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1.  Is The Allergen Really Needed in Allergy Immunotherapy? 
Opinion Statement
Immunotherapy for type I allergies is well established and is regarded to be the most efficient treatment option besides allergen avoidance. As of today, different forms of allergen preparations are used in this regard, as well as different routes of application. Virus-like particles (VLPs) represent a potent vaccine platform with proven immunogenicity and clinical efficacy. The addition of toll-like receptor ligands and/or depot-forming adjuvants further enhances activation of innate as well as adaptive immune responses. CpG motifs represent intensively investigated and potent direct stimulators of plasmacytoid dendritic cells and B cells, while T cell responses are enhanced indirectly through increased antigen presentation and cytokine release. This article will focus on the function of VLPs loaded with DNA rich in nonmethylated CG motifs (CpGs) and the clinical experience gained in the treatment of allergic rhinitis, demonstrating clinical efficacy also if administered without allergens. Several published studies have demonstrated a beneficial impact on allergic symptoms by treatment with CpG-loaded VLPs. Subcutaneous injection of VLPs loaded with CpGs was tested with or without the adjuvant alum in the presence or absence of an allergen. The results encourage further investigation of VLPs and CpG motifs in immunotherapy, either as a stand-alone product or as adjuvants for allergen-specific immunotherapy.
PMCID: PMC4335088  PMID: 25722959
Virus-like particles; CpG motifs; Vaccine; Allergy; Allergic rhinitis; Immunotherapy
2.  Intralymphatic immunotherapy 
Gold Standard allergen-specific immunotherapy is associated with low efficacy because it requires either many subcutaneous injections of allergen or even more numerous sublingual allergen administrations to achieve amelioration of symptoms. Intralymphatic vaccination can maximize immunogenicity and hence efficacy. We and others have demonstrated that as few as three low dose intralymphatic allergen administrations are sufficient to effectively alleviate symptoms. Results of recent prospective and controlled trials suggest that this strategy may be an effective form of allergen immunotherapy.
PMCID: PMC4352255  PMID: 25780493
Administration routes; Allergen immunotherapy; Intralympathic; Vaccination
3.  Epicutaneous Immunotherapy for Aeroallergen and Food Allergy 
Opinion statement
IgE-mediated allergies today affect up to 30 % of the population in industrialized countries. Allergen immunotherapy is the only disease-modifying treatment option with a long-term effect. However, very few patients (<5 %) choose immunotherapy, due to the long treatment duration (between 3–5 years) and possible local and systemic allergic side effects of the allergen administrations. The latter occur when an allergen accidentally reaches the blood circulation. Therefore, the ideal application route for allergen immunotherapy should be characterized by two hallmarks: firstly, by a high number of potent antigen-presenting cells, which enhance efficacy and thus shorten treatment duration. Secondly, the allergen administration site is ideally non-vascularized, so that inadvertent systemic distribution of the allergen and consequent systemic allergic side effects are minimized. The epidermis contains high numbers of potent antigen-presenting Langerhans cells and, as an epithelium, is non-vascularized. Therefore, the epidermis represents an interesting administration route. Historical evidence for the clinical efficacy of epicutaneous allergy immunotherapy (EPIT) has now been strengthened by a number of recent double-blinded placebo-controlled clinical trials performed by independent groups. We review the immunological rationale, history and clinical experience with epicutaneous allergy immunotherapy.
PMCID: PMC4025904  PMID: 24918342
Epicutaneous allergen-specific immunotherapy; Transcutaneous allergen-specific immunotherapy; Respiratory allergy; Food allergy
4.  New routes for allergen immunotherapy 
Human Vaccines & Immunotherapeutics  2012;8(10):1525-1533.
IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review.
PMCID: PMC3660774  PMID: 23095873
allergy; immunotherapy; administration route; intralymphatic; epicutaneous; transcutaneous; clinical trials
5.  Relief from Zmp1-Mediated Arrest of Phagosome Maturation Is Associated with Facilitated Presentation and Enhanced Immunogenicity of Mycobacterial Antigens▿ 
Pathogenic mycobacteria escape host innate immune responses by blocking phagosome-lysosome fusion. Avoiding lysosomal delivery may also be involved in the capacity of mycobacteria to evade major histocompatibility complex (MHC) class I- or II-dependent T-cell responses. In this study, we used a genetic mutant of Mycobacterium bovis BCG that is unable to escape lysosomal transfer and show that presentation of mycobacterial antigens is affected by the site of intracellular residence. Compared to infection with wild-type BCG, infection of murine bone marrow-derived dendritic cells with a mycobacterial mutant deficient in zinc metalloprotease 1 (Zmp1) resulted in increased presentation of MHC class II-restricted antigens, as assessed by activation of mycobacterial Ag85A-specific T-cell hybridomas. The zmp1 deletion mutant was more immunogenic in vivo, as measured by delayed-type hypersensitivity (DTH), antigen-specific lymphocyte proliferation, and the frequency of antigen-specific gamma interferon (IFN-γ)-producing lymphocytes of both CD4 and CD8 subsets. In conclusion, our results suggest that phagosome maturation and lysosomal delivery of BCG facilitate mycobacterial antigen presentation and enhance immunogenicity.
PMCID: PMC3122614  PMID: 21471301
6.  Lymph Node-Targeted Immunotherapy Mediates Potent Immunity Resulting in Regression of Isolated or Metastatic HPV-Transformed Tumors 
The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic HPV 16-transformed murine tumors.
Experimental design
Animals bearing E7-expressing tumors were co-immunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and anti-tumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease.
In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen-specific T lymphocytes in the range of 1/10 CD8+ T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with anti-tumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization.
This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells.
PMCID: PMC2756704  PMID: 19789304
T Cells; Peptides; Tumor Immunity; Vaccination; HPV
7.  Lentiviral Transduction of Dendritic Cells Confers Protective Antiviral Immunity In Vivo 
Journal of Virology  2004;78(14):7843-7845.
Control of a viral infection in vivo requires a rapid and efficient cytotoxic-T-lymphocyte response. We demonstrate that lentivirus-mediated introduction of antigen in dendritic cells confers a protective antiviral immunity in vivo in a lymphocytic choriomeningitis virus model. Therefore, lentiviral vectors may be excellent vaccine candidates for viral infections.
PMCID: PMC434082  PMID: 15220461
8.  Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8+ T-cell responses in melanoma patients 
European Journal of Immunology  2012;42(11):3049-3061.
Optimal vaccine strategies must be identified for improving T-cell vaccination against infectious and malignant diseases. MelQbG10 is a virus-like nano-particle loaded with A-type CpG-oligonucleotides (CpG-ODN) and coupled to peptide16–35 derived from Melan-A/MART-1. In this phase IIa clinical study, four groups of stage III-IV melanoma patients were vaccinated with MelQbG10, given (i) with IFA (Montanide) s.c.; (ii) with IFA s.c. and topical Imiquimod; (iii) i.d. with topical Imiquimod; or (iv) as intralymph node injection. In total, 16/21 (76%) patients generated ex vivo detectable Melan-A/MART-1-specific T-cell responses. T-cell frequencies were significantly higher when IFA was used as adjuvant, resulting in detectable T-cell responses in all (11/11) patients, with predominant generation of effector-memory-phenotype cells. In turn, Imiquimod induced higher proportions of central-memory-phenotype cells and increased percentages of CD127+ (IL-7R) T cells. Direct injection of MelQbG10 into lymph nodes resulted in lower T-cell frequencies, associated with lower proportions of memory and effector-phenotype T cells. Swelling of vaccine site draining lymph nodes, and increased glucose uptake at PET/CT was observed in 13/15 (87%) of evaluable patients, reflecting vaccine triggered immune reactions in lymph nodes. We conclude that the simultaneous use of both Imiquimod and CpG-ODN induced combined memory and effector CD8+ T-cell responses.
PMCID: PMC3549564  PMID: 22806397
IFA (Montanide); Imiquimod; Melanoma; Melan-A/MART-1 antigen; Peptide-based vaccination

Results 1-8 (8)