K. Lund

ALK-Abelló, København, Capital Region, Denmark

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Publications (54)452.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The most widespread ragweed (Ambrosia) species in North America are short ragweed (Ambrosia artemisiifolia; Amb a), giant ragweed (Ambrosia trifida; Amb t), and western ragweed (Ambrosia psilostachya; Amb p). Varied geographic distributions of ragweed species raise questions regarding the need for ragweed species-specific allergen immunotherapy. Objective: To determine allergenic cross-reactivity among ragweed species by immunologic analyses of sera from subjects allergic to ragweed from North America and Europe. Methods: Sera were collected from 452 subjects allergic to ragweed who participated in Amb a sublingual immunotherapy tablet clinical trials. All subjects had positive skin prick test and serum IgE against Amb a. Ragweed-specific IgE (pre treatment) and IgG4 (post treatment) were measured by ImmunoCAP. IgE inhibition studies among Amb a, Amb t, and Amb p were conducted. Using pooled sera from another ragweed-allergic population, IgE inhibition studies of 7 less widespread Ambrosia species also were conducted. Results: A strong correlation between Amb a vs Amb p and Amb t serum IgE levels was observed. In the vast majority of pretreatment sera, Amb a inhibited Amb a, Amb p, and Amb t IgE reactivity by more than 90%. Strong correlations were observed between Amb a vs Amb p and Amb t post-treatment IgG4 levels. In pooled sera, Amb a extract inhibited the binding of serum IgE to all 10 ragweed species by 98%-100%. Conclusion: In a population of subjects allergic to Amb a, substantial allergenic cross-reactivity among Amb a, Amb p, and Amb t was demonstrated, indicating Amb a-based single-species ragweed allergen immunotherapy is clinically sufficient for patients exposed to diverse ragweed pollens. Trial registry: Clinicaltrials.gov, NCT00770315, NCT00783198, and NCT00330083.
    No preview · Article · Oct 2015 · Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology
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    ABSTRACT: Airway epithelial cells (AECs) form polarized barriers that interact with inhaled allergens and are involved in immune homeostasis. We examined how monocyte-derived dendritic cells (MDDCs) are affected by contact with the airway epithelium. In traditional setups, bronchial epithelial cell lines were allowed to polarize on filter inserts, and MDDCs were allowed to adhere to the epithelial basal side. In an optimized setup, the cell application was reversed, and the culture conditions were modified to preserve cellular polarization and integrity. These two parameters were crucial for the MDDCs' immunoregulatory properties; thus, previous observations obtained using traditional setups should be considered with caution. Using the optimized setup, AEC conditioning of MDDCs led to increased expression of programmed death 1 ligand 1 (PD-L1), Immunoglobulin-Like Transcript 3, CD40, CD80 and CD23. This increased expression was accompanied by decreased secretion of MCP-1 and eotaxin and donor-variable effects on IL-12 and IL-10 secretion. Conditioning varied between maturation states and depended partly on direct contact between AECs and MDDCs. The setup allowed MDDCs on the basal side of the epithelium to sample allergens administered to the apical side. Allergen uptake depended on both polarization and the nature of the allergen. AEC conditioning led to decreased birch allergen-specific proliferation of autologous T cells and a trend toward decreased secretion of the Th2-specific cytokines IL-5 and IL-13. In conclusion, we determined that AEC conditioning favoring cellular integrity leads to a tolerogenic MDDC phenotype, which is likely to be important in regulating immune responses against commonly inhaled allergens.
    No preview · Article · Jan 2015 · American Journal of Respiratory Cell and Molecular Biology

  • No preview · Article · Jul 2013 · The Journal of allergy and clinical immunology
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    ABSTRACT: Subcutaneous specific immunotherapy (SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide (AlOH). It has been shown that allergen-specific IgG antibodies are induced as a result of successful SIT. To investigate the possibility of optimizing the formulation of AlOH-based grass-pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine. Mice were immunized with various concentrations of Phleum pratense (Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p-specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed. Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo-induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation. The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity. This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing.
    No preview · Article · Sep 2012 · Clinical & Experimental Allergy
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    ABSTRACT: The governing factor of both effector-cell activation and facilitated antigen presentation is IgE-repertoire complexity (IgE-clonality, -affinity and -concentration). Yet, the compositions of individual IgE repertoires and correlation between IgE-repertoire complexity and establishment of allergic sensitization remain to be determined. In complex formation assays with recombinant IgE, allergen and CD23(+) B cells, we assess the composition of serum IgE repertoires and examine the correlation between IgE-titre and IgE-repertoire complexity. The capacity of sera, from house dust mite-sensitized individuals, to mediate IgE-Der p 2-CD23 complex formation on CD23(+) B cells was measured. In parallel experiments, the effect of supplementing each serum with one or more Der p 2-specific monoclonal recombinant IgE antibodies on complex formation was determined. Only sera with the highest concentration of Der p 2-specific IgE resulted in complex formation without supplementary recombinant IgE. Intermediately titred sera supported complex formation to various degrees when supplemented with individual recombinant IgE. The degree of complex formation depended on the affinity and epitope specificity of the recombinant IgE. Complex formation by combining serum and recombinant IgEs could not be obtained with sera of relatively low titres of specific IgE. However, these sera had the capacity to dramatically enhance the low complex formation achieved with pairs of affinity-engineered recombinant IgEs. Serum IgE complexity can be indirectly assessed by combining sera with defined monoclonal IgEs in IgE-allergen-CD23 complex assays. The observed differences in epitope-coverage of Der p 2-specific serum-IgE in sera of different specific IgE titres indicate that increased IgE titres correlate with increased complexity of the IgE-repertoire. A detailed knowledge of the composition and complexity of allergen-specific IgE repertoires (and the relation to IgE titre), particularly in the early phase of sensitization, may be used to improve the prediction of the persistence and severity of allergic symptoms, as well as the progression of the Allergic March.
    No preview · Article · Aug 2012 · Clinical & Experimental Allergy
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    ABSTRACT: Nasal allergen challenge can be used to assess the clinical and immunological aspects of rhinitis due to inhalant allergens. We aimed to develop a reproducible technique for grass pollen nasal allergen challenge and to study biomarkers within nasal secretions. 20 Grass pollen allergic individuals underwent nasal challenges with purified Timothy grass allergen. An initial dose-titration challenge was used to determine dose-response characteristics. Subsequently, volunteers underwent 3 further challenges using individualised threshold doses. Symptom scores, visual analogue scores, and peak nasal inspiratory flow (PNIF) were recorded at baseline and up to 6h after challenge. Nasal secretions were collected at each time point using synthetic filter papers or absorptive polyurethane sponges and analysed for IL-4, -5, -10, -13, IFN-γ, Tryptase and Eosinophil Cationic Protein (ECP). Challenges gave reproducible symptom scores and decreased PNIF. Tryptase levels in nasal fluid peaked at 5 min after challenge and returned to baseline levels at 1h. ECP, IL-5, IL-13 and IL-4 levels were increased from 2-3 h and showed progressive increases to 5-6 h. Sponges proved the superior nasal fluid sampling technique. We have developed a reproducible nasal allergen challenge technique. This may be used as a surrogate clinical endpoint in trials assessing the efficacy of treatments for allergic rhinitis. Tryptase in local nasal secretions is a potential biomarker of the early phase response; ECP and the Th2 cytokines IL-5, -13 and -4 markers of late phase allergic responses. Our model allows correlation between clinical responses and local biomarkers following nasal allergen challenge.
    No preview · Article · Jun 2012 · Journal of immunological methods
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    ABSTRACT: Effector cell activation and T-cell activation, the latter mediated by facilitated antigen presentation, are immunological mechanisms that play crucial roles in the manifestation and maintenance of allergic disease. In addition to their relevance for the pathogenesis of allergy in-vivo, in-vitro assays based on these immunological mechanisms have been established and used for diagnostics, for monitoring the progression of disease and for the effect of specific immunotherapy as well as for basic research purposes. Here we review different parameters that affect effector cell activation and facilitated antigen uptake and presentation, including assay designs, readout parameters and critical experimental conditions. Central to the two immunological mechanisms is complex formation between allergen-specific IgE, allergen, and cell surface-anchored immunoglobulin receptor; the high affinity IgE-receptor FcεRI on basophils and mast cells, and the low affinity IgE-receptor FcεRII (CD23) on B-cells. Accordingly, the effect of IgE repertoire complexity and allergen diversity on effector cell and facilitated antigen presentation is discussed in detail.
    No preview · Article · Jun 2012 · Journal of immunological methods
  • S.U. Patil · A. Ma · G. Lund · K. Lund · W.G. Shreffler

    No preview · Article · Feb 2012 · Journal of Allergy and Clinical Immunology

  • No preview · Article · Feb 2012 · Journal of Allergy and Clinical Immunology
  • A. Ma · S. Patil · G. Lund · K. Lund · W.G. Shreffler

    No preview · Article · Feb 2012 · Journal of Allergy and Clinical Immunology

  • No preview · Article · Jan 2012
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    ABSTRACT: Induction of allergen-specific IgG(4) antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG(4) antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG(4) titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response. In an 8-month dose-response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100,000 SQ-U, 10,000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG(4) titres and IgG-associated inhibitory activity were evaluated. A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollen-specific IgG(4) antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom-rescue medication scores (IgE-FAB: r = -0.25, P = 0.0002; IgE-blocking factor: r = -0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG(4) levels (r = -0.11, P = 0.12). Functional assays of inhibitory IgG(4) and IgE-blocking factor may be more useful surrogates of clinical response than IgG(4). Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation.
    No preview · Article · Nov 2011 · Allergy
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    ABSTRACT: The antibody repertoires of allergic subjects are characterized by the presence of allergen-specific IgE antibodies. We have previously shown that the composition of the IgE repertoire is critical for allergen-mediated activation of human effector cells. Activation of CD4(+) T cells in allergic subjects is highly potentiated by the process of facilitated antigen presentation (FAP), in which allergen in complex with IgE is taken up by B cells through the low-affinity IgE receptor CD23 and presented to T cells. We sought to investigate the influence of IgE repertoire complexity on the formation of IgE/allergen/CD23 complexes on B cells and subsequent T-cell activation. Using defined allergen-specific recombinant IgE and IgG antibodies, we investigated the influence of individual IgE affinity, IgE clonality, specific IgE concentration, and the ratio between IgE specificities on IgE/allergen/CD23 complex formation in vitro. Although IgE affinity is an important factor, IgE clonality seems to be governing complex formation, especially with medium- and low-affinity IgE antibodies. We demonstrate that differences in allergen-specific IgE affinity correlate with the efficiency of subsequent T-cell activation. In addition, we show that the complexity of an IgE repertoire also affects the ability of allergen-specific IgG antibodies to block FAP. The composition of allergen-specific IgE repertoires in individual patients, especially with respect to IgE clonality, might play an important role in the manifestation of allergic disease not only for the immediate allergic reaction through activation of basophils and mast cells but also for the exacerbation of allergic inflammation through recurring activation of allergen-specific T cells by FAP.
    No preview · Article · Mar 2011 · The Journal of allergy and clinical immunology
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    ABSTRACT: Birch-allergic patients often experience oral allergy syndrome upon ingestion of vegetables and fruits, most prominently apple, that is caused by antibody cross-reactivity of the IgE antibodies in patients to proteins sharing molecular surface structures with the major birch pollen group 1 allergen from Betula verrucosa (Bet v 1). Still, to what extent two molecular surfaces need to be similar for clinically relevant antibody cross-reactivity to occur is unknown. Here, we describe the grafting of a defined conformational antibody epitope from Bet v 1 onto the surface of the homologous apple allergen Malus domestica group 1 (Mal d 1). Engineering of the epitope was accomplished by genetic engineering substituting amino acid residues in Mal d 1 differing between Bet v 1 and Mal d 1 within the epitope defined by the mAb BV16. The kinetic parameters characterizing the antibody binding interaction to Bet v 1 and to the mutated Mal d 1 variant, respectively, were assessed by Biacore experiments demonstrating indistinguishable binding kinetics. This demonstrates that a conformational epitope defined by a high affinity antibody-allergen interaction can successfully be grafted onto a homologous scaffold molecule without loss of epitope functionality. Furthermore, we show that increasing surface similarity to Bet v 1 of Mal d 1 variants by substitution of 6-8 residues increased the ability to trigger basophil histamine release with blood from birch-allergic patients not responding to natural Mal d 1. Conversely, reducing surface similarity to Bet v 1 of a Mal d 1 variant by substitution of three residues abolished histamine release in one patient reacting to Mal d 1.
    Full-text · Article · Mar 2011 · Journal of Biological Chemistry

  • No preview · Article · Feb 2011 · Journal of Allergy and Clinical Immunology

  • No preview · Article · Feb 2011 · Journal of Allergy and Clinical Immunology
  • K. Lund · G. Lund · J. Holm · J. Skovsgaard

    No preview · Article · Feb 2011 · Journal of Allergy and Clinical Immunology
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    ABSTRACT: Sublingual immunotherapy (SLIT) is safe and effective as treatment of allergic rhinitis and mild asthma. Oral mucosal Langerhans cells (oLCs) play a central role. However, little is known about allergen binding by oLCs during mucosal allergen resorption and its impact on oLC functions. Binding of Phl p 5 to oLCs was studied in a standardized ex vivo model to investigate mechanisms important for SLIT. Human oral mucosal biopsies were incubated with the grass pollen allergen Phl p 5. Migration, binding of Phl p 5, phenotype and cytokine production, and T-cell priming of Phl p 5-binding oLCs were analyzed. Significant uptake required more than 5 minutes, and dose-dependent binding of Phl p 5 to oLCs was saturated at 100 microg/mL Phl p 5. Furthermore, Phl p 5 significantly increased the migratory capacity of oLCs but attenuated their maturation and strongly promoted the release of TGF-beta1 and IL-10 by oLCs themselves as well as by cocultured T cells. Oral mucosal Langerhans cells bind Phlp5 in a dose-dependent and time-dependent manner, leading to an increased production of tolerogenic cytokines and an enhanced migratory capacity but decelerated maturation of oLCs.
    No preview · Article · Sep 2010 · The Journal of allergy and clinical immunology
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    ABSTRACT: Allergen-specific immunotherapy (SIT) leads to reduced symptoms upon allergen exposure through as yet unresolved mechanisms. Desensitization of basophils to specific allergens during the updosing phase of injection immunotherapy may contribute to the clinical effect of SIT. Here we report a protocol for efficient in vitro allergen-mediated desensitization of basophils in whole blood and the effect of desensitization on the expression of basophil activation markers (CD203c and CD63) as well as histamine release in response to allergen challenge. Whole blood from grass pollen-allergic subjects was incubated with Phleum pratense extract by stepwise increase of the allergen concentration in the culture from well below to well above the allergen threshold concentration for activation of basophils. Desensitization was determined by measuring the expression of the basophil activation markers CD63 and CD203c by FACS following challenge with high allergen concentrations. The basophil desensitization protocol reported here affected both the expression of the cell-surface markers and the levels of histamine release. Following the stepwise desensitization procedure the whole-blood basophils were not activated when challenged with more than 10-fold increased allergen concentration. We have established a protocol for basophil desensitization. By mimicking the updosing phase of immunotherapy we raised the allergen threshold for basophil activation and obtained efficient desensitization for all donors. We showed that conditions leading to desensitization affect histamine release and expression of different basophil markers alike.
    No preview · Article · Jun 2010 · International Archives of Allergy and Immunology
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    C Rask · J Brimnes · K Lund
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    ABSTRACT: Current day practice of sublingual immunotherapy (SLIT) includes varying modalities of treatment that differ with regard to formulation, dosing and administration regimens. The aim of this study was to explore the importance of the dosing intervals in SLIT. The immunological effect of increased SLIT dosing frequency was tested in a mouse model of allergic inflammation. Mice sensitized to Phleum pratense (Phl p) were SLIT-treated with the same weekly cumulative dose administered with different administration frequencies. A SLIT sham-treated group was also included. All mice were challenged intra-nasally with Phl p extract following SLIT. Local and systemic cytokine production, eosinophil infiltration into airways and the development of Phl p-specific antibody responses were determined. Higher frequency of sublingual administration of allergen extract has a profound positive impact on the effect of SLIT, measured as induction of IgG and IgA antibodies. The once daily SLIT was the only treatment regimen being able to reduce all systemic Th2 cytokines and systemic IgE antibody responses when compared to sham-treated mice after the intra-nasal challenge period. The group receiving SLIT with the highest frequency of administration had the most pronounced effect of the treatment. In the same group, there was also a higher degree of protection against increase in IgE antibody levels after intra-nasal challenge with the allergen, our data demonstrate that a once daily regimen is more efficacious than regimens where SLIT, with the same weekly cumulative allergen dose, is administered with longer intervals but higher doses.
    Preview · Article · Jun 2010 · Scandinavian Journal of Immunology

Publication Stats

609 Citations
452.78 Total Impact Points


  • 2006-2015
    • ALK-Abelló
      København, Capital Region, Denmark
  • 2010
    • Medical University of Vienna
      Wien, Vienna, Austria
  • 2005
    • University of Salzburg
      • Department of Molecular Biology
      Salzburg, Salzburg, Austria