Search PubMed⌕ Search

Biomedical subjects

M L Kapsenberg

Publications and source records attributed to M L Kapsenberg.

At least 73 records · Page 4Linked to original sources
PubMed1994

T-cell regulation in allergic reactions.

Atopy is characterized by an increased tendency to form antibodies to airborne and food proteins. Specific IgE is central to the induction of allergic diseases through its binding of the high-affinity receptor on mast cells and basophils. Cross-linking by allergens of the bound IgE leads to an immediate release of various inflammatory mediators at the local site in the shock organ. Repeated exposure to allergens may lead to the induction of a more chronic inflammatory process where the local influx of T-lymphocytes and eosinophils appears to be an important event. There has been increasing recognition that cytokines, produced by a variety of inflammatory cell subsets, including T-cells, induce this ongoing inflammatory state. Besides, CD4+ T-helper-2 (Th2) cell products like IL-4 play a crucial role in the regulation of the production of specific IgE by B-cells. IL-4 appears to be the immunoregulatory cytokine with a relatively restricted action on reactive cells in this specific immune reaction. The effects of IL-4 are antagonised by IFN-gamma, and vice versa. Proliferation and differentiation of Th2 subsets producing predominantly IL-4 and IL-5 and no IFN-gamma provide an essential signal for isotype switching to IgE in B-cells, on the one hand, and direct the activation and influx of inflammatory effector cells such as eosinophils, on the other hand. In this report the causal relationship between the induction and expression of Th2 cells the IgE production and eosinophilia in atopic allergies is briefly reviewed.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen Presentation↗
PubMed1994

Characterization of lesional psoriatic skin T lymphocyte clones.

T cells are considered to play a role in the pathomechanism of psoriasis. Therefore we investigated the cytokine production patterns of T cell clones that were randomly prepared from chronic plaque psoriasis lesions of 2 patients. 67% of the 49 T lymphocyte clones (TLC) expressed CD4 and 33% expressed CD8 (ratio 2:1), while gamma delta-TCR expression was absent. The production of IL-4, IFN-gamma, IL-2 and IL-6 was measured in supernatants of TLC following PHA plus PMA stimulation. Different groups of clones could be distinguished according to their IL-4/IFN-gamma production ratio. In addition to Th0 cells (low IL-4/low IFN-gamma), low IL-4/high IFN-gamma producers as well as high IL-4/low IFN-gamma producing clones were found, suggesting the presence of Th1- and Th2-like subsets. Upon stimulation, all TLC secreted low levels of IL-2 whereas a minority of the TLC secreted low levels of IL-6. These results may imply that T cells in psoriasis lesions do not show shifts towards either a Th1 or a Th2 cytokine production profile.

CD4-CD8 Ratio↗
PubMed1993

Relative contributions of human types 1 and 2 T-helper cell-derived eosinophilotrophic cytokines to development of eosinophilia.

The relative contributions of type 1 and 2 T-helper (Th1 and Th2) cell-derived interleukin (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3 were studied in the regulation of sequential events in the development of eosinophilia. Using eosinophils from normal donors and neutralizing antibodies that selectively block cytokine activities, we analyzed the effects of these cytokines in supernatants (SN) of well-characterized allergen-specific Th2 and Th1 T-lymphocyte clones (TLC) generated from atopic and nonatopic individuals, respectively. Eosinophil colony formation from CD34+ bone marrow progenitor cells in semisolid cultures could be induced both by Th1 and Th2 SN, mainly mediated by the synergistic effects of GM-CSF and IL-3, whereas IL-5 had only a minor additive effect. High production of mature eosinophils in liquid cultures of unseparated mononuclear bone marrow cells could only be induced by Th2 SN, which could be more than 90% blocked by anti-IL-5, but not by anti-IL-3 or anti-GM-CSF. Chemotaxis of mature peripheral blood eosinophils could equally well be induced by Th1 and Th2 SN, although the relative contribution of the individual cytokines was clearly different in the two sets of SN. Priming of platelet-activating factor (PAF) release by peripheral blood eosinophils was regulated by additive effects of the three cytokines and was stronger induced by the Th2 SN than by the Th1 SN. The present results indicate that IL-5, GM-CSF, and IL-3 control eosinophils throughout the course of development of eosinophilia, having different individual contributions in different compartments. The apparent strong and selective IL-5-dependence of certain yet undefined steps in eosinophil production in the bone marrow supports the concept of the generally assumed causal relation between predominant activation of IL-5-producing Th2 cells in response to allergens and development of eosinophilia in atopic disease.

Bone Marrow Cells↗
PubMed1993

T cell epitopes of house dust mite major allergen Der p II.

Recent work has indicated the significance of IL-4- and IL-5-secreting allergen-specific human Th2 lymphocytes in the control of immune responses to allergens in atopic individuals. The precise allergenic epitopes that activate these allergen-specific Th2 cells are, however, hardly known. We analyzed the epitope-specificity of T lymphocytes specific for Der p II, one of the major allergens of house dust mite Dermatophagoides pteronyssinus. Using a panel of overlapping synthetic peptides that span the entire Der p II molecule, we could demonstrate that polyclonal Der p II-specific T cell lines prepared from the peripheral blood of five atopic patients can react with at least 10 different epitopes of the molecule. Each donor showed a different pattern of reactivity with the synthetic peptides, suggesting that Der p II contains multiple T cell epitopes that may differ from individual to individual. We studied the specificity of the T cell response to Der p II in more detail in one atopic patient using a short term polyclonal T cell line that strongly reacted to one single peptide (116-129) of the allergen. From this patient we established a panel of 11 Der p II-specific TLC. Ten TLC were of the CD3+ CD4+ phenotype and showed a high IL-4/IFN-gamma production ratio, whereas another TLC expressed CD3 and CD8 and failed to secrete substantial IL-4 and IFN-gamma. The use of at least four different TCR V beta gene segments was shown within this panel TLC. All TLC tested recognized the allergen in an HLA-DR1-restricted manner. Although this patient reacted to only one peptide on the polyclonal level, two T cell epitopes were identified on the clonal level by using synthetic peptides and autologous APC to stimulate the TLC. Combining data of CD4/CD8 expression, TCR V beta usage, and epitope specificity, at least six different types of Der p II-specific TLC could be identified within this patient. Binding of IgE to all synthetic peptides of Der p II is low and of low affinity, which may be of particular importance with respect to possible desensitization protocols using such peptides.

Allergens↗
PubMed1993

Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes.

PGE2 is a well known immunomodulator that has multiple effects on the immune system. We demonstrate that PGE2 selectively and dose dependently inhibits IL-2 and IFN-gamma production by mitogenically stimulated human PBL and CD4+ TLC, although at low concentrations IL-4 production is not affected and IL-5 production is even up-regulated. In the tested TLC, PGE2 induced a dramatic elevation (up to 85-fold) of the intracellular cAMP levels. The action of PGE2 may, therefore, be associated with elevation of intracellular cAMP levels, affecting IL-4 and IL-5 differentially from IL-2 and IFN-gamma production. To test this hypothesis we investigated cytokine production by TLC in the absence or presence of agents that affect cAMP levels, either directly (2'-O-dibutyrylcAMP) or through activation of adenylate cyclase (forskolin) or by blocking of phosphodiesterase (3-isobutyl-1-methyl-xanthine). Similar to PGE2, forskolin, 2'-O-dibutyrylcAMP, and 3-isobutyl-1-methyl-xanthine induced inhibition of IL-2 production by TLC and up-regulation of IL-5 production. However, in contrast to PGE2, these agents suppressed IL-4 production although IFN-gamma production was only moderately affected. No significant differences were found between intracellular cAMP levels of mitogenically stimulated Th1 cell clones, which predominantly secrete IL-2 and IFN-gamma, and those of Th2 cell clones, which mainly secrete IL-4 and IL-5. Our results indicate that PGE2 selectively modulates cytokine secretion profiles of human T cells and that elevation of cAMP levels has an important, but possibly not exclusive, regulatory role in this phenomenon.

Animals↗
PubMed1993

Serum-IgE-facilitated allergen presentation in atopic disease.

The occurrence of facilitated Ag presentation (FAP) was investigated in atopic disease using an in vitro model in which the ability of CD23-expressing EBV-B cells was tested to present Der p II, a major allergen of housedust mite Dermatophagoides pteronyssinus, to cells of autologous Der p II-specific CD4+ T lymphocyte clones. Purified Der p II protein was immune complexed with Ig by preincubation in sera from atopic patients containing Der p II-specific IgE. Incubation of EBV-B cells with these complexes before using the cells as APC results in proliferation of the Der p II-specific T cells at a 1000-fold lower Der p II concentration than required for T cell activation by presentation of uncomplexed Der p II. FAP is not evident using sera from allergic and nonallergic control donors not containing Der p II-specific IgE. FAP is mediated by IgE and not by IgG, because it can be blocked completely by preincubating the serum from atopics with polyclonal anti-IgE and not with polyclonal anti-IgG. After pulsing EBV-B with precomplexed Der p II at 4 degrees C, FAP is as strong as after incubation at 37 degrees C, suggesting that FAP is the result of facilitated trapping of IgE-complexed allergen. CD23 was involved in facilitated trapping of the complexes, because FAP is blocked by preincubation of EBV-B with anti-CD23. In contrast to FAP of Der p II, which was mediated by all Der p II-specific sera tested, only one of four sera containing cat allergen-specific IgE was appropriate to mediate FAP to cat allergen-specific T cell clones. Inasmuch as FAP enables functional presentation of allergen in vivo at doses as low as several nanograms, FAP may contribute to the continuing of chronic allergic reactions in response to minute doses of aeroallergens, especially housedust mite allergens, in the environment.

Allergens↗
PubMed1993

The skin immune system: progress in cutaneous biology.

The skin is an active, and in many ways unique, immunological microenvironment quite different from the other primary interfaces between the body and the environment (namely the mucosae). Here Jan D. Bos and Martien L. Kapsenberg identify the components of the skin immune system and describe the inflammatory and immunological responses that they can mount. New findings with regard to the immunophysiology and physiopathology of the human integument are emphasized.

Autoimmune Diseases↗
PubMed1992

Role of type 1 and type 2 T helper cells in allergic diseases.

Various characteristics of atopic allergic disorders seem to be causally related with the activation of allergen-specific T helper lymphocytes with a type 2 cytokine secretion profile, including high levels of interleukin-4 and interleukin-5. These cytokines are responsible for the occurrence of elevated levels of serum allergen-specific IgE and eosinophilia and play an important role in local inflammatory reactions.

Humans↗
PubMed1992

A comparison of the inhibitory effects of immunosuppressive agents cyclosporine, tetranactin, and didemnin B on human T cell responses in vitro.

The agents cyclosporine, tetranactin (TN), and didemnin B (DB) were compared for their ability to inhibit proliferative human T cell responses in vitro, using anti-CD3, PHA, alloantigen, or tetanus toxoid as stimuli and using monocytes or Langerhans cells as antigen-presenting cells/accessory cells (APC/AC). We found that all three agents suppressed T cell activation in a dose-dependent fashion, irrespective of the stimulus of APC/AC type used. Both T cells and APC/AC were affected by the drugs. DB appeared to be the most potent suppressive drug (IC50 = 1-4 ng/ml), whereas CsA and TN exerted approximately similar potency (IC50 = 50-60 ng/ml). Remarkably however, DB was toxic at a concentration of 10 ng/ml, which is quite close to the inhibition-inducing dose. No toxicity was observed with CsA and TN at doses up to 5000 ng/ml. The agents TN and DB could interrupt ongoing T cell responses and could block responsiveness to exogenous recombinant IL-2. Expression of IL-2 receptors was slightly inhibited by all three drugs. Expression of MHC class II molecule HLA-D and of adhesion molecules LFA-1, LFA-3, and ICAM-1 was clearly reduced by DB, giving an explanation for the observed inhibition of cluster formation between T cells and APC/AC. Except for a slight reduction of LFA-3 by TN, CsA and TN did not affect the expression of any of these cell surface markers or the formation of clusters. Differences in the effects of CsA, TN, and DB on immune responses in vitro and on the phenotype of T cells and APC/AC suggest that these immunosuppressive drugs have different inhibitory mechanisms.

Cell Survival↗
PubMed1992

Th1 lymphokine production profiles of nickel-specific CD4+T-lymphocyte clones from nickel contact allergic and non-allergic individuals.

Panels of nickel-specific T-lymphocyte clones (TLC) were prepared from nickel-allergic and non-allergic donors. TLC from both panels showed similar levels of expression of TCR alpha/beta, CD4, CD2, CD25, and CD29 and recognized nickel in association with class II HLA molecules with restriction determinants in HLA-DR, HLA-DP, and HLA-DQ. The lymphokine secretion was analyzed in TLC from both panels upon antigen-specific or non-specific stimulation and was compared with the secretion profiles of representants of pre-established human atopen-specific Th1 and Th2 cells. Nickel-specific TLC from both panels showed a lymphokine secretion pattern similar to the atopen-specific Th1 cells, although there was some variation from clone to clone. Most TLC secreted substantial amounts of IFN-gamma, IL-2, TNF-alpha, and GM-CSF, but little or no IL-4 and IL-5. The variation observed mainly concerned IL-2 secretion that could be low or absent in some of the TLC. The general secretion pattern did not change upon different modes of stimulation, including activation via CD3, CD2, or CD28. Because nickel-specific TLC from allergic and non-allergic individuals show a similar Th1 secretion pattern, the present results give no evidence that aberrant lymphokine secretion by CD4+T cells determines the contact allergic state, as was found for atopic allergy in a previous study.

CD4-Positive T-Lymphocytes↗
PubMed1992

Immune dysregulation in atopic eczema.

BACKGROUND: In this review, present knowledge of atopic eczema immunopathogenesis is summarized, emphasizing recent new findings. Systemic abnormalities in cell-mediated immunity have not been demonstrated firmly in patients with atopic eczema. Within the skin itself, there is evidence for decreased cell-mediated immunity, which is partially correlated with the severity of skin disease. Atopic eczema, however, cannot be regarded as a direct result of decreased cutaneous cell-mediated immunity, since immunophenotyping studies have revealed activated T cells as well as dendritic cells within involved skin. In addition, disease marker studies in peripheral blood indicate vigorous T-cell activation in atopic dermatitis. OBSERVATIONS: The original observation of IgE molecules on the membranes of Langerhans cells may indicate trapping of IgE allergen complexes, their processing, and subsequent presentation to allergen-specific T cells within involved skin. Recent findings as to the abnormal regulation of IgE synthesis in atopy point to a preferential expansion of interleukin 4 and interleukin 5 producing allergen-specific T cells, leading to increased production of interleukin 4 and thus increased levels of allergen-specific IgE. We have prepared atopic skin as well as peripheral blood-derived T-cell clones and determined their specificity and cytokine production profile. Results indicate in situ production of interleukin 4 and interleukin 5 within involved skin in response to environmental antigens. CONCLUSIONS: These new findings as to the basis of IgE dysregulation in atopy, as well as to the identification of an abnormal cytokine secretion pattern by T cells presumed to be central in immunopathogenesis of atopy-related disorders, suggest a distorted and cytokine-mediated self-perpetuating response of the skin immune system to environmental allergen(s) in the pathogenesis of skin disease in atopy. These observations may have important implications for the development of new therapies for atopic eczema.

Dermatitis, Atopic↗
PubMed1991

Human atopen-specific types 1 and 2 T helper cell clones.

Eight representative T lymphocyte clones (TLC) randomly selected from previously described panels of CD4+ housedust mite Dermatophagoides pteronyssinus (Dp)-specific TLC from atopic and nonatopic donors were studied in more detail in a comparative investigation. The TLC from the atopic donors closely resembled murine type 2 Th (Th2) cells by secreting substantial IL-4, IL-5, IL-6, TNF-alpha, and granulocyte-macrophage (GM)-CSF, minimal IFN-gamma, and relatively little IL-2. In contrast, the nonatopic's TLC resembled murine type 1 Th (TH1) cells by secreting substantial IFN-gamma, IL-2, TNF-alpha, and GM-CSF, no IL-4, and little IL-5. A difference with murine Th1 cells was their additional secretion of IL-6. These cytokine profiles were consistent upon stimulation via different activation pathways including stimulation with specific Dp Ag, mitogenic lectins, and antibodies to CD2, CD3, or CD28. The observed differences in IL-2 secretion, however, were most evident upon stimulation with anti-CD28. If TLC cells were cultured with highly purified B cells and stimulated with anti-CD3 in the absence of exogenous IL-4, IgE synthesis was induced only in cultures with the atopics' Th2 clones, which could be completely abrogated by anti-IL-4. The mere presence of exogenous rIL-4, however, did not result in IgE synthesis, nor did unstimulated TLC cells alone. But if unstimulated TLC cells (that proved not to secrete detectable amounts of cytokines) were added together with rIL-4, again IgE synthesis was induced only in cultures with the atopics' Th2 clones, suggesting the involvement of an additional, as yet unidentified accessory helper function of the atopics' Th2 clones for IgE induction. Unstimulated Th2 clones showed a significantly higher expression of CD28 than the Th1 clones, but three days after stimulation, CD28 expression was elevated to comparable levels on both subsets. When added to B cells at this time point, together with rIL-4 and anti-IFN-gamma, still only the atopics' Th2 clones supported IgE synthesis, arguing against a role for CD28 in this accessory helper function. Whereas the atopics' Th2 clones were excellent helper cells for IgE induction, a unique property of the nonatopic's Th1 clones was their cytolytic activity toward autologous APC which could be induced by specific Dp Ag and by anti-CD3. The present data provide clear evidence for the existence of Th1 and Th2 cells in man.

Allergens↗
PubMed1991

Functional subsets of allergen-reactive human CD4+ T cells.

After a period of resistance, the concept of human helper T (TH)-cell subsets is gaining currency. This is the result of analyses from a number of laboratories on the cytokine profiles of T-cell clones prepared from chronically-infected and hypersensitive individuals. Here, Martien Kapsenberg and colleagues summarize these studies and speculate on the significance of skewed TH1 and TH2 responses.

Allergens↗
PubMed1991

High frequency of IL-4-producing CD4+ allergen-specific T lymphocytes in atopic dermatitis lesional skin.

In atopic dermatitis (AD) hypersensitivity reactions to allergens are commonly observed and are assumed to make a major contribution in the pathomechanism of the disease. It may be expected that allergen-reactive Th cells play a central role in these reactions. In the present study the occurrence and function of allergen-specific T lymphocytes in dermal inflammatory lesions were studied. To this aim panels of randomly cloned CD4+ T cells from lesional skin biopsies of two housedust mite Dermatophagoides pteronyssinus (Dp)-allergic AD patients were screened for reactivity with Dp allergens. The results were compared with similar tests for Dp reactivity of T-lymphocyte clones (TLC) from the peripheral blood of these patients. In the panels of TLC generated from lesional skin (S-TLC), a considerable number of TLC appeared to be Dp-specific, 47% (n = 17) and 10% (n = 29), respectively. In the panels from the peripheral blood, the percentages of Dp-specific TLC were only 0% (n = 22) and 3% (n = 34), suggesting accumulation or expansion of these T cells in lesional skin. The function of these TLC was studied by assaying the secretion of IL-4 and IFN-gamma, which have been shown to be produced in aberrant ratios by Dp-specific TLC from the peripheral blood of AD patients (Wierenga et al: J Immunol 144:4651, 1990). All Dp-specific S-TLC produced IL-4 in combination with no or low levels of IFN-gamma, whereas many of the non-Dp-specific S-TLC and blood-derived TLC (B-TLC) were observed to produce high levels of IFN-gamma without significant amounts of IL-4. A functional consequence of these cytokine profiles was demonstrated by the finding that TLC producing substantial amounts of IL-4 enhanced expression of the low-affinity Fc receptor for IgE (CD23) on antigen-presenting cells to a greater extent than did IFN-gamma-producing TLC.

Adult↗
PubMed1991

Inhibitory effect of cyclosporin A on antigen and alloantigen presenting capacity of human epidermal Langerhans cells.

The effect of cyclosporin A (CyA) on the capacity of human epidermal Langerhans cells (LC) to stimulate allogeneic T cells or to present antigen to autologous T cells was investigated. Preparations of LC enriched by discontinuous density gradient centrifugation were pulsed for 2 or 16 h with graded doses (5-5000 ng/ml) of CyA prior to co-culture with T cells. Pretreatment of LC with CyA resulted in a dose-dependent decrease of the functional capacity of LC to stimulate T cells. This inhibition (up to 90%), already achieved after a pulse of 2 h, was not due to a cytotoxic effect of the drug and appeared to be reversible. The possibility that CyA exerted its effect indirectly on T cells via release of CyA from LC into the supernatant during co-culture was excluded. The suppression of immunostimulatory function was a direct effect of the drug on LC. CyA did not affect the production by LC of IL-1 or prostaglandin, nor the expression of MHC class II products HLA-D and RFD1 or adhesion molecules ICAM-1 and LFA-3. These results suggest that inhibition of contact allergic skin reactions by CyA may be due in part to an impairment of the function of LC.

Antigen-Presenting Cells↗
PubMed1991

Aberrant T cell regulation of IgE production in atopy.

Atopy is associated with elevated serum levels of allergen-specific immunoglobulin E (IgE). IgE production is preferentially induced by the T cell-derived lymphokine interleukin-4 (IL-4) and is suppressed by interferon and prostaglandins, of which interferon-gamma (IFN-gamma) is produced by T cells. We review our studies on the question of whether atopy is associated with CD4+ allergen-specific T cells with an unbalanced lymphokine production. We prepared panels of housedust mite (Dermatophagoides pteronyssinus)-specific T lymphocyte clones (TLC) from atopic and non-atopic individuals and found that TLC from housedust mite-allergic patients produced IL-4 but not IFN-gamma, whereas such TLC from a non-atopic individual produced IFN-gamma and only in some cases small amounts of IL-4. Candida albicans- and tetanus toxoid-specific TLC, established from one of the atopic donors, also produced IFN-gamma without IL-4, suggesting that the atopic state is characterized by a defective accumulation of IL-4-producing CD4+ T lymphocytes into the allergen-specific T cell repertoire.

Allergens↗
PubMed1990

Evidence for compartmentalization of functional subsets of CD2+ T lymphocytes in atopic patients.

Lymphokine secretion profiles were studied of human allergen-specific CD4+ T lymphocyte clones (TLC). To this aim, panels of house dust mite Dermatophagoides pteronyssinus (Dp)-specific TLC were generated from two atopic Dp-allergic patients, suffering from severe atopic dermatitis (AD1) and allergic asthma (AD2), respectively, and from a non-atopic individual (NAD). From AD1 additional TLC were cloned specific for tetanus toxoid or Candida albicans, both Ag that were not relevant for the atopic state of this patient. Secretion of IL-2, IL-4, and IFN-gamma was determined after specific stimulation of these TLC, using autologous monocytes as APC. With respect to the production of IL-4 and IFN-gamma, clearly distinct profiles were observed. All Dp-specific TLC from both atopic donors produced IL-4 but not IFN-gamma, whereas the Dp-specific TLC from NAD, as well as the tetanus toxoid- and C. albicans-specific TLC from AD1, all produced IFN-gamma but not or small quantities of IL-4. Most TLC from all panels produced IL-2. These lymphokine profiles were consistent for at least 3 days and were neither dependent on the dose of allergen nor on the atopic or nonatopic state of the donor of APC. The functional consequence of these restricted lymphokine profiles was stressed by the observation that, whereas Dp-specific TLC from AD1 and AD2 supported in vitro IgE production, this support could be abrogated by a Dp-specific TLC from NAD. The present results suggest that CD4+ T lymphocytes that produce IL-4, but not IFN-gamma, occur in high frequencies in the allergen-specific T cell repertoires of atopic donors, which may have important implications for the pathomechanism of atopic disease.

Allergens↗