| 1. |
- Broos, Sissela, et al.
(author)
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Immunomodulatory nanoparticles as adjuvants and allergen-delivery system to human dendritic cells: Implications for specific immunotherapy.
- 2010
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In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 28, s. 5075-5085
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Journal article (peer-reviewed)abstract
- Novel adjuvants and antigen-delivery systems with immunomodulatory properties that shift the allergenic Th2 response towards a Th1 or regulatory T cell response are desired for allergen-specific immunotherapy. This study demonstrates that 200-nm sized biodegradable poly(gamma-glutamic acid) (gamma-PGA) nanoparticles (NPs) are activators of human monocyte-derived dendritic cells (MoDCs). gamma-PGA NPs are efficiently internalized by immature MoDCs and strongly stimulate production of chemokines and inflammatory cytokines as well as up-regulation of co-stimulatory molecules and immunomodulatory mediators involved in efficient T cell priming. Furthermore, MoDCs from allergic subjects stimulated in vitro with a mixture of gamma-PGA NPs and extract of grass pollen allergen Phleum pratense (Phl p) augment allergen-specific IL-10 production and proliferation of autologous CD4(+) memory T cells. Thus, gamma-PGA NPs are promising as sophisticated adjuvants and allergen-delivery systems in allergen-specific immunotherapy.
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| 2. |
- Broos, Sissela
(author)
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Specific targeting of antigen-presenting cells for immunotherapy
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Immunotherapy, which involves strategies to activate, enhance or redirect immune responses to achieve long-lasting immunity, has the potential to play an important role in the treatment of a variety of diseases. This thesis, based on four original papers, highlights different approaches to modulate immune responses by specific targeting of antigen-presenting cells. The first two studies focuses on regulation of allergic responses. In Paper I, we showed that biodegradable poly(γ-glutamic acid) (γ-PGA) nanoparticles influence allergen-specific T cell activation, suggesting a beneficial role as adjuvants in allergen-specific immunotherapy. In Paper II, the histamine H4 receptor was shown to mediate histamine-induced activation of human dendritic cells and enhance their Th2 cell stimulating capacity in response to allergen. This suggests that blocking of the histamine H4 receptor may be a promising strategy to modulate allergic responses. The last two studies involve strategies to optimise CD40-targeted cancer immunotherapy. In Paper III, adsorption of agonistic anti-CD40 monoclonal antibodies to γ-PGA nanoparticles was shown to enhance their efficacy and reduce the systemic release of cytokines after local drug delivery. In Paper IV, we demonstrated that increasing the affinity and the isoelectric point of an anti-CD40 antibody resulted in enhanced potency and tumour retention of the locally applied drug. The above strategies may thus serve to improve the efficacy and safety of local CD40-targeted immunotherapy. In conclusion, this thesis underlines the promise of directing immunotherapies to antigen-presenting cells, and in particular dendritic cells, which are central decision makers of the immune system.
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| 3. |
- Broos, Sissela, et al.
(author)
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Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(γ-glutamic acid) nanoparticles.
- 2012
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In: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 33:26, s. 6230-6239
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Journal article (peer-reviewed)abstract
- Agonistic anti-CD40 monoclonal antibodies (mAbs) hold great potential for cancer immunotherapy. However, systemic administration of anti-CD40 mAbs can be associated with severe side effects, such as cytokine release syndrome and liver damage. With the aim to increase the immunostimulatory potency as well as to achieve a local drug retention of anti-CD40 mAbs, we linked an agonistic mAb to immune activating amphiphilic poly(γ-glutamic acid) nanoparticles (γ-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to γ-PGA NPs (anti-CD40-NPs) improved the stimulatory capacity of the CD40 agonist, resulting in upregulation of costimulatory CD80 and CD86 on antigen-presenting cells, as well as IL-12 secretion. Interestingly, anti-CD40-NPs induced strong synergistic proliferative effects in B cells, possibly resulting from a higher degree of CD40 multimerization, enabled by display of multiple anti-CD40 mAbs on the NPs. In addition, local treatment with anti-CD40-NPs, compared to only soluble CD40 agonist, resulted in a significant reduction in serum levels of IL-6, IL-10, IL-12 and TNF-α in a bladder cancer model. Taken together, our results suggest that anti-CD40-NPs are capable of synergistically enhancing the immunostimulatory effect induced by the CD40 agonist, as well as minimizing adverse side effects associated with systemic cytokine release. This concept of nanomedicine could play an important role in localized immunotherapy of cancer.
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| 4. |
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| 5. |
- Lundberg, Kristina, et al.
(author)
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Allergen-Specific Immunotherapy Alters the Frequency, as well as the FcR and CLR Expression Profiles of Human Dendritic Cell Subsets.
- 2016
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:2
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Journal article (peer-reviewed)abstract
- Allergen-specific immunotherapy (AIT) induces tolerance and shifts the Th2 response towards a regulatory T-cell profile. The underlying mechanisms are not fully understood, but dendritic cells (DC) play a vital role as key regulators of T-cell responses. DCs interact with allergens via Fc receptors (FcRs) and via certain C-type lectin receptors (CLRs), including CD209/DC-SIGN, CD206/MR and Dectin-2/CLEC6A. In this study, the effect of AIT on the frequencies as well as the FcR and CLR expression profiles of human DC subsets was assessed. PBMC was isolated from peripheral blood from seven allergic donors before and after 8 weeks and 1 year of subcutaneous AIT, as well as from six non-allergic individuals. Cells were stained with antibodies against DC subset-specific markers and a panel of FcRs and CLRs and analyzed by flow cytometry. After 1 year of AIT, the frequency of CD123+ DCs was increased and a larger proportion expressed FcεRI. Furthermore, the expression of CD206 and Dectin-2 was reduced on CD141+ DCs after 1 year of treatment and CD206 as well as Dectin-1 was additionally down regulated in CD1c+ DCs. Interestingly, levels of DNGR1/CLEC9A on CD141+ DCs were increased by AIT, reaching levels similar to cells isolated from non-allergic controls. The modifications in phenotype and occurrence of specific DC subsets observed during AIT suggest an altered capacity of DC subsets to interact with allergens, which can be part of the mechanisms by which AIT induces allergen tolerance.
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| 6. |
- Lundberg, Kristina, et al.
(author)
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Histamine H(4) receptor antagonism inhibits allergen-specific T-cell responses mediated by human dendritic cells.
- 2011
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In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 651:1-3, s. 197-204
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Journal article (peer-reviewed)abstract
- Dendritic cells are potential targets in allergy therapy as they, under the influence of their microenvironment, regulate T-cell responses. Histamine has been shown to promote Th2 polarization by dendritic cells. However, neither the mechanism nor the functionality of the different histamine receptors in this process has been fully elucidated. The aim of the present study was to identify factors involved in histamine-mediated dendritic cell activation as well as to study dendritic cell expression of histamine H(1) and H(4) receptors and their influence on allergen-specific T-cell responses in grass pollen allergy. Assessment of dendritic cell gene regulation by histamine using mRNA microarrays demonstrated that histamine alters many immunoregulatory genes of which the majority are novel in this context. Additionally, immunocytochemical stainings showed protein expression of histamine H(1) and H(4) receptors on dendritic cells from healthy and allergic donors. Furthermore, histamine H(1) and H(4) receptor antagonists (pyrilamine/N-(4-methoxybenzyl)-N',N'-dimethyl-N-pyridin-2-ylethane-1,2-diamine and JNJ7777120/1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine, respectively) were shown to influence histamine-induced dendritic cell maturation. Interestingly, JNJ7777120 inhibited dendritic cells' capacity to induce allergen-specific T-cell proliferation. In conclusion, H(4) receptor antagonism suppressed DC-induced, allergen-specific T-cell responses in humans and might thus inhibit allergic responses. This finding indicates that the H(4) receptor is a potential treatment target in human allergic conditions.
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| 7. |
- Mangsbo, Sara M, et al.
(author)
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The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity.
- 2015
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 21:5, s. 1115-1126
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Journal article (peer-reviewed)abstract
- Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results: Activation of dendritic cells (DCs) by ADC-1013 results in up-regulation of the co-stimulatory molecules CD80 and CD86, and secretion of IL-12. ADC-1013 also activates dendritic cells from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated dendritic cells induce antigen-specific T cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant anti-tumor effects and long-term tumor-specific immunity. Further, ADC-1013 demonstrates significant anti-tumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. Conclusions: Our data demonstrate that ADC-1013 induces long-lasting anti-tumor responses and immunological memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.
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| 8. |
- Nilsson, Johan S, et al.
(author)
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Amphiphilic γ-PGA nanoparticles administered on rat middle ear mucosa produce adjuvant-like immunostimulation in vivo.
- 2014
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In: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 134:10, s. 1034-1041
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Journal article (peer-reviewed)abstract
- Abstract Conclusion: Amphiphilic biodegradable nanoparticles (NPs) composed of poly(γ-glutamic acid) conjugated with L-phenylalanine ethylester (γ-PGA-Phe NPs) applied on the rat middle ear mucosa produce an inflammatory type 1 response. The observation is of relevance for the use of γ-PGA-Phe NPs as a concomitant antigen delivery system and adjuvant measure in the context of vaccinations.
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