PubMed1996

Food allergen (peanut)-specific TH2 clones generated from the peripheral blood of a patient with peanut allergy.

BACKGROUND: Increasing evidence indicates a prominent role of allergen-specific TH2 cells, with high IL-4 and IL-5 production and low interferon-gamma production, in the regulation of IgE and eosinophil production in allergic disorders. However, most studies have concentrated on T cells reactive with inhalation allergens, whereas little is known about the properties of food allergen-reactive T cells. OBJECTIVES: In this study we therefore characterized peanut-specific T cells, cloned from a patient with severe peanut allergy. METHODS: Peripheral blood mononuclear cells from patients with peanut allergy and nonallergic individuals were stimulated with crude peanut extract (CPE) to compare the proliferative responses and to select a suitable patient for the cloning of CPE-specific T cells. The resultant panel of CPE-reactive T-lymphocyte clones was serologically phenotyped by flow cytometry and analyzed for cytokine secretion by ELISA. RESULTS: The patients' peripheral blood mononuclear cells showed a dose-dependent proliferation response to CPE, which was significantly higher (p < 0.05) than in peripheral blood mononuclear cells of nonallergic donors. The CPE-specific T-lymphocyte clones generated from the selected patient were all CD4+/CD8- T helper cells with a TH2 cytokine profile, secreting high amounts of IL-4 and IL-5, but little or no interferon-gamma. CONCLUSIONS: This study demonstrates that peanut-specific T cells do occur in the peripheral blood of patients with peanut allergy and suggests an increased frequency of these T cells in patients compared with nonallergic control subjects. The CD4+ phenotype and the TH2 cytokine profile of the CPE-specific T-lymphocyte clones suggest a functional role of allergen-specific TH2 cells in the pathophysiology of food allergy, similar to the function of inhalation allergen-specific TH2 cells.

Adult↗
PubMed1996

Production and modulation of T-cell cytokines in atopic allergy.

Atopic allergy is associated with allergen-specific CD4+ T cells showing a bias to production of the type-2 cytokines interleukin (IL)-4 and IL-5. There are indications that this bias is also evident in atopic T-helper (Th) cells with other antigen specificities. The balance between the production of type-1 and type-2 cytokines is influenced by various factors present in the microenvironment of the Th cells during their activation. Factors of special interest are antigen-presenting cell-derived IL-12 and prostaglandin E2, skewing to type-1 and type-2 cytokine production, respectively. The production of IL-12 and prostaglandin E2 is induced by the interaction between CD40 and CD40 ligand expressed by Th cells, and by biologically active agents such as micro-organisms or their products. The IL-12/prostaglandin E2 production ratio depends on the antigen-presenting cell type, the type of stimulus and the presence of certain cytokines. Other Th-cytokine-skewing factors are autocrine or paracrine IFN-gamma and IL-4. In fact, the type-1/type-2 cytokine production balance in Th cells is under the control of various soluble products that act in a complex network of type-1 (e.g. IL-12, IFN-gamma) or type-2 (e.g. IL-4, IL-10 and prostaglandin E2) factors and are produced by Th cells and their accessory antigen-presenting or bystander cells. The levels of these factors may further be determined by gene polymorphisms or aberrant hormone levels. Despite the growing knowledge of the regulation of Th-cell cytokine production, the etiology of biased cytokine production in atopic allergic individuals is still enigmatic.

Animals↗
PubMed1996

Novel predictive assay for contact allergens using human skin explant cultures.

Contact allergens sensitize the immune system by the binding to and subsequent activation of Langerhans cells (LCs), the antigen-presenting cells of the skin. At present, new chemicals are usually tested for their contact allergenicity in animal models. To develop an animal-replacing predictive in vivo assay for the identification of potential contact allergens, we compared the effects of epicutaneous application of six known contact allergens, five known irritants and two dermatologically inactive chemicals on LCs in skin biopsy cultures from seven healthy donors. Immunohistochemical analysis of cryostat sections of all the biopsies treated with contact allergens showed 1) a large reduction in the number of LCs in epidermis, as evaluated by a decrease in human leukocyte antigens (HLA)-DR-expressing cells, and CD1a-expressing cells and 2) accumulation of the remaining LCs at the epidermal-dermal junction. In contrast, the irritants, inactive chemicals, and solvents did not induce these changes. Morphometrical analysis indicated that the contact allergen-induced reduction in the number of HLA-DR+ and CD1a+ LCs per millimeter of epidermis was significant and was dependent on the concentration of the contact allergens. Flow cytometric analysis of isolated epidermal cells confirmed the immunohistochemical findings. In combination, these results suggest that the culture of ex vivo human skin explants provides a promising model to predict potential allergenicity of newly produced chemical compounds and can therefore replace current animal models.

Allergens↗
PubMed1996

Effects of contact allergens on human Langerhans cells in skin organ culture: migration, modulation of cell surface molecules, and early expression of interleukin-1 beta protein.

Epidermal Langerhans cells (LC) and cytokines play a critical role in the initiation phase of contact hypersensitivity reactions in the skin. Most of the studies of these aspects have been performed in animal models and relatively little is known about the human system. Short-term human skin organ cultures, in which LC preserved their characteristics and distribution within the epidermis, were used to examine the time course effects of contact allergens on human LC in situ and whether these effects are mediated by cytokines. Epicutaneous application of nontoxic concentrations of contact allergens 2,4-dinitrofluorobenzene, 2,4-dinitrochlorobenzene, and nickel sulphate, but not the irritants sodium dodecylsuphaye and croton oil or the tolerogen 2,4-dichloronitrobenzene, significantly reduced the total number of LC in the epidermis: remaining LC were localized along the epidermal-dermal junction, suggesting a migration of LC within and out of the epidermis. LC that are migrated to the epidermal-dermal junction showed a decreased expression of CD1a+ and MHC-II and an upregulation of ICAM-I. While these effects were observed after 24 hours, the expression of IL-1 beta protein was induced exclusively by LC as early as 4 hours after skin challenge with contact allergens alone. After 24 hours, contact allergens not only increased the expression of IL-1 beta but also induced the expression of IL-1 alpha, TNF-alpha, GM-CSF, and IL-6 proteins mainly by suprabasal keratinocytes. In an attempt to study the possible relation between allergen-induced epidermal cytokines and the migration and phenotypic changes of LC, skin explants were incubated with corresponding human recombinant (hr) cytokines. After 12 hours, hr IL-1 beta, but not other hr cytokines (IL-1 alpha, TNF-alpha, GM-CSF, and IL-6), induced the migration within and out of the epidermis and decreased the expression of CD1a+ and MHC-II on remaining epidermal LC similar to that caused by contact allergens. Pre-incubation of skin explants with neutralizing IL-1 beta antibodies, but not antibodies to IL-1 alpha, TNF-alpha, or GM-CSF, significantly prevented the allergen-induced migration of LC. This study showed that contact allergens preferentially induced the migration of LC within and out of the epidermis and modulated the expression of cell surface molecules on migrated LC as well as induced the early expression of LC-derived IL-1 beta. We also provide evidence that IL-1 beta is critically involved in contact allergen-induced changes on human epidermal LC and suggest that IL-1 beta plays a role in the initiation of contact hypersensitivity in human skin in vivo.

Allergens↗
PubMed1996

Modulation of T-cell cytokine secretion by accessory cell-derived products.

Several major pathological characteristics of atopic disease are causally related to CD4+ allergen-specific type 2 T-helper (Th2) cells with an aberrant cytokine secretion profile, comprising high levels of interleukin (IL)-4 and IL-5 and low levels of interferon (IFN)-gamma. Although the cytokine secretion patterns of CD4+ T-cells may be stable, they can be modulated by physiological factors which may be expected to be present during activation of these T-cells. In this review, we will focus on two secretion products of professional antigen presenting cells (APCs) and accessory cells with opposite modulatory effects on T-cell cytokine profiles, i.e. prostaglandin E2 (PGE2) and IL-12. PGE2 favours Th2-like cytokine secretion profiles by inhibiting the production of the Th1-associated cytokines, IL-2 and IFN-gamma, and in the presence of sufficient levels of IL-2, upregulating the production of the Th2-associated cytokines, IL-4 and IL-5, IL-12, on the other hand, induces and enhances IFN-gamma secretion in activated CD4+ T-cells, thereby promoting the generation of Th1 cells. PGE2 and IL-12 act via independent mechanisms and, therefore, do not mutually interfere with their modulatory effects. These data suggest that the relative contribution of PGE2 and IL-12 to the levels of secreted Th1- and Th2-associated cytokines are determined by their concentration ratio during T-cell activation.

Antigen Presentation↗
PubMed1995

Functional maturation of human naive T helper cells in the absence of accessory cells. Generation of IL-4-producing T helper cells does not require exogenous IL-4.

In the human model, requirements for the primary onset of IFN-gamma and IL-4 production in maturing T helper lymphocytes were compared. Stimulation of freshly isolated CD4+CD45RA+ naive Th cells with immobilized CD3 mAb in the presence of exogenous IL-2 resulted in the proliferative response of this subset, which was equal to or higher than CD4+CD45R0+ memory Th cells. Throughout the first 6 days after this mode of stimulation, naive Th cells did not secrete IL-4 and produced only small amounts of IFN-gamma, whereas high amounts of both lymphokines were secreted by stimulated autologous memory Th cells. Under these conditions, naive Th cells acquired the CD45RA-CD45R0+ memory phenotype. After restimulation, such in vitro-generated CD45R0+ cells produced high amounts of IFN-gamma but, despite the full phenotype conversion, they produced only trace amounts of IL-4. In contrast, when the primary stimulation and the expansion of cells proceeded in the presence of IL-1 beta or CD28 mAb, both IFN-gamma and IL-4 were produced after restimulation, in similar amounts compared with those produced by memory Th cells. The effect of IL-1 beta and CD28 signaling could not be obtained by the administration of exogenous IL-4 nor could the onset of IL-4 production be prevented by the presence of a neutralizing anti-IL-4 Ab in primary cultures. These data show that the development of human IL-4-producing Th cells can proceed in the absence of any pre-existing source of IL-4 and can be driven solely by the APC-related signals.

Antigen-Presenting Cells↗
PubMed1995

Differential modulation of T helper type 1 (Th1) and T helper type 2 (Th2) cytokine secretion by prostaglandin E2 critically depends on interleukin-2.

Prostaglandin E2 (PGE2) favors T helper type 2 (Th2)-like cytokine secretion profiles in murine and human CD4+ T cells by inhibiting the production of the Th1-associated cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and up-regulating the production of the Th2-associated cytokines IL-4 and IL-5 in a dose-dependent way. However, the potent inhibition of IL-2 production by PGE2 seems to be in contrast with the simultaneous up-regulation of IL-4 and IL-5 production, because the induction of these cytokines requires IL-2. We, therefore, investigated to which extent the net modulatory effect of PGE2 is determined by the availability of IL-2. To this aim, we examined the effects of PGE2 on the cytokine secretion profiles of a panel of human Th0 clones upon stimulation via different activation pathways, resulting either in high or low IL-2 production. The differential modulation of Th1 and Th2 cytokines by PGE2 was observed only upon modes of stimulation resulting in high IL-2 production. When IL-2 production was low, PGE2 inhibited the secretion of all four cytokines. These different modulation patterns were directly related to the IL-2 availability, because (i) neutralizing antibody to IL-2 abrogated the up-regulatory effect of PGE2 on IL-4 and IL-5 secretion in experiments with high endogenous IL-2 levels, (ii) lack of differential cytokine modulation by PGE2 in conditions with low levels of endogenous IL-2 could be restored with exogenous IL-2, and (iii) cell viability was comparable in all conditions. These results demonstrate that the net modulatory effect of PGE2 on the cytokine secretion profile of T cells critically depends on the availability of IL-2. Since this parameter varies with the experimental conditions and the T cell population studied, this finding may explain why certain immune responses may be either up- or down-regulated by PGE2 under different conditions.

Animals↗
PubMed1995

Corticosteroids class-dependently inhibit in vitro Th1- and Th2-type cytokine production.

Corticosteroids (CS) are very potent immunosuppressive agents and are widely used to treat inflammatory diseases. On the basis of their clinical efficacy and potency CS have been divided into different classes. In the present study we investigated whether the class-associated effects of CS are correlated with a differential in vitro effect on cytokine production by T lymphocytes. Therefore, we determined the in vitro effects of CS on the production of Th1- and Th2-type cytokines. The addition of CS, in the range of 10(-9) to 10(-4) M, resulted in a class- and dose-dependent inhibition of the production of both IFN-gamma and IL-4. Notably, at the lowest doses tested, hydrocortisone and hydrocortisone 17-butyrate had a stimulatory effect on IL-4 production. CS class-dependently inhibited the IL-2 production by T cells but did not affect IL-2R expression of the T cells. Addition of rIL-2 could not completely restore the inhibitory effect of the CS on proliferation and on IFN-gamma and IL-4 production, indicating that CS act only partially via inhibition of IL-2 production. The demonstrated positive correlation between the clinical efficacy and the in vitro effects of the different classes of CS strongly suggests that the effect of CS on T-cell-mediated inflammation follows from inhibition of proliferation and cytokine production by T lymphocytes. The in vitro method used will be valuable for investigating and classifying new types of CS and other substances for applications in T-cell-mediated diseases.

Adrenal Cortex Hormones↗
PubMed1995

Cross-reactivity of human nickel-reactive T-lymphocyte clones with copper and palladium.

Twenty Ni-reactive T-lymphocyte clones were obtained from eight different donors and analyzed for their ability to cross-react with other metals. All Ni-reactive T-lymphocyte clones were CD4+CD8- and recognized Ni in association with either HLA-DR or -DQ molecules. Based on the periodic table of the elements, the metals Cr, Fe, Co, Cu, and Zn from the same horizontal row as Ni, and Pd and Pt from the same vertical row, were selected to study T-lymphocyte clone cross-reactivity. Distinct cross-reactivity patterns were found that could be divided into three major groups: Ni-reactive T-lymphocyte clones i) cross-reacting with Cu, ii) cross-reacting with Pd, or iii) without cross-reactivity. Major histocompatibility complex class II-restriction patterns of Cu- and Pd-induced proliferative responses did not differ from those for the Ni-induced responses. In vitro cross-reactivities with Cu and Pd may be favored by their bivalency and location next to Ni in the periodic table, and the similarity of these metals to Ni in binding to histidine residues of peptides in the pocket of major histocompatibility complex class II molecules. The present findings suggest that Cu and Pd hypersensitivities, which are occasionally observed in Ni-allergic patients, may be due to cross-reactivities at the T-cell clonal level rather than to concomitant sensitization.

Cells, Cultured↗
PubMed1995

Relationship between facilitated allergen presentation and the presence of allergen-specific IgE in serum of atopic patients.

Allergen presentation to allergen-specific T cells can be facilitated when IgE-allergen complexes are endocytosed by antigen-presenting cells (APC) after binding to the low-affinity Fc epsilon R type II (CD23). Here we present a study on the relative capabilities of sera of atopic patients to mediate facilitated antigen presentation (FAP). To this aim FAP was studied in an in vitro model in which CD23-expressing Epstein-Barr virus (EBV)-B cells act as APC to T lymphocyte clones (TLC) that are specific for Der p 2, a major allergen of housedust mite Dermatophagoides pteronyssinus (Dp). Der p 2 is immune-complexed by preincubation in sera from atopic patients, containing allergen-specific IgE. If EBV-B cells are preincubated with these complexes before using the cells as APC, the allergen-specific TLC proliferate at 100-1000-fold lower allergen concentration than required for T cell activation after presentation of uncomplexed allergen. The relative capability of various sera to mediate FAP was correlated with total serum IgE, and especially with Der p 2-specific serum IgE. In the model used, a high FAP capacity could be demonstrated only in sera with a total serum IgE concentration above approximately 2 micrograms/ml or with Der p 2-specific IgE above approximately 100 ng/ml. Maximal FAP, i.e. the ability to induce maximal proliferation of the TLC, was obtained in the presence of more than +/- 600 ng Der p 2-specific IgE/ml. At 100-600 ng/ml Der p 2-specific IgE the level of FAP was correlated with the concentration of allergen-specific IgE, whereas at lower concentrations FAP was low or absent. All tested sera from eczema patients, all having serum anti-Der p 2-IgE concentrations > 600 ng/ml, showed a high FAP capacity, whereas all tested sera from atopic patients without eczema, which had serum anti-Der p 2-IgE levels < 600 ng/ml, showed no or a low FAP capacity. The association of high FAP capacity with eczema may reflect a functional role of FAP in the pathogenesis of atopic dermatitis.

Allergens↗
PubMed1995

In situ behavior of human Langerhans cells in skin organ culture.

BACKGROUND: Epidermal Langerhans cells (ELC) play a critical role in the initiation of cutaneous immune responses. ELC are characterized by the expression of major histocompatibility complex (MHC) class II Ag and a number of adhesion/costimulatory molecules. Evidence suggests that cytokines induced within the epidermis regulate the functions of ELC, including their phenotypic expression. In the human system, no information is available regarding the behavior of the ELC in situ: their changes in morphology, expression of functional molecules or migration within the microenvironment. In the present study, using an ex vivo human skin organ culture model, we addressed the above questions and also examined the phenotypic modulation of ELC in situ by cytokines. EXPERIMENTAL DESIGN: Skin explants were cultured either in a Trowell-type method or free in the medium. Skin explants were cultured with and without cytokines and were processed for light and electron microscopy and for immunohistochemical definition of ELC phenotypes. RESULTS: In the Trowell-type skin organ culture, morphologic integrity of ELC, CD1a molecule, and Birbeck granules could be preserved intact up to 3 to 4 days in culture. During the first 3 days of culture, the intensity of MHC-II (HLA-DR, DP, and DQ) and CD1a expression on ELC increased sharply, and the dendritic appearance of ELC became more prominent at Day 3. Adhesion molecules, ICAM-1, LFA-3, HECA-452, sLx, and B7/BB1 were also spontaneously acquired in varying amounts by CD1a+ ELC after 3 days in culture. Significant increase of CD1a and ICAM-1 expression on ELC was observed within 12 hours, when skin explants were cultured free in the medium with GM-CSF and TNF-alpha, respectively. Further, we demonstrated spontaneous migration of ELC within the epidermis and then to the dermis during the Trowell-type skin culture. We also showed the migration of ELC out of the human skin when skin explants were cultured directly in the medium. CONCLUSIONS: Human ELC showed significant phenotypic changes within the epidermis and acquired migratory capacity during the skin organ culture. ELC in skin organ culture appear to undergo a phenotypic maturation within the epidermis. ELC in situ rapidly respond to GM-CSF and TNF-alpha by increasing the expression of CD1a and ICAM-1 molecules, respectively. These results suggest the modulation of phenotypic characteristics of ELC and their migration in response to the changes of epidermal microenvironment and cytokines and implicate the potential use of skin organ culture model to elucidate the role of human ELC in the immunopathology of skin diseases.

Antigens, CD1↗
PubMed1994

Characterization of cat dander-specific T lymphocytes from atopic patients.

Fel d I, the major cat dander allergen, is recognized by serum IgE of more than 80% of all cat-allergic patients. Because IgE synthesis by B lymphocytes is under the control of T lymphocytes, we studied the specificity and lymphokine production profiles of cat dander-specific T lymphocytes. Polyclonal cat dander-specific T cell lines were found to react with purified Fel d I, but not with cat albumin, the only other characterized cat allergen. Similarly, within a panel of CD4+ T lymphocyte clones (TLC) that was generated from these cat dander-specific T cell lines, 5 of 16 TLC were found to react with Fel d I, and 0 of 16 with cat albumin. The remaining 11 TLC were shown to recognize at least two different proteins. In general, the TLC had a high IL-4/IFN-gamma production ratio, and could recognize the cat dander extract in an HLA-DR, HLA-DQ, or HLA-DP restricted manner. In addition, five distinct T cell epitopes of Fel d I were identified by using a panel of overlapping synthetic peptides of both chains of Fel d I. The data presented here indicate that, even though multiple proteins in cat dander extract are recognized by T lymphocytes of allergic patients, Fel d I, the major IgE binding allergen, is also important in T cell activation. The fact that the cat-specific TLC are Th2-like indicates that these cells may play an important role in the pathophysiology of allergic responses to cat allergens. However, the diversity of HLA-class II restriction of cat dander- and Fel d I-specific TLC and the presence of multiple T cell epitopes in the allergen may complicate future immunotherapies.

Amino Acid Sequence↗
PubMed1994

Peptide specificity and HLA restriction do not dictate lymphokine production by allergen-specific T-lymphocyte clones.

Human and murine CD4+ T lymphocytes can be subdivided into distinct subsets [T-helper type 0 (Th0), Th1 or Th2], based on their lymphokine production profiles. Not much is known about the factors that determine these restricted lymphokine secretion profiles. Peptide specificity and human leucocyte antigen (HLA) restriction may be such factors. As it is well established that allergen-specific T lymphocytes from atopic individuals and non-atopic controls differ in their lymphokine secretion profile, we studied two allergen-specific T-lymphocyte clones (TLC) with identical peptide specificity and HLA restriction that were generated from the peripheral blood of an atopic donor and a non-atopic control donor. The two CD4+ TLC recognize the same epitope (20-33) of the house dust mite Dermatophagoides pteronyssinus major allergen Der p II. Both TLC recognize the epitope in an HLA-DQB1*0602-restricted manner. However, the lymphokine production profiles of these TLC show clear differences after allergen-specific or polyclonal activation. As expected, TLC JBD4 from the atopic donor produced high levels of interleukin-4 (IL-4) without detectable interferon-gamma (IFN-gamma), whereas TLC PBA1 from the non-atopic donor produced both IFN-gamma and IL-4 upon allergen-specific or polyclonal activation. Inasmuch as both TLC recognized the same epitope of Der p II in association with the same HLA-DQ molecule, these data suggest that peptide specificity and HLA restriction of human allergen-specific TLC do not dictate their lymphokine secretion profile.

Allergens↗