Sublingual immunotherapy (SLIT) is established as a safe and efficacious treatment for patients with type I respiratory allergies. The ability of SLIT to elicit antigen (allergen)-specific tolerance ...is linked to the peculiar biology of oral antigen-presenting cells. In the absence of danger signals, Langerhans cells, myeloid dendritic cells, and macrophages located in oral tissues, tonsils, and draining cervical lymph nodes are biased toward the induction of T(H)1 and IL-10-producing CD4(+) regulatory T cells, thus supporting tolerance as opposed to inflammation. Sublingual administration does not lead to any detectable systemic exposure of intact allergens nor to IgE neosensitization. Oral tissues contain limited numbers of mast cells located in submucosal areas, thereby explaining the well-established safety profile of SLIT, with mostly local but rare systemic reactions. The induction of CD4(+) regulatory T cells and blocking anti-inflammatory IgGs or IgAs are considered important for tolerance induction after SLIT. Specific molecular signatures associated with tolerogenic dendritic cells were recently reported during the onset of SLIT efficacy in the peripheral blood of patients exhibiting clinical benefit. Collectively, these observations confirm the induction of strong allergen-specific suppressive/tolerogenic immune responses during SLIT and pave the ground for the identification of biomarkers of efficacy. Practical implications of this emerging scientific knowledge are presented (1) to support the rational design of second-generation sublingual vaccines based on purified allergens, vector systems and/or adjuvants and (2) to help the clinician in decision making during his/her practice.
Allergen-specific immunotherapy is used to treat patients exposed and co-sensitized to the two common house dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae. Based on ...seroepidemiological studies and a detailed characterization of mite allergens, an optimal immunotherapeutic product should associate extracts from the two Dermatophagoides species, and include both bodies and fecal particles. Both subcutaneous and sublingual immunotherapies performed with aqueous mite extracts are safe and efficacious in children and adults with mite-induced rhinitis and/or asthma. Double-blind placebo-controlled studies are conducted to further document the efficacy of immunotherapeutic products, with promising results that were obtained already with sublingual tablets. Current developments of second-generation products relying upon recombinant allergens and peptides are reviewed.
Adjuvants for allergy vaccines Moingeon, Philippe
Human vaccines & immunotherapeutics,
10/2012, Volume:
8, Issue:
10
Journal Article
Peer reviewed
Open access
Allergen-specific immunotherapy is currently performed via either the subcutaneous or sublingual routes as a treatment for type I (IgE dependent) allergies. Aluminum hydroxide or calcium phosphate ...are broadly used as adjuvants for subcutaneous allergy vaccines, whereas commercial sublingual vaccines rely upon high doses of aqueous allergen extracts in the absence of any immunopotentiator. Adjuvants to be included in the future in products for allergen specific immunotherapy should ideally enhance Th1 and CD4+ regulatory T cell responses. Imunomodulators impacting dendritic or T cell functions to induce IL10, IL12 and IFNγ production are being investigated in preclinical allergy models. Such candidate adjuvants encompass synthetic or biological immunopotentiators such as glucocorticoids, 1,25-dihydroxy vitamin D3, selected probiotic strains (e.g., Lactobacillus and Bifidobacterium species) as well as TLR2 (Pam3CSK4), TLR4 (monophosphoryl lipid A, synthetic lipid A analogs) or TLR9 (CpGs) ligands. Furthermore, the use of vector systems such as mucoadhesive particules, virus-like particles or liposomes are being considered to enhance allergen uptake by tolerogenic antigen presenting cells present in mucosal tissues.
Multiomic molecular profiling data of large cohorts of patients with autoimmune and autoinflammatory disorders (AIIDs) combined with the use of artificial intelligence (AI) and machine learning allow ...disease models to be created that support drug development.AI-based predictive models are used to (i) stratify patients into homogeneous clusters, (ii) represent the pathophysiology as a perturbed biological system with inferences of causality, (iii) design and optimize drug candidates or combination therapies, and (iv) evaluate the efficacy and safety of drug candidates in virtual patient models.AI fosters the evolution of a computational precision medicine aiming to relate individual patient characteristics with predicted properties of drug candidates so as to offer more personalized treatments for AIIDs.
Artificial intelligence (AI)-based predictive models are being used to foster a precision medicine approach to treat complex chronic diseases such as autoimmune and autoinflammatory disorders (AIIDs). In the past few years the first models of systemic lupus erythematosus (SLE), primary Sjögren syndrome (pSS), and rheumatoid arthritis (RA) have been produced by molecular profiling of patients using omic technologies and integrating the data with AI. These advances have confirmed a complex pathophysiology involving multiple proinflammatory pathways and also provide evidence for shared molecular dysregulation across different AIIDs. I discuss how models are used to stratify patients, assess causality in pathophysiology, design drug candidates in silico, and predict drug efficacy in virtual patients. By relating individual patient characteristics to the predicted properties of millions of drug candidates, these models can improve the management of AIIDs through more personalized treatments.
To the Editor: A new family of lymphocyte-like cells, termed innate lymphoid cells (ILCs), lacking a specific antigen receptor, belonging to the innate immune system, and with a likely ...proinflammatory role in allergic rhinoconjunctivitis and asthma has been described recently.1,2 ILCs are currently subdivided into 3 subsets, ILC1s, ILC2s, and ILC3s, based on specific patterns of cytokine production matching those of polarized CD4+ T lymphocytes.1 To better understand the dynamics of circulating ILCs in human subjects, we studied the frequencies, phenotypes, and functions of ILC1s, ILC2s, and ILC3s in the peripheral blood of allergic patients with rhinoconjunctivitis (associated or not with asthma), as well as in samples from nonallergic control subjects. ...our results do not preclude that a longer course of AIT could modulate ILC blood frequencies. Because our study was performed outside of the pollen season, our data do not oppose the recent observation that AIT can blunt the upregulation of blood ILC2s induced by seasonal allergen exposure.12 Altogether, we provide evidence for multiple differences in the regulation of circulating ILCs between allergic and nonallergic subjects.
Background The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The ...allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. Objective We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. Methods Patients with grass pollen–induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. Results In the intention-to-treat population (n = 89) a significant treatment effect was achieved after the first month ( P = .0042) and second month ( P = .0203) and was maintained through to the fourth month ( P = .0007). In the active group the ARTSS (means ± SDs) decreased at each challenge: week 1, 7.40 ± 2.682; month 1, 5.89 ± 2.431; month 2, 5.09 ± 2.088; and month 4, 4.85 ± 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergen–specific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. Conclusions In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.
Abstract
Background
The identification of patients with knee osteoarthritis (OA) likely to progress rapidly in terms of structure is critical to facilitate the development of disease-modifying drugs.
...Methods
Using 9280 knee magnetic resonance (MR) images (3268 patients) from the Osteoarthritis Initiative (OAI) database , we implemented a deep learning method to predict, from MR images and clinical variables including body mass index (BMI), further cartilage degradation measured by joint space narrowing at 12 months.
Results
Using COR IW TSE images, our classification model achieved a ROC AUC score of 65%. On a similar task, trained radiologists obtained a ROC AUC score of 58.7% highlighting the difficulty of the classification task. Additional analyses conducted in parallel to predict pain grade evaluated by the WOMAC pain index achieved a ROC AUC score of 72%. Attention maps provided evidence for distinct specific areas as being relevant in those two predictive models, including the medial joint space for JSN progression and the intra-articular space for pain prediction.
Conclusions
This feasibility study demonstrates the interest of deep learning applied to OA, with a potential to support even trained radiologists in the challenging task of identifying patients with a high-risk of disease progression.
A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s) for nonclinical evaluation of sublingual immunotherapy products. With this aim, we ...studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species.
Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek) obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs) and non-rodents (i.e. rabbits, dogs, minipigs and monkeys) were characterized by histology and immunohistology in comparison with a human tongue.
Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP) and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species.
The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products.
In allergen immunotherapy there is debate as to whether polysensitized patients are best treated with many allergens simultaneously (chosen according to the sensitization profile, a predominantly ...North American approach) or a single allergen (chosen according to the most clinically problematic allergy, a predominantly European approach). In patients seeking treatment for moderate-to-severe respiratory allergies, polysensitization is more prevalent (range, 50% to 80%) than monosensitization in both the United States and Europe. Safe, effective, single-allergen preparations will most likely have been tested in polysensitized patients. In robust, large-scale clinical trials of grass pollen sublingual tablets, polysensitized patients benefited at least as much from allergen immunotherapy as monosensitized patients. A recent review of multiallergen immunotherapy concluded that simultaneous delivery of multiple unrelated allergens can be clinically effective but that there was a need for additional investigation of therapy with more than 2 allergen extracts (particularly in sublingual allergen immunotherapy). More work is also required to determine whether single-allergen and multiallergen immunotherapy protocols elicit distinct immune responses in monosensitized and polysensitized patients. Sublingual and subcutaneous multiallergen immunotherapy in polysensitized patients requires more supporting data to validate its efficacy in practice.
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