lipid-a and Hypersensitivity

Allergen-specific Immunotherapy (AIT) is the only available treatment aimed to tackle the underlying causes of allergy. The active components of subcutaneous vaccines traditionally consist of natural or modified allergen extracts which can be combined with adjuvant platforms. In recent years new targets have been further developed in an attempt to raise the safety and efficacy profile of AIT. Areas covered: In this review, we discuss the desirable attributes of adjuvants and delivery systems from empiricism to rational design, for current and future clinical applications in AIT. Expert commentary: The introduction of novel adjuvants, in combination with active targets, has been demonstrated to reduce symptoms of AIT, increase clinical efficacy of allergy treatment and reduce the number of doses. The evolution of vaccine development for AIT is entering a phase of scientific progress that challenges dogmas. Over the past century the traditional concept of immunotherapy, entailing long-course administration of native extract preparations and first generation adjuvants, has seen evolution in the past decade from proof-of-concept to clinical development pipelines encompassing the advent of second generation adjuvants and delivery systems forming essential components of modern AIT development.

Topics: Adjuvants, Immunologic; Allergens; Animals; Desensitization, Immunologic; Drug Delivery Systems; Humans; Hypersensitivity; Lipid A; Nanoparticles; Vaccines

Allergy vaccination (AV) consists of injecting increasing amounts of offending allergens into sensitive patients with the intention of reducing their level of sensitivity to allergens. This form of therapy was first used over one hundred years ago and until recently had not changed in principle. The vaccines themselves are now far better characterised and standardised, according to new regulatory requirements. The therapy is believed to exert its effects by a combination of means: by the induction of blocking antibodies; a switch from a T helper (Th)2 to a more Th1 allergen-specific immune response; and induction of anergy, probably via the development of allergen-specific regulatory T cells. New allergen forms and formulations are being designed with these targets in mind. Allergoids (allergens chemically modified to reduce allergenicity, but to retain immunogenicity) are becoming employed more frequently. More modern depot forms, such as those containing tyrosine or calcium phosphate, are replacing aqueous extracts and older depot adjuvants such as alum. T cell-reactive peptides and recombinant allergens or their muteins are also being studied as replacements for whole extracts and have shown some potential. Immunomodulators, such as monophosphoryl lipid A (MPL), designed with defined targets in mind are now included in some vaccines and help to accelerate the process. All these measures have led to a reduction in the need for the traditional long injection schedules. The authors are very familiar in particular with the background to the use of MPL as an adjuvant. They have been personally involved in the development of this approach, which has led to a product being available for use on a regular basis in some European countries. Hence, this work is reported in considerable detail. Other similar immunomodulators, such as CpG motifs, are in development, while new targets, such as the Notch protein/receptor interaction, are exciting new developments that may eventually bear fruit. The excellent safety profile of the sublingual route of administration of allergy vaccines could lead to the wider use of AV, and locally active immunomodulators could make AV a therapy of choice for many more patients than at present.

Topics: Adjuvants, Immunologic; Allergens; Chemistry, Pharmaceutical; Clinical Trials as Topic; CpG Islands; Delayed-Action Preparations; Desensitization, Immunologic; Humans; Hypersensitivity; Immunologic Factors; Lipid A; Membrane Proteins; Receptors, Notch; Rhinitis, Allergic, Seasonal; Th1 Cells; Th2 Cells

MPL (Corixa) adjuvant is a chemically modified derivative of lipopolysaccharide that displays greatly reduced toxicity while maintaining most of the immunostimulatory activity of lipopolysaccharide. MPL adjuvant has been used extensively in clinical trials as a component in prophylactic and therapeutic vaccines targeting infectious disease, cancer and allergies. With over 33,000 doses administered to date, MPL adjuvant has emerged as a safe and effective vaccine adjuvant. Recently, scientists at Corixa Corporation have developed a library of synthetic lipid A mimetics (aminoalkyl glucosaminide 4-phosphates) with demonstrated immunostimulatory properties. Similar to MPL adjuvant, these synthetic compounds signal through Toll-like receptor 4 to stimulate the innate immune system. One of these compounds, Ribi.529 (RC-529), has emerged as a leading adjuvant with a similar efficacy and safety profile to MPL adjuvant in both preclinical and clinical studies.

Topics: Adjuvants, Immunologic; Antigens; Cancer Vaccines; Cell Wall Skeleton; Clinical Trials as Topic; Cord Factors; Hepatitis B Vaccines; Herpes Simplex Virus Vaccines; Humans; Hypersensitivity; Ligands; Lipid A; Malaria Vaccines; Membrane Glycoproteins; Pneumococcal Vaccines; Receptors, Cell Surface; Safety; Toll-Like Receptor 4; Toll-Like Receptors; Vaccines

The clinical efficacy of Monophosphoryl lipid A-adjuvanted immunotherapy (MPLA-SCIT) is ascertained, but there are no data on its possible long-lasting effect. We assessed in a real-life setting the persistence of the clinical effect five years after discontinuation.. Patients with parietaria-induced respiratory allergy and fulfilling the criteria for immunotherapy prescription were evaluated at baseline, after the third year of MPLA-SCIT and five years after discontinuation. Visual analog scores, severity of the disease, pulmonary function and skin reactivity were assessed. Matched subjects who refused immunotherapy served as controls.. Twenty nine patients received MPLA-SCIT and 28 were the control group. There was a significant clinical improvement, as assessed by VAS only in the active group after 3 years that remained significant at 5 years versus baseline and controls. The distribution of severity of rhinitis was overall decreased at 3 and 8years as well. The number of patients with conjunctivitis in the active group decreased from 19 to 6 at the end of the treatment and to 9 after 5 years. There was also a decrease in the number of patients with asthma symptoms (from 6 to 2 to 4), which doubled in the control group. A significant reduction in the wheal of the Parietaria skin test was seen in the active group at the end of the treatment (9.5 +/- 2.1 mm vs. 6.4 +/- 2.6 mm; p = .01), but this reduction was lost at the 5-year. No relevant change was overall detected in pulmonary function.. MPLA-SCIT is effective, and the clinical efficacy is maintained after 5 years of discontinuation.

Topics: Adjuvants, Immunologic; Asthma; Conjunctivitis; Desensitization, Immunologic; Humans; Hypersensitivity; Injections, Subcutaneous; Lipid A; Parietaria; Prospective Studies; Rhinitis

Specific immunotherapy (SIT) is believed to modulate CD4+ T-helper cells. In order to improve safety, SIT vaccines are often formulated with allergoids (chemically modified allergens). Interaction between T-cells and allergoids is necessary to influence cellular cytokine expression. There have been few reports on identification the early cellular effects of SIT.. Patients allergic to grass and/or mugwort pollen (n= 21) were treated with a 4-shot allergy vaccine (Pollinex Quattro) containing appropriate allergoids (grass/rye and/or mugwort) adsorbed to L-tyrosine plus a Th1 adjuvant, monophosphoryl lipid A (MPL). Fourteen grass-allergic patients served as untreated controls. Using the peripheral blood mononuclear cells of these patients, an optimized lymphocyte transformation test (LTT) was employed to monitor the in vitro proliferative response of T-cells to an allergoid challenge (solubilised Pollinex Quattro) before the first and last injection and then 2 and 20 weeks after the final injection. Control challenges utilised preparations of a similar pollen vaccine without the adjuvant MPL and a tree pollen vaccine with and without MPL.. The LTT showed increased LTT stimulation indices (SI) in 17/20 SIT patients when the solublised vaccine preparation was used as a challenge before the last injection and 2 weeks after, in comparison to pre-treatment levels. Twenty weeks after therapy, the SI decreased to baseline level. A vaccine challenge without MPL gave lower SI levels. A challenge of a clinically inappropriate tree allergoid vaccine gave no response, and a nontreated group also showed no response.. Following a short-course SIT adjuvated with MPL, challenges of allergoids were shown to activate allergen-specific T cells in vitro. There was an additional stimulating effect when the challenge was in combination with MPL. There were no non-specific effects of MPL, shown by the tree allergoid/MPL control. The timing of the response was closely correlated to the treatment course; reactivity fell two weeks after the final injection and 20 weeks later it was at baseline level. Thus an immunological response to SIT was detected after very few injections. This methodology could provide a basis for monitoring the immediate progress of allergy vaccinations.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Allergens; Allergoids; Artemisia; Female; Humans; Hypersensitivity; Immunotherapy; Lipid A; Male; Middle Aged; Plant Extracts; Poaceae; Secale; T-Lymphocytes; Th1 Cells; Tyrosine; Vaccines

We present data showing that a Th1-inducing adjuvant can reduce the number of injections required for allergy vaccination. Allergy vaccination is the only treatment for type 1 hypersensitivity that can alter the underlying disease process. A switch of specific T-cell activity from Th2 >Th1 to Th1 >Th2 is believed to be an important change seen after long-term vaccination therapy. An immunologic adjuvant that enhances such a switch could be used to reduce the number of injections required. This would improve compliance with the treatment and provide pharmacoeconomic advantages. Such an adjuvant is 3-deacylated monophosphoryl lipid A (MPL adjuvant, Corixa).. A multicentre, placebo-controlled, randomized, double-blind clinical study was performed with a new standardized allergy vaccine comprising a tyrosine-adsorbed glutaraldehyde-modified grass pollen extract containing MPL adjuvant. Four subcutaneous injections of the active product were given preseasonally to 81 grass pollen-sensitive subjects, and 60 received placebo injections (tyrosine alone). Diary cards were used to record symptoms and medication taken during approximately 30 days of the grass pollen season.. There was a statistical advantage in favour of the active treatment for nasal (P = 0.016) and ocular (P = 0.003) symptoms and combined symptom and medication scores (P=0.013). Titrated skin prick testing revealed a significant reduction of skin sensitivity in the active group compared to placebo (P = 0.04). Grass-pollen-specific IgG antibody was raised by active treatment (P < 0.01). A rise in IgE antibody was seen in the placebo group during the season (P < 0.01). The first year's treatment rise of IgE was not seen in the active group, and no rise occurred during the pollen season. More local adverse events were seen in the active group. There was no difference in generalized adverse events.. A new, well-tolerated allergy vaccine, incorporating a Th1-inducing adjuvant, MPL, was efficacious and after only four preseasonal injections produced antibody changes normally associated with long injection schedules. This may encourage wider application of allergy vaccination. The vaccine is now available in a number of countries as Pollinex Quattro.

Topics: Adjuvants, Immunologic; Adult; Austria; Double-Blind Method; Female; Germany; Humans; Hypersensitivity; Immune Tolerance; Immunoglobulin E; Immunoglobulin G; Immunotherapy, Active; Lipid A; Male; Middle Aged; Pollen; Sensitivity and Specificity; Skin Tests; Vaccines

Topics: Adult; Allergy and Immunology; Costs and Cost Analysis; Female; Herpes Zoster; Herpes Zoster Vaccine; Herpesvirus 3, Human; Humans; Hypersensitivity; Insurance, Health, Reimbursement; Lipid A; Male; Mass Vaccination; Middle Aged; Practice Guidelines as Topic; Saponins; United States; Vaccines, Synthetic; Viral Envelope Proteins

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Asthma; Child; Child, Preschool; Female; Humans; Hypersensitivity; Italy; Lipid A; Male; Middle Aged; Prevalence; Prospective Studies; Rhinitis, Allergic, Seasonal; Risk Factors; Treatment Outcome; Young Adult

Allergen-specific immunotherapy (SIT) effectively alleviates type I allergic diseases characterized by T helper (Th)2-type immunity. Our recent studies have shown that a synthetic trivalent glycocluster, triacedimannose (TADM), suppresses the Th2-type allergic inflammation. The aim of this study was to compare TADM with two well-known adjuvants, unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG) and monophosphoryl lipid A (MPLA) in a grass allergen-induced chronic allergic inflammation model in mice.. Female BALB/c mice were intranasally sensitized with 50 μL of timothy grass pollen extract (TE) twice a week for a period of 15 weeks. Therapeutic intranasal treatments were then performed once a week after the tenth intranasal TE instillation using TADM (10 or 25 μg/50 μL), CpG-ODN (20 μg/50 μL) or MPLA (2 μg/50 μL). Groups of 9-10 animals per treatment were killed 24 hours after the last timothy dosage. Blood, bronchoalveolar lavage (BAL) fluids and lung biopsies were taken for subsequent analysis.. When mice were repeatedly exposed to TE for 15 weeks, the number of eosinophils and lymphocytes increased in the BAL fluids. The eosinophil and lymphocyte counts decreased dose-dependently and were practically abolished in the mice treated with TADM. Treatments with MPLA or CpG significantly increased the numbers of neutrophils, while CpG nonsignificantly decreased eosinophilia compared to timothy exposure.. A novel synthetic glycocluster molecule inhibited the development of grass-induced eosinophilic pulmonary inflammation in mice when administrated in the airways. This compound could be a candidate to be used either as an adjuvant in SIT or as a topical anti-inflammatory treatment.

Topics: Adjuvants, Immunologic; Allergens; Animals; Bronchoalveolar Lavage Fluid; Desensitization, Immunologic; Disaccharides; Disease Models, Animal; Eosinophils; Female; Hypersensitivity; Lipid A; Lymphocyte Count; Mannans; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Phleum; Plant Extracts; Pneumonia; Pollen; Statistics, Nonparametric

To compare the immunological and clinical changes induced by allergen-specific immunotherapy (AIT) using different adjuvants.. Olea europaea pollen-sensitized mice were treated with olea plus aluminum hydroxide, calcium phosphate, monophosphoryl lipid A (MPL) or immunostimulatory sequences (ISS).. Aluminum hydroxide seems to drive initially to a Th2-type response. Bacteria-derived adjuvants (MPL and ISS) skew the immune response toward Th1 and Treg pathways. Specific-IgE production was lower after AIT with MPL and ISS. Moreover, IgG2a production significantly increased in ISS-treated mice. Bacteria-derived adjuvants also improved the Th1 cytokine response due to IFN-γ higher secretion. In addition, they improved bronchial hyper-reactivity and lung inflammation.. Bacteria-derived adjuvants may enhance the efficacy of AIT.

Topics: Adjuvants, Immunologic; Allergens; Aluminum Hydroxide; Animals; Antigens, Plant; Calcium Phosphates; Desensitization, Immunologic; Disease Models, Animal; Female; Humans; Hypersensitivity; Lipid A; Mice; Mice, Inbred BALB C; Olea; Plant Extracts; Pollen; Respiratory Function Tests

Insect bite hypersensitivity (IBH) is an IgE-mediated dermatitis of horses caused by bites of Culicoides insects, not indigenous to Iceland. Horses born in Iceland and exported to Culicoides-rich areas are frequently affected with IBH. The aims of the study were to compare immunization with recombinant allergens using the adjuvant aluminum hydroxide (Alum) alone or combined with monophosphoryl lipid A (MPLA) for development of a preventive immunization against IBH. Twelve healthy Icelandic horses were vaccinated intralymphatically three times with 10 μg each of four recombinant Culicoides nubeculosus allergens in Alum or in Alum/MPLA. Injection with allergens in both Alum and Alum/MPLA resulted in significant increase in specific IgG subclasses and IgA against all r-allergens with no significant differences between the adjuvant groups. The induced antibodies from both groups could block binding of allergen specific IgE from IBH affected horses to a similar extent. No IgE-mediated reactions were induced. Allergen-stimulated PBMC from Alum/MPLA horses but not from Alum only horses produced significantly more IFNγ and IL-10 than PBMC from non-vaccinated control horses. In conclusion, intralymphatic administration of small amounts of pure allergens in Alum/MPLA induces high IgG antibody levels and Th1/Treg immune response and is a promising approach for immunoprophylaxis and immunotherapy against IBH.

Topics: Allergens; Alum Compounds; Animals; Ceratopogonidae; Cytokines; Dermatitis; Horse Diseases; Horses; Hypersensitivity; Immunoglobulin E; Injections, Intralymphatic; Insect Bites and Stings; Insect Proteins; Lipid A; Vaccination; Vaccines, Synthetic

Topics: Epigenomics; Humans; Hypersensitivity; Lipid A

Pollinex(®) Quattro Grass has been developed for the prevention or relief of allergic symptoms caused by pollen in both adults and children. Reproduction and juvenile animal toxicology studies have been performed. Subcutaneous injection on Day 14 prior to pairing and on Days 6 and 13 of gestation to pregnant rats at 2000SU/0.5 mL elicited no signs of maternal or embryo-foetal toxicity. Mating, fertility, fecundity and pup parameters were all unaffected by treatment. Once-weekly subcutaneous administration at ascending doses of 300, 800, 2000 and 2000SU/0.5 mL followed by a 4 week non-dose period to juvenile rats from 3 weeks of age showed no signs of obvious toxicity. As in a previously performed adult animal toxicology study with the vaccine, not unexpected, but relatively minor, immuno-stimulatory effects were seen in this study along with injection site reaction which can largely be attributed to the presence of tyrosine in the formulation.

Topics: Adjuvants, Immunologic; Albumins; Animals; Female; Globulins; Hypersensitivity; Leukocyte Count; Lipid A; Male; Poaceae; Pregnancy; Rats; Reproduction; Tyrosine; Vaccines

Therapeutic vaccination for the treatment of allergy has been used for nearly a century but it is only recently that the mechanisms whereby benefits can be achieved have begun to be identified [Bousquet J, Lockey FR, Mailing HJ. Allergy immunotherapy: therapeutic vaccines for allergic diseases. WHO Position Paper. Allergy 1998;53:1-42.]. The induction of blocking antibodies was originally thought to lead to amelioration of allergic symptoms. There is now evidence that a switch from a Th2 (IgE/inflammatory) response to a Thl biased allergen specific response is part of the answer [Durham SR, Till SJ, Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol, 1998; 102:157-64.]. Specific anergy induced by raised IL 10 and TGF3 and the induction of regulatory T cells may also be important [Akdis CA, Blaser K, Allergen-specific immunotherapy. Allergy 2000;55:522-30.]. A new adjuvant complex, L-tyrosine-MPL can accelerate these processes.

Topics: Adjuvants, Immunologic; Allergens; Cytokines; Humans; Hypersensitivity; Immunoglobulins; Lipid A; T-Lymphocytes, Regulatory; Th1 Cells; Tyrosine; Vaccines

Lipopolysaccharides (LPSs) and lipooligosaccharides (LOSs) are major components of the cell surface of Gram-negative bacteria with diverse roles in bacterial pathogenesis of animals and plants that include elicitation of host defenses. Little is known about the mechanisms of perception of these molecules by plants and about the associated signal transduction pathways that trigger plant immunity. Here we address the issue of the molecular basis of elicitation of plant defenses through the structural determination of the LOS of the plant pathogen Xanthomonas campestris pv. campestris strain 8004 and examination of the effects of LOS and fragments obtained by chemical treatments on the immune response in Arabidopsis thaliana. The structure shows a strong accumulation of negatively charged groups in the lipid A-inner core region and has a number of novel features, including a galacturonyl phosphate attached at a 3-deoxy-D-manno-oct-2-ulosonic acid residue and a unique phosphoramide group in the inner core region. Intact LOS and the lipid A and core oligosaccharides derived from it were all able to induce the defense-related genes PR1 and PR2 in Arabidopsis and to prevent the hypersensitive response caused by avirulent bacteria. Although LOS induced defense-related gene transcription in two temporal phases, the core oligosaccharide induced only the earlier phase, and lipid A induced only the later phase. These findings suggest that plant cells can recognize lipid A and core oligosaccharide structures within LOS to trigger defensive cellular responses and that this may occur via two distinct recognition events.

Topics: Arabidopsis; Gene Expression Regulation; Genes, Plant; Hypersensitivity; Immunity, Innate; Kinetics; Lipid A; Lipopolysaccharides; Mass Spectrometry; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phosphorus Isotopes; Plant Leaves; Protons; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Transcription, Genetic; Xanthomonas campestris

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Aged, 80 and over; Allergens; Antigens, Plant; Child; Child, Preschool; Clinical Trials as Topic; Desensitization, Immunologic; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypersensitivity; Infant; Injections, Subcutaneous; Lipid A; Middle Aged; Plant Extracts

Topics: Adjuvants, Immunologic; Allergens; Cytokines; Humans; Hypersensitivity; Immunoglobulin E; Immunoglobulin G; Immunotherapy; Lipid A; Lipopolysaccharides; Receptors, IgE

A new allergy vaccine is currently under clinical evaluation for the prevention or relief of symptoms caused by specific housedust mites. It consists of a 50:50 mixture of the mite Dermatophagoides pteronyssinus and D. farinae protein derived from aqueous extracts of the mites which is chemically modified by glutaraldehyde and adsorbed onto L-tyrosine with addition of the immunostimulatory adjuvant, monophosphoryl lipid A (MPL) "Polymite". A specific preclinical safety testing strategy was developed to support clinical use and comprised single and repeat dose toxicity, reproduction toxicity and local tolerance studies. Dose levels of up to 0.5ml for the mouse and up to 1ml for both the rat and the rabbit were used. Overall, the product was shown to produce no toxicological findings of significance at levels greatly in excess to those proposed for clinical use. A not unexpected, but relatively minor, immunostimulatory effect was seen following repeated dosing (once weekly for 13 weeks) at 1ml per rat; the Polymite formulation also resulted in injection site reaction which can largely be attributed to the presence of tyrosine. No reproduction toxicity was found.

Topics: Adjuvants, Immunologic; Adsorption; Allergens; Animals; Dust; Embryonic and Fetal Development; Female; Glutaral; Humans; Hypersensitivity; Lipid A; Mites; Pregnancy; Rabbits; Rats; Rats, Sprague-Dawley; Reproduction; Safety; Tyrosine; Vaccines