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Biomedical subjects

H Yssel

Publications and source records attributed to H Yssel.

At least 19 recordsLinked to original sources
PubMed1997

Reversal of human allergic T helper 2 responses by engagement of signaling lymphocytic activation molecule.

Allergen-specific Th2 cells accumulate at high frequencies in the skin of patients with atopic dermatitis (AD), where they contribute to the induction and maintenance of the lesions that are characteristic for the disease. Attenuation of these lesions in response to successful therapy is associated with a reduction in IL-4-producing Th2 cells and the appearance of IFN-gamma-producing Th cells. In this study, we demonstrate that engagement of the signaling lymphocytic activation molecule (SLAM) by an agonistic mAb, during allergen-specific expansion of highly polarized Th2 cell populations derived from skin biopsies of AD patients, results in the generation of stable populations of IFN-gamma-producing cells. SLAM-mediated reversal of Th cell phenotype has important biologic consequences, because supernatants of these activated, allergen-specific Th cells fail to induce IgE synthesis by purified B cells costimulated by anti-CD40 mAbs. Thus, highly polarized, allergen-specific Th2 cell populations derived from the skin of AD patients can be reversed into Th cell populations that contain IFN-gamma-producing cells and that do not support IgE synthesis. These results define a new mechanism to promote Th0/Th1 differentiation and suggest a potential role for anti-SLAM mAbs in the treatment of Th2-mediated allergic diseases.

Antigens, CD↗
PubMed1997

Induction of human T helper cell type 1 differentiation results in loss of IFN-gamma receptor beta-chain expression.

Differential expression of cytokine receptors accounts for an important regulatory mechanism in differentiation of Th1/Th2 subsets. Here, we report that human Th0 and Th2 clones constitutively express transcripts for the IFN-gammaR beta-chain, whereas mRNA for this signaling component of the IFN-gamma receptor is absent in Th1 clones. Activation of T cell clones, however, resulted in a transient induction or enhancement of IFN-gammaR beta-chain mRNA expression in Th1 clones and Th0/Th2 clones, respectively. IL-12-mediated Th1 cell differentiation of naive CD4+, CD45RA+ cord blood T cells, which constitutively express IFN-gammaR beta-chain mRNA, resulted in a loss of expression of this cytokine receptor chain after 6 to 12 days of culture. In contrast, Th2 populations, differentiated from CD4+, CD45RA+ cord blood T cells in the presence of IL-4, continued to express high levels of IFN-gammaR beta-chain transcripts. The loss of IFN-gammaR beta-chain expression in Th1 populations was accompanied by a failure of IFN-gamma to induce the expression of the IFN-gamma-inducible gene, IFN response factor-1, whereas IFN-gamma was effective in inducing IFN response factor-1 mRNA expression in Th0 and Th2 cells. These results indicate that down-regulation of the IFN-gammaR beta-chain correlates with impaired IFN-gamma-induced signaling in Th1 cells. Finally, Th2 populations, generated in the presence of both IL-4 and IFN-gamma, expressed levels of IFN-gammaR beta-chain transcripts similar to those produced by cells differentiated in the presence of IL-4 only, demonstrating that IFN-gamma does not modulate the expression of its receptor. Together, these data indicate that human Th0/Th2 and Th1 subsets, respectively, can be distinguished based on the expression of the IFN-gammaR beta-chain.

CD4-Positive T-Lymphocytes↗
PubMed1997

Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the Fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells.

Cross-linking of allergen specific IgE bound to the high affinity IgE receptor (FC epsilonRI) on the surface of mast cells with multivalent allergens results in the release of both pre-formed and newly generated mediators, and in the manifestation of allergic symptoms. The expression of Fc epsilonRI, and the synthesis of IgE are therefore critical for the development of allergic diseases. In this study, we report that nasal mast cells (NMC) from patients with perennial allergic rhinitis (PAR) expressed significantly greater levels of the Fc epsilonRI, CD40L, IL-4, and IL-13 as compared to NMC from patients with chronic infective rhinitis (CIR). The level of Fc epsilonRI expression in NMC of PAR patients strongly correlated with the levels of serum total (r = 0.8, P < 0.003) and specific IgE (r = 0.89, P < 0.0004) antibodies. In addition, stimulation of NMC with IL-4, upregulated the Fc epsilonRIalpha chain expression both at the protein and mRNA levels, as detected by flow cytometry and reverse transcriptase-polymerase chain reaction. Furthermore, NMC from PAR, but not CIR, patients induced IgE synthesis by purified B cells in the presence of Der fII (mite antigen). These results suggest novel and critical roles for mast cells in promoting the allergic reaction through the increased expression of Fc epsilonRI and by enhancing and amplifying the IgE production, within the local microenvironment.

Adult↗
PubMed1997

New developments in the immunology of asthma, with a focus on mechanisms and treatment.

Asthma is a chronic inflammatory disease of the airways involving the activation of many different cell types. The immunologic basis of asthma is widely accepted for allergic asthma, and the synthesis of IgE is dependent on cytokines. A process of healing and repair follows on from inflammation and this leads to a variable degree of remodelling of the airways. The treatment of asthma should take into account that the disease is associated with short-lived symptoms that can be prevented or reversed by bronchodilators, exacerbations that can be treated or reversed by anti-inflammatory drugs, and remodelling of the airways, for which no definite treatment has yet been validated.

Adult↗
PubMed1996

RANTES induces tyrosine kinase activity of stably complexed p125FAK and ZAP-70 in human T cells.

The chemokine RANTES is a chemoattractant and activating factor for T lymphocytes. Investigation of the signal transduction mechanisms induced by RANTES in T cells revealed tyrosine phosphorylation of multiple protein species with prominent bands at 70-85 and 120-130 kD. Immunoprecipitation and Western analyses revealed that a protein of 125 kD was identical to the focal adhesion kinase (FAK) pp125FAK. RANTES stimulated phosphorylation of FAK as early as 30 seconds and immunoblots using antiphosphotyrosine monoclonal antibodies revealed that there was consistent phosphorylation of a 68-70 kD species in the pp125FAK immunoprecipitates. Immunoblotting and kinase assays showed this to be two separate proteins, the tyrosine kinase zeta-associated protein (ZAP) 70, and the focal adhesion protein paxillin. These results indicate a potentially important role for RANTES in the generation of T cell focal adhesions and subsequent cell activation via a molecular complex containing FAK, ZAP-70, and paxillin.

Cell Adhesion↗
PubMed1996

Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level.

The development of CD4+ T helper (Th) type 1 and 2 cells is essential for the eradication of pathogens, but can also be responsible for various pathological disorders. Therefore, modulation of Th cell differentiation may have clinical utility in the treatment of human disease. Here, we show that interleukin (IL) 12 and IL-4 directly induce human neonatal CD4- T cells, activated via CD3 and CD28, to differentiate into Th1 and Th2 subsets. In contrast, IL-13, which shares many biological activities with IL-4, failed to induce T cell differentiation, consistent with the observation that human T cells do not express IL-13 receptors. Both the IL-12-induced Th1 subset and the IL-4-induced Th2 subset produce large quantities of IL-10, confirming that human IL-10 is not a typical human Th2 cytokine. Interestingly, IL-4-driven Th2 cell differentiation was completely prevented by an IL-4 mutant protein (IL-4.Y124D), indicating that this molecule acts as a strong IL-4 receptor antagonist. Analysis of single T cells producing interferon gamma or IL-4 revealed that induction of Th1 cell differentiation occurred rapidly and required only 4 d of priming of the neonatal CD4+ T cells in the presence of IL-12. The IL-12-induced Th1 cell phenotype was stable and was not significantly affected when repeatedly stimulated in the presence of recombinant IL-4. In contrast, the differentiation of Th2 cells occurred slowly and required not only 6 d of priming, but also additional restimulation of the primed CD4+ T cells in the presence of IL-4. Moreover, IL-4-induced Th2 cell phenotypes were not stable and could rapidly be reverted into a population predominantly containing Th0 and Th1 cells, after a single restimulation in the presence of IL-12. The observed differences in stability of IL-12- and IL-4-induced human Th1 and Th2 subsets, respectively, may have implications for cytokine-based therapies of chronic disease.

CD4-Positive T-Lymphocytes↗
PubMed1996

Interleukin-13 is produced by activated human CD45RA+ and CD45RO+ T cells: modulation by interleukin-4 and interleukin-12.

Interleukin (IL)-13 is a cytokine originally identified as a product of activated T cells. Little is known however, about IL-13 production by human T cells and its modulation by other cytokines. Here, we show that IL-13 is produced by activated human CD4+ and CD8+ CD45RO+ memory T cells and CD4+ and CD8+ CD45RA+ naive T cells. In contrast, IL-4, which shares many biological activities with IL-13, is only produced by CD45RO+ T cells following activation. Analysis of intracellular cytokine production by single CD45RA+ and CD45RO+ T cells indicated that IL-13 continued to be produced for more than 24 h after stimulation, whereas IL-4 could not be detected after 24 h. These data were confirmed by measurement of specific mRNA and suggest that IL-13, unlike IL-4, but like interferon-gamma (IFN-gamma), is a cytokine with long-lasting kinetics. The majority of human CD45RO+ T cells produced IL-4 and IL-13 simultaneously. In contrast, IFN-gamma protein was generally not co-expressed with IL-4 or IL-13. IL-4 added to primary cultures of highly purified peripheral blood T cells activated by the combination of anti-CD3+anti-CD28 mAb enhanced IL-13 production by CD45RA+ and to a lesser extent by CD45RO+ T cells. Under these conditions, however, IL-12 inhibited IL-13 production by CD45RA+ T cells and to a lesser extent by CD45RO+ T cells in a dose-dependent fashion. These inhibiting effects were not related to enhanced IFN-gamma production induced by IL-12, since IFN-gamma by itself did not affect IL-13 production. Collectively, our data indicate that IL-13 is produced by peripheral blood T cells which also produce IL-4, but not IFN-gamma, and by naive CD45RA+ T cells which, in contrast, fail to produce IL-4. These observations, together with the long-lasting production of IL-13, suggest that IL-13 may have IL-4 like functions in situations where T cell-derived IL-4 is still absent or where its production has already been down-regulated.

Adjuvants, Immunologic↗
PubMed1996

Cloning of Human T and Natural Killer Cells

The discovery of the lymphokine interleukin 2 (IL-2), which induces growth of T cells, set the stage for establishing methods for in vitro cloning of human T cells. More recently, it has become clear that in addition to IL-2, other T-cell growth factors, such as IL-4 and IL-7, can be used for generation and expansion of T-cell clones. In the past it was shown that it is possible to grow T cells differing in function and phenotype. In vitro-expanded T-cell clones have been instrumental in studies on the antigen specificities and biological properties of these cells. Cloned lines of natural killer (NK) cells can also be established using IL-2, permitting detailed studies on the biology of these cells. Here we describe the methods we use to generate and to expand human T-cell and NK cell clones. We discuss the differences between IL-2 and IL-4 as growth factors to expand T-cell clones. In addition, we summarize some recent findings of studies using T- and NK cell clones.

Journal Article↗
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

Factors affecting the cytokine production of human T cells stimulated by different modes of activation.

According to the widely accepted classification, human TH cell clones can be divided into two mutually exclusive subsets, TH1 and TH2, based on their profile of cytokine production. The intracellular difference between these clones is not clear. To characterize the biochemical nature of T-cell receptor (TCR)/CD3 complex-mediated signal transduction pathways, we introduced several human TH cell clones of THO- or TH1-like phenotype and analyzed the effects of various drugs and antibodies on cytokine production or proliferation of these clones. The tyrosine kinase inhibitor herbimycin inhibited the production of interferon-gamma (IFN-gamma) by THO-like clone, after stimulation with anti-CD3 monoclonal antibody alpha CD3-mAb) or with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore A23187. However, whereas herbimycin strongly inhibited the production of IL-4 and IL-5 by alpha CD3 mAb stimulated T cells, it did not affect the production of these cytokines after PMA/A23187 stimulation. Cyclosporin A inhibited the proliferation as well as the production of the cytokines, including that of IL-2, IL-4, IL-5, and IFN-gamma, irrespective of the mode of stimulation. A23187, which synergizes with PMA in the induction of IL-4 and IFN-gamma, inhibited PMA-induced IL-10 production in a dose-dependent manner. Transforming growth factor-beta and anti-IL-2 receptor monoclonal antibody partially inhibited alpha CD3 mAb-mediated T-cell proliferation, but had no effect on the proliferation induced by PMA and A23187. Cyclic adenosine monophosphate (cAMP)-elevating drugs, like prostaglandin E2 and dibutyryl cAMP, inhibited the TCR-mediated cytokine production but shifted the cytokine production profile from a TH0 to a TH2 type after stimulation with PMA and A23187. Finally, we analyzed the induction of activity of two transcription factors, nuclear factor-kappa B (NF-kappa B) and nuclear factor of activated T cells, involved in the regulation of cytokine gene expression, after a different mode of activation. The induction of NF-kappa B (p50/p65 heterodimer) by using alpha CD3-mAb stimulation but not by using PMA/A23187 stimulation was found to be inhibited by using cAMP-elevating drugs.

Antibodies, Monoclonal↗
PubMed1996

CD45 isoforms on human CD4+ T-cell subsets.

We have examined the level of surface expression and functional properties of leukocyte function associated antigen-1, very late antigen-4, and CD45 isoforms on a panel of human CD4+ T-cell clones representative of TH0, TH1, and TH2 cells. There were no qualitative differences in the expression of these antigens among the three types of CD4+ T-cell clones. However, CD45RB was the only CD45 isoform that provided a costimulatory signal in a solid-phase antibody-induced cellular proliferation assay. Additionally, the antigen-induced proliferative response of T-cell clones was inhibited by soluble anti-CD45RO and anti-CD45RB antibodies. Our results suggest that CD45 isoforms differentially provide costimulatory signals to T cells. However, the ability of each CD45 isoform to provide a costimulatory signal does not differ among the TH0, TH1, or TH2 T-cell populations.

CD4-Positive T-Lymphocytes↗
PubMed1996

DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes.

Intercellular adhesion molecules play an important role in the generation of T lymphocyte-mediated immune responses. Here, we describe a novel accessory molecule, DNAX accessory molecule-1 (DNAM-1), that is constitutively expressed on the majority of peripheral blood T lymphocytes. DNAM-1 is a 65 kDa transmembrane glycoprotein consisting of 318 aa including two immunoglobulin-like domains. Anti-DNAM-1 monoclonal antibody (MAb) inhibits T and NK cell-mediated cytotoxicity against a variety of tumor cell targets and blocks cytokine production by alloantigen-specific T cells. In addition, DNAM-1 is a tyrosine-phosphorylated signal-transducing molecule that participates in primary adhesion during cytotoxic T lymphocyte (CTL)-mediated cytotoxicity.

Amino Acid Sequence↗
PubMed1996

Defective antigen processing associated with familial disseminated mycobacteriosis.

To gain insights into a possible immune defect predisposing to disseminated mycobacteria infection, we studied three of six surviving children with disseminated Mycobacterium avium complex infection, who had no recognized form of immunodeficiency. We used mycobacteria isolated from the patients and diphtheria, tetanus and pertussis vaccine (DTP) to study antigen-specific T lymphocyte responses. We observed that interferon-gamma (IFN-gamma) production by T cells in response to antigens (both mycobacteria and DTP) in these patients with disseminated infection was greatly impaired. This defect did not seem to be the result of T cell unresponsiveness, as phytohaemagglutinin (PHA) stimulation was able to induce high levels of IFN-gamma comparable to those seen in control patients with localized infection. Further experiments showed that peripheral blood mononuclear cells (PBMC) from patients with disseminated infection were able to present influenza haemagglutinin (HA) peptides to specific T cell clones. However, this ability was lost when the whole HA protein was used as source of antigen. Taken together, these observations support the notion that the primary immune defect in these patients with disseminated mycobacterial infection rests in the antigen-processing functions of their antigen-presenting cells (APC). These findings may provide clues to the wider problem of susceptibility to mycobacteria and other intracellular pathogens and have implications in designing therapy for these patients.

Antigen Presentation↗
PubMed1996

Reversal of the inhibitory effects of HIV-gp120 on CD4+ T cells by stimulation through the CD28 pathway.

The effects of exposure to HIV-gp120 on proliferation and cytokine production by T cell lines were investigated. T cell lines were generated by stimulation of peripheral blood mononuclear cells from several healthy donors with cross-linked anti-CD3 antibodies and IL-2. These T cell lines exhibited the characteristics of Th1 cells, producing IL-2 and interferon-gamma (IFN-gamma), but not IL-4, on stimulation with anti-CD3 antibodies. In the presence of gp120, stimulation with anti-CD3 antibodies was inhibited in terms of both proliferative responses and the secretion of IL-2 and IFN-gamma. Similar effects were observed when a T cell line was stimulated in the presence of a synthetic peptide representing the CD4-binding region of gp120. Neither gp120 nor the CD4-binding region peptide had any effect on IL-4 production by the T cell lines. Stimulation through the CD28 pathway partially restored both the proliferative effect and cytokine production by T cell lines in response to anti-CD3 antibodies in the presence of gp120. Anti-CD28 antibodies also partially restored cytokine production when purified CD4+ T cells from a T cell line were stimulated with anti-CD3 antibodies in the presence of gp120. Anti-gp120 antibodies partially or completely reversed the inhibitory effects of gp120 on T cell proliferation. These results indicate that stimulation through the CD28 pathway may restore defective CD4+ T cell responses in HIV-infected individuals.

Abatacept↗
PubMed1996

Contribution of HLA class I and class II alleles to the regulation of antibody production to hepatitis B surface antigen in humans.

The HLA multigene family consists of HLA class I (HLA-A, B and C) and class II (HLA-DR, DQ and DP) genes, and plays a central role in the regulation of immune response. To investigate how each HLA gene and each HLA allele contribute to the human immune response, we immunized 339 healthy Japanese medical students with recombinant hepatitis B surface antigen (rHBsAg) and determined the HLA types of all vaccinated subjects at the DNA level. The anti-HBs antibody titers showed a log-normal distribution, implying that the immune response to HBsAg in humans is a multifactorial and continuous trait. A stepwise multiple regression analysis demonstrated the alleles at the HLA-class I (HLA-A and B) and class II (HLA-DRB1, DQA1, DQB1, DPA1 and DPB1) loci significantly contributed to antibody production to HBsAg. The predicting equation of anti-HBs antibody levels for individuals with any HLA phenotype was proposed based on a multiple regression analysis. The multiple correlation coefficient of antibody production to HBsAg with the HLA-DRB1 locus was highest (0.34) among all of the HLA loci, whereas those with whole HLA class I or class II loci were 0.36 or 0.44 respectively. The incorporated correlation coefficient of the presence of all HLA gene families with antibody production became 0.50, suggesting that HLA class I and class II loci within the HLA multigene family are dynamically involved in regulation of the immune response to HBsAg.

Alleles↗
PubMed1996

Regulation of cytokine and chemokine transcription in a human TH2 type T-cell clone during the induction phase of anergy.

BACKGROUND: Selected cytokines produced by allergen specific CD4+ T cells from atopic individuals contribute to both the specific and non-specific effector mechanisms of the allergic immune response. The chemokine family of cytokines and tumour necrosis factor (TNF)-alpha are leucocyte regulatory and proinflammatory molecules. The chemokines include interleukin (IL)-8 and the RANTES/SIS cytokines. OBJECTIVE: There has been no systematic survey of chemokine production in T-cell subtypes. Because of their wide range of biological properties, it might be expected that they would be closely regulated by T cells. This paper illustrates one way (through the characterization of T-cell clones) these questions might be addressed. METHODS: Northern blot analysis was used to quantitate steady state transcription of selected cytokine genes and enzyme linked immunosorbent assay (ELISA) was used to quantitate soluble product. RESULTS: mRNA expression of the chemokines (IL-8, HuMIP-1 alpha and HuMIP-1 beta) and TNF alpha is upregulated in TH2-like cloned house dust mite reactive human CD4+ T cells under conditions of activation and during the induction phase of anergy. Although the development of anergy superinduces mRNA for both IL-8 and TNF alpha, protein production is low compared with that released during activation. In contrast, RANTES, a chemoattractant for CD4+/CD45RO+ memory T cells, eosinophils and basophils, is constitutively expressed at the RNA level by the T cells and not modulated by signals of activation and anergy induction. The production of IL-2, IL-4 and IL-5 mRNA and proteins during the induction of anergy peaks at 2 h after stimulation, whereas the kinetics following activation of the T cells is delayed in comparison. CONCLUSION: These data show that the induction of the anergic state coincides with post-transcriptional regulation of selected cytokine genes. Further study of these phenomena will impact on our understanding of the mechanisms of induction of anergy and the regulation of allergic immune responses in desensitization.

Animals↗
PubMed1996

Modulation of the human IgE response.

Studies on the immunological basis of allergic diseases have indicated that enhanced production of the cytokines interleukin (IL)-4 and IL-13 and the reduced production of interferon-gamma (IFN-gamma) by allergen-specific T-cells contribute to enhanced immunoglobulin E (IgE) synthesis and the development of allergic disease in certain individuals. Therefore, inhibition of IL-4 and IL-13 synthesis or blocking of activities of these cytokines would be one approach to inhibiting IgE production. In the present communication, novel approaches toward this goal are discussed. It is shown that an IL-4 mutant protein, in which the tyrosine residue at position 124 is replaced by aspartic acid (IL-4,Y124D), binds with high affinity to the IL-4 receptor, without receptor activation. IL-4,Y124D acts as a potent antagonist both of IL-4 and IL-13 activity in vitro, and inhibits immunoglobulin G4 (IgG4) and IgE production induced by these cytokines. These data are compatible with the notion that the IL-4 and IL-13 receptors are complex receptors, which share a common component, which is required for signal transduction. In addition, it has been demonstrated that allergen-specific T-cells, belonging to the T-helper 2 (Th2) subset can be rendered anergic after incubation with allergen-derived peptides representing minimal T-cell activation inducing epitopes. These anergic Th2 cells failed to produce IL-4 and IL-13, and failed to proliferate after activation with allergen and antigen-presenting cells (APC). The anergized T cells also failed to give B-cells help in IgE synthesis, although they expressed normal levels of the CD40 ligand (CD40L). Exogenous IL-4 and IL-13 failed to restore IgE synthesis, indicating that in addition to CD40L other co-stimulatory signals are required for productive T-cell/B-cell interactions, resulting in IgE synthesis. IgE production was restored by exogenous IL-2, demonstrating that IL-2 reverses the nonresponsive state and helper function of these nonresponsive T-cells. It is tempting to speculate that induction of T-cell nonresponsiveness by allergen-derived peptides may represent the underlying mechanisms for successful immunotherapy in allergenic patients.

Animals↗