Biomedical subjects

C Heusser

Publications and source records attributed to C Heusser.

At least 19 recordsLinked to original sources

PubMed2001

Aromatic quinolinecarboxamides as selective, orally active antibody production inhibitors for prevention of acute xenograft rejection.

The prevention of xenograft rejection is substantially dependent on inhibiting antibodies (Ab) produced by B-cells independently of T-cell signals (TI-1). Due to their ubiquitous biochemical mechanisms of action, the immunosuppressants currently employed not only fail to discriminate between B- and T-cells but also have a narrow therapeutic window and, thus, their prolonged use in complex immunosuppressive regimens is problematic. By capitalizing on the target enzyme-bound (DHODH) structure 1b of one of these compounds, leflunomide, and modulating part of its multiple mechanisms of action to gain selectivity, the quinoline-8-carboxamide 3 was designed as a potentially weak enzyme inhibitor but effective immunosuppressant. Compound 3 fulfilled the mechanistic criteria set and had 10-fold B-cell over T-cell selectivity. Its pyridyl analogue 4 was found to be a highly potent and selective B-cell immunosuppressant with a 75-fold selectivity for B- over T-cells (as judged by the MLR data) and no general cytotoxicity at concentrations up to 160-fold higher than those required to inhibit B-cells. In the mouse, 4 effectively blocked TI-1 Ab production and suppressed Ab-mediated xenograft rejection in a xenotransplantation model under a once-daily dosing regimen, with efficacy down to 0.3 mg/kg/day po. These are the first data demonstrating the feasibility of the development of drugs specific for impeding Ab production.

Animals↗

PubMed2001

Pulmonary inflammation induced by a recombinant Brugia malayi gamma-glutamyl transpeptidase homolog: involvement of humoral autoimmune responses.

BACKGROUND: A major allergen from the lymphatic filarial parasite Brugia malayi implicated in the pathogenesis of tropical pulmonary eosinophilia (TPE) has recently been cloned and identified as the homolog of the membrane-bound mammalian enzyme gamma-glutamyl transpeptidase (gamma-GT). Patients with acute TPE show autoreactive antibodies against endogenous gamma-GT from the pulmonary epithelium. MATERIALS AND METHODS: Recombinant B. malayi gamma-GT, alone or adsorbed to aluminium hydroxide (AL), was used in a BALB/c mouse model to analyze its antigenic/allergenic potential, its potential to induce pulmonary inflammation, and its capacity to induce autoreacting antibodies. RESULTS: Mice immunized with B. malayi gamma-GT showed significant levels of gamma-GT-specific IgG1, IgG2a, IgG3, IgA, IgE antibodies, and mild blood eosinophilia, even in the absence of adjuvant. Intranasal challenge with B. malayi gamma-GT induced peribronchial and perivascular inflammation characterized by a mixed infiltrate of lymphocytes, neutrophils, eosinophils, and macrophages. Both IL-4 and IFN-gamma were detected in the peripheral blood and in the bronchoalveolar lavage fluid of immunized and intranasally challenged mice. Histological analysis of murine lungs using affinity-purified antibodies from mice immunized with the parasite's gamma-GT revealed the presence of autoimmune antibodies against pulmonary epithelium. Western blot analysis identified the 55 kDa heavy chain subunit of the murine gamma-GT as the target of autoreactive/crossreacting antibodies. CONCLUSION: Our data from the in vivo mouse model demonstrate the potent allergenicity/antigenicity of B. malayi gamma-GT, and its capacity to induce pulmonary inflammation upon intranasal challenge. This leads to breakdown of tolerance against endogenous murine gamma-GT. Thus, humoral autoimmunity against the airways epithelium may contribute to the pathogenesis of TPE.

Animals↗

PubMed2000

Allergen-derived long peptide immunotherapy down-regulates specific IgE response and protects from anaphylaxis.

To evaluate a long peptide-based allergy vaccine in a murine model, CBA/J mice were sensitized with low dose alum-adsorbed phospholipase A2 (PLA2), a major bee venom allergen. Presensitized mice were treated by daily i.p. injections of a mixture of three long overlapping peptides (44- to 60-mer) spanning the entire PLA2 molecule (100 microg/peptide) for 6 consecutive days. This therapeutic approach induced a sharp drop in PLA2-specific IgE, an increase in specific IgG2a, and a marked T cell hyporesponsiveness. T cell cytokine secretion was characterized by a shift from a Th2 to a Th1 profile. Prophylactic treatment of naive mice with long peptides prior to sensitization with PLA2 induced a comparable modulation of B and T cell responses. Upon i.p. challenge with native PLA2, presensitized mice treated with the long peptide mixture were fully protected from anaphylaxis. This indicated that allergen-derived long overlapping peptides were safe and able to modulate an established Th2 response or to prevent its development. Furthermore, long peptide-based immunotherapy provided clinical protection against anaphylaxis, thus appearing as a promising approach of the therapy of allergic diseases.

Allergens↗

PubMed1999

Suppression of immediate and late responses to antigen by a non-anaphylactogenic anti-IgE antibody in a murine model of asthma.

Eosinophils are recruited to the airways during allergic reactions, but animal models have shown that their mere presence is not sufficient for the development of bronchopulmonary hyperreactivity. Other factors, such as immunoglobulin (Ig)E, seem to be required. Using mice selected for the production of large amounts of IgE, the effects of antibody neutralization of IgE on antigen-induced lung recruitment of eosinophils and induction of bronchopulmonary hyperreactivity and of other indicators of inflammation were studied. A monoclonal non-anaphylactogenic rat anti-mouse IgE (mAb1-5), given within 24 h of the challenge with antigen, reduced tissue eosinophilia, the recruitment of IgE-bearing cells identified as basophils, mucous cell metaplasia, anaphylactic bronchoconstriction and bronchopulmonary hyperreactivity. mAb1-5 inhibited interleukin (IL)4 titres in the bronchoalveolar lavage fluid, but not those of I1-5. Inhibition by mAb1-5 may result from competitive displacement of immunoglobulin E from its different receptors, thus preventing cell stimulation. Moreover, the inhibition of the massive recruitment of immunoglobulin E-bearing basophils into the lungs within hours after challenge and of interleukin4 production by mAb1-5 may be important factors leading to the reduction of pulmonary eosinophilia and bronchopulmonary hyperreactivity. Thus, immunoglobulin (Ig)E and allergic IgE-bearing cells seem to play an essential role in the initial development of the late allergic airway responses.

Animals↗

PubMed1999

Anti-interleukin 5 but not anti-IgE prevents airway inflammation and airway hyperresponsiveness.

The role of IL-5 and allergen-specific IgE in the development of eosinophilic airway inflammation and airway hyperresponsiveness (AHR) was investigated in a murine model. BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injection on Days 1 and 14, followed by airway challenge with OVA on Days 28 and 29. Anti-IL-5 (TRFK-5) or anti-IgE (antibody 1-5) was administered before each airway challenge. Sensitized and challenged mice developed increased OVA-specific IgE serum levels, Th2 cytokine production by peribronchial lymph node (PBLN) cells, increased numbers of eosinophils (predominantly located in the peribronchial regions of the lungs), and increased airway responsiveness to methacholine (MCh). Anti-IgE treatment significantly decreased serum anti-OVA IgE levels and prevented the development of anaphylaxis but failed to affect T cell function, eosinophil airway infiltration, and AHR in sensitized and challenged mice. In contrast, treatment with anti-IL-5 antibody did not affect B cell (Ig serum levels), T cell (cytokine production), or mast cell function (immediate cutaneous reactivity) but completely inhibited development of eosinophilic lung inflammation and AHR. These data identify IL-5-mediated eosinophilia as a major target for development of AHR in this model, with little effect resulting from neutralization of IgE.

Analysis of Variance↗

PubMed1998

Frequencies of T cells expressing interleukin-4 and interleukin-5 in atopic asthmatic children. Comparison with atopic asthmatic adults.

T-cell-derived cytokines have been implicated in the pathogenesis of asthma and it has been suggested that Th2-type cytokines (interleukin-4 [IL-4], interleukin-5 [IL-5]) are pivotal in the allergic inflammation. However, there are little data on human cytokine production by individual T cells at the protein level, in particular in asthmatic children. In this study we analyzed the cytokine production at the single cell level in peripheral blood from mild atopic asthmatic (AA) children and adults and age-matched atopic nonasthmatic (AN) and nonatopic nonasthmatic (NN) control subjects (n = 9 in each group) using the technique of intracellular cytokine detection by flow cytometry. Comparing asthmatic children with atopic and nonatopic control subjects, an increased percentage of IL-5-producing T cells (AA: median 4.9% [range 1.1 to 8.9%]; AN: 0.3% [0.2 to 0.9%], p = 0.003; NN: 0.4% [0.1 to 3.8%], p = 0.001) was detectable, with a positive correlation to the number of peripheral eosinophils and to bronchial hyperresponsiveness. The frequency of IL-4-producing T cells was increased in both atopic groups compared with nonatopic controls (AA: 1.2% [0.2 to 2.6%], p = 0.011; AN: 0.8% [0.4 to 3.7%], p = 0.007; NN: 0.4% [0.2 to 0.9%]) with a positive correlation to total IgE concentration. In adults there were no differences in IL-5- or IL-4-producing T cells between all three groups. A substantial proportion of T cells coproducing IL-4 and IL-5 was not detectable in children and adults. These findings indicate that in asthmatic children the frequencies of Th2-type-producing T cells are increased and that expression of IL-4 and IL-5 is regulated independently.

Adult↗

PubMed1997

The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics.

CGP 51901 is a non-anaphylactogenic mouse/human chimeric anti-human IgE antibody that binds to free IgE and surface IgE of IgE-expressing B cells but not to IgE bound to high affinity IgE receptors (Fc epsilonR1) on mast cells and basophils or low affinity IgE receptors (Fc epsilonR2) on other cells. A phase 1 double-blind, placebo-controlled, single dose study with doses of 3, 10, 30, and 100 mg of CGP 51901 was conducted in 33 pollen-sensitive subjects who had raised levels of serum IgE and received either intravenous CGP 51901 or placebo. The administration of CGP 51901 was well tolerated and resulted in a decrease of serum free IgE levels in a dose-dependent manner, with suppression after 100 mg of CGP 51901 reaching > 96%. Time of recovery to 50% of baseline IgE correlated with the dose of administered antibody and ranged from a mean of 1.3 d for the 3 mg to 39 d for the 100 mg dose. Total IgE, comprised of free and complexed IgE, increased as stored and newly synthesized IgE bound to CGP 51901. Complexed IgE was eliminated at a rate comparable with the terminal half-life of free CGP 51901 (11-13 d at all doses). Only one subject showed a weak antibody response against CGP 51901. We conclude that the use of anti-human IgE antibody is safe and effective in reducing serum IgE levels in atopic individuals and provides a potential therapeutic approach to the treatment of atopic diseases.

Adolescent↗

PubMed1997

Therapeutic potential of anti-IgE antibodies.

Anti-IgE antibodies directed against the Fc epsilon RI-binding region on IgE inhibit binding of IgE to IgE receptors without inducing mediator release from IgE sensitized cells. In mice these antibodies selectively reduce serum IgE, inhibit antigen induced skin reactions, cytokine production by lung Th2 cells, and pulmonary eosinophil infiltration. Clinical trials in humans reveal that such antibodies are well tolerated and reduce rhinitis symptoms and early and late phase bronchoconstriction responses. Thus interruption of the allergic cascade at the IgE antibody level with non-anaphylactogenic anti-IgE antibodies is effective and represents an attractive intervention for the treatment of allergic diseases.

Animals↗

PubMed1997

A subset of CD8+ T cells from allergic patients produce IL-4 and stimulate IgE production in vitro.

BACKGROUND AND OBJECTIVE: A subset of IL-4 producing CD8+ T cells was recently identified in HIV patients. Based on these findings we examined whether IL-4 producing CD8+ T cells would also be present in allergic patients and what would be the functional relevance of this T-cell population. METHODS: We investigated the role of CD8+ T cells in IgE production of allergic diseases by analysing the cytokine profile of individual CD4+ and CD8+ T cells. RESULTS: In allergic patients about twice as many CD4+ T cells and six times as many CD8+ T cells produced IL-4 as in non-allergic controls. In contrast the frequency of IFNgamma+ T-cell subsets did not significantly differ between the allergic and non-allergic individuals. The frequency of IL4+ CD8+ T cells correlated with the level of serum IgE. Coculture experiments with T cells or purified CD8+ T cells together with autologous B cells indicated that CD8+ T cells enhanced IgE in vitro, but not IgM production, even when they were physically separated from B cells. This effect could be partially blocked by addition of an IL-4 binding protein, a soluble IL-4 receptor indicating that IL-4 is involved in CD8+ T-cell mediated IgE production. CONCLUSIONS: These data indicate a positive role of IL-4 secreting CD8+ T cells in IgE regulation in allergic patients.

Adult↗

PubMed1997

Role of IL-13 in CD4 T cell-dependent IgE production in atopy.

IgE isotype switching of human B cells requires physical interaction of T and B cells via surface molecules, and either IL-4 or IL-13 secreted by T cells. In this study we analyzed the role of IL-4 versus IL-13 in IgE production in atopy. We found that peripheral blood mononuclear cells (PBMC) from atopic individuals but not from nonatopic subjects secreted IgE without addition of IL-4 or IL-13, if T and B cells were simultaneously activated by anti-CD3 mAb and soluble CD40L, respectively. IgE production by atopic PBMC was dependent on endogenously secreted IL-4 and IL-13, since it could be blocked by a combination of anti-IL-4 plus anti-IL-13 antibodies. No differences in the B cell compartment of nonatopics and atopics were detectable, since PBMC from both donor populations secreted comparable amounts of IgE, if only the B cells were activated by soluble CD40L plus either exogenous IL-4 or IL-13. Further phenotypic analysis of T cells from atopics revealed that activated CD4+45RO- secreted IL-4 but no IL-13, whereas CD4+45RO+ memory T cells secreted low amounts of IL-4, but large amounts of IL-13. Accordingly, prolonged activation of native CD4+45RO- T cells in vitro induced expression of CD45RO, and strongly favored secretion of IL-13 rather than IL-4. Addition of exogenous IL-4 during activation further increased both IL-4 and IL-13 production to a similar degree. However, the potential of CD4 T cells from atopics to deliver contact-dependent activation signals to B cells and to induce IgE production (in the absence of soluble CD40L) increased with prolonged activation, and coincided with IL-13 rather than IL-4 production. Under similar conditions, CD8 effector cells secreted IL-13 but no IL-4, did not express CD40L, and could not help Ig(E) production by B cells. These results suggest that, in atopy, persistently stimulated CD4+45RO+memory/effector T cells provide contact-dependent activation signals to B cells, and that these cells may induce IgE switching largely via secretion of IL-13.

Adult↗

PubMed1996

Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: inhibition by a non-anaphylactogenic anti-IgE antibody.

Elevated levels of immunoglobulin (Ig) E are associated with bronchial asthma, a disease characterized by eosinophilic inflammation of the airways. Activation of antigen-specific T helper (Th) 2 cells in the lung with the subsequent release of interleukin (IL) 4 and IL-5 is believed to play an important role in the pathogenesis of this disease. In this study, we have used a non-anaphylactogenic anti-mouse-IgE antibody to investigate the relationship between IgE, airway eosinophil infiltration, and the production of Th2 cytokines. Immunization of mice with house dust mite antigen increased serum levels of IgE and IgG. Antigen challenge of immunized but not control mice induced an infiltration of eosinophils in the bronchoalveolar lavage associated with the production of IL-4 and IL-5 from lung purified Thy1.2+ cells activated through the CD3-T cell receptor complex. Administration of the anti-IgE monoclonal antibody (mAb) 6h before antigen challenge neutralized serum IgE but not IgG and inhibited the recruitment of eosinophils into the lungs and the production of IL-4 and IL-5 but not interferon gamma. Studies performed using an anti-CD23 mAb, CD23 deficient and mast cell deficient mice suggest that anti-IgE mAb suppresses eosinophil infiltration and Th2 cytokine production by inhibiting IgE-CD23-facilitated antigen presentation to T cells. Our results demonstrate that IgE-dependent mechanisms are important in the induction of a Th2 immune response and the subsequent infiltration of eosinophils into the airways. Neutralization of IgE, for example, non-anaphylactogenic anti-IgE mAbs may provide a novel therapeutic approach to the treatment of allergic airway disease.

Anaphylaxis↗

PubMed1996

The development of IgE+ memory B cells following primary IgE immune responses.

We studied whether long-lived IgE+ memory B cells develop following three types of primary IgE immune responses. Immunization of mice with anti-IgD antibody induced a T cell-dependent, interleukin (IL)-4-dependent primary IgE response and the formation of IgE isotype switched (IgE+) memory B cells. These IgE+ memory B cells could be stimulated in vivo by injection with goat anti-IgE antibodies to produce a profound IL-4-independent memory IgE response. By contrast, both infection of mice with Nippostrongylus brasiliensis or repeated immunization with benzylpenicilloyl-keyhole limpet hemocyanin (BPO-KLH) in alum stimulated good primary IgE responses and profound memory T cell-dependent antigen-specific IgE responses, but failed to induce the development of long lived IgE+ memory B cells because they could not be recalled with goat anti-IgE antibodies. Mice receiving double immunizations combining anti-IgD with either N. brasiliensis infection or BPO-KLH immunization mounted significant goat anti-IgE-induced secondary IgE responses, but no N. brasiliensis or BPO-KLH-specific IgE could be detected. This indicates that the N. brasiliensis and BPO-KLH induced immune responses do not suppress the development of IgE+ B cells, but rather, do not provide the necessary conditions for their formation. Taken together these data indicate that long-lived IgE+ B cells fail to develop during the primary IgE response to N. brasiliensis infection or BPO-KLH immunization. By contrast, significant numbers of IgE+ memory B cells form during the primary IgE immune response induced by anti-IgD immunization. Our observations suggest that immunization protocols involving membrane IgD cross-linking and limited duration of cognate T cell help are necessary for the formation of IgE+ memory B cells. It will be important to determine the relevance of membrane IgD interaction with allergens, as this would influence the design of new therapies for the treatment of allergy and asthma.

Animals↗

PubMed1996

Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis.

Bronchial biopsies have made possible the detailed study of the pathology of the airways of humans with respiratory disease. Much data has been accumulated on asthmatics or normal controls but much less is known about chronic bronchitics. The aim of this study was to characterize the cellular and cytokine pattern seen in chronic bronchitics and to compare these with control and asthmatic subjects. The patients were also characterized clinically. In this study, immunocytochemistry on cryostat sections from bronchial biopsies were used to determine the level of inflammatory cells and cells of the immune system as well as the pattern of cytokines. This study revealed a distinct cellular and cytokine pattern for each of the three different patient groups, although the diversity of the cytokines analysed was limited by the size of the biopsies. In the inflammatory infiltrate of patients with asthma, CD4+ T-cells and eosinophils were the most prominent cell types discerned. All of the expected cytokines such as IL-1, TNF-alpha, IL-4, IL-5 and IFN-gamma were found. In contrast, the emphasis in chronic bronchitic patients was quite different. The predominant cell types were macrophages, neutrophils, mast cells and CD8+ T-cells, but eosinophils were also abundant. In addition, IL-4 and TNF-alpha were the only cytokines present of those tested.

Adult↗

PubMed1995

Interleukin-4 and interleukin-5 are rarely co-expressed by human T cells.

Interleukin (IL)-4 and IL-5 are two cytokines which synergize in the induction of several biological effector functions. They are produced by mouse and human T helper 2 (Th2) and T helper 0 (Th0) cells. Little is known about the regulation of the two cytokines at the single-cell level. Here we show, using a flow cytometric intracellular staining technique, that IL-4 and IL-5 are predominantly produced by different human peripheral CD4+ and CD8+ T cells, whereas interferon (IFN)-gamma and IL-2 are produced by the same cells. In contrast, cloned human Th0 and Th2 cells were able to produce IL-4 and IL-5 simultaneously. The segregation of IL-4 and IL-5 in activated peripheral T cells was found within 72 h of activation upon anti-CD3 or phorbol ester + ionomycin stimulation. The kinetics of IL-4 and IL-5 production were different at the mRNA and the intra- and extracellular protein level, indicating that the cytokines are regulated differently. T cells from three patients with hyper-IgE syndrome did not display a substantial proportion of IL-4/IL-5 double-positive cells. However, simultaneous production could be induced in normal human T cells after prolonged stimulation with a minimum of two restimulation cycles. We conclude that the simultaneous production of IL-4 and IL-5 is a feature of repetitively activated human T cells.

Base Sequence↗

PubMed1994

Neutralizing monoclonal antibodies define two different functional sites in human interleukin-4.

Human interleukin-4 (IL-4) is a small four-helix-bundle protein which is essential for organizing defense reactions against macroparasites, in particular helminths. Human IL-4 also appears to exert a pathophysiological role during various IgE-mediated allergic diseases. Seven different monoclonal antibodies neutralizing the activity of human IL-4 were studied in order to identify functionally important epitopes. A collection of 41 purified IL-4 variants was used to analyse how defined amino acid replacements affect binding affinity for each individual mAb. Specific amino acid positions could be assigned to four different epitopes. mAbs recognizing epitopes on helix A and/or C interfered with IL-4 receptor binding and thus inhibited IL-4 function. However, other mAbs also inhibiting IL-4 function recognized an epitope on helix D of IL-4 and did not inhibit IL-4 binding to the receptor protein. One mAb, recognizing N-terminal and C-terminal residues, partially competed for binding to the receptor. The results of these mAb epitope analyses confirm and extend previous data on the functional consequences of the amino acid replacements which showed that amino acid residues in helices A and C of IL-4 provide a binding site for the cloned IL-4 receptor and that a signalling site in helix D interacts with a further receptor protein.

Amino Acid Sequence↗

PubMed1994

In vitro maturation of human neonatal CD4 T lymphocytes. II. Cytokines present at priming modulate the development of lymphokine production.

The development of naive CD4 T cells into type 1 or type 2 Th cells has been extensively analyzed in the mouse. Using neonatal CD4 T lymphocytes as a source of human naive cells, we report that these cells may be induced to differentiate into effector cells producing predominantly Th1 or Th2 cytokines. After 3 days of stimulation with anti-CD3 mAb immobilized on CD32 transfected mouse fibroblasts, followed by 3 days of culture in the presence of IL-2, neonatal cells acquire the phenotypic and functional characteristics of effector cells. Primed cells are enriched in CD45R0hi and CD31- cells, and upon stimulation with PMA+ ionomycin they release significant amounts of IL-2, IFN-gamma, IL-4, IL-5, and IL-10. Addition of exogenous cytokines during the period of activation with anti-CD3 markedly alters the profile of cytokine production by primed cells: 1) IL-2 uniformly enhances Th1 and Th2 cytokine production; 2) IL-4 markedly enhances the release of IL-4, IL-5, and IL-10 and suppresses that of IFN-gamma; 3) IFN-gamma strongly inhibits IL-4 and IL-5 production but slightly enhances IFN-gamma release; 4) IFN-alpha markedly inhibits IL-4 and IL-5 production and increases the production of both IFN-gamma and of IL-10; 5) TGF-beta suppresses IL-4 and IL-5 (and to a lesser extent IL-2) production but has inconsistent effect on IL-10 and IFN-gamma production. These effects of exogenous cytokines are not associated with an alteration of CD31 expression on primed cells.

Animals↗

PubMed1994

Transfected Chinese hamster ovary cells as a model system for cytokine immunocytochemistry and in situ hybridisation.

The presence of cytokine producing cells is most easily revealed by techniques measuring the secreted cytokines in culture supernatants or body fluids. However, these techniques only measure the bulk cytokine release by a given, often mixed cell population. To demonstrate cytokine production at the single cell level, immunocytochemistry (ICC) and in situ hybridisation (ISH) are now widely used techniques. To establish these techniques, an easily accessible model system is needed which permits the evaluation of different ICC and ISH protocols. It can be used to demonstrate the specificity of the antibodies and may serve as a positive control for samples of unknown cytokine content. Here we propose the use of Chinese hamster ovary (CHO) cells transfected to express one specific cytokine as such a model system. Its usefulness is demonstrated by the characterisation of six monoclonal antibodies to human interleukin-4 and the establishment of two in situ hybridisation protocols.

Animals↗

PubMed1994

Epitope-dependent nonreciprocal regulation of IgE and IgG2a antibody formation.

The antigen dose-dependent production of IgE versus IgG2a antibodies has been investigated using keyhole limpet hemocyanin (KLH) and bee venom phospholipase A2 (PLA2) as antigens. Repeated injections of minute doses (0.1 microgram/mouse) of KLH into CBA/J mice lead to relatively high titers of IgE antibodies which are gradually reduced in animals that had received higher doses of antigen. In contrast, the IgG2a antibody titers are inversely correlated, resulting in low titers after repeated injection of 0.1 microgram KLH and high titers after repeated doses of 10 micrograms/mouse. With PLA2 as antigen, one finds a comparable dose-dependent downregulation of IgE antibody production. In contrast to the response to KLH, there is, however, only a marginal IgG2a response at all doses tested, and no dose-dependent increase can be found. The data show that an inverse regulation of IgE and IgG2a responses is not mandatory. Instead there seems to be an additional regulation dictated by antigen epitopes.

Animals↗