Conflicting verdicts on peanut oral immunotherapy from the Institute for Clinical and Economic Review and US Food and Drug Administration Advisory Committee: Where do we go from here? J Allergy Clin Immunol

Conflicting verdicts on peanut oral immunotherapy from the Institute for Clinical and Economic Review and US Food and Drug Administration Advisory Committee: Where do we go from here? J Allergy Clin Immunol. be used as a preventive treatment. However, broad application of AIT is limited by mainly technical issues such as the quality of allergen preparations and the risk of inducing side Pomalidomide-C2-NH2 effects which results in extremely cumbersome treatment schedules reducing patients compliance. In this article we review progress in AIT made from its beginning and provide an overview of Pomalidomide-C2-NH2 the state of the art, the needs for further development, and possible technical solutions available through molecular allergology. Finally, we consider visions for AIT development towards prophylactic application. Keywords: allergen, allergen\specific immunotherapy, allergy, molecular allergy vaccines AbbreviationsAEsAdverse eventsAITAllergen\specific immunotherapyBreg cellsB regulatory cellsDCDendritic cellELISAEnzyme\linked immunosorbent assayEPITEpicutaneous immunotherapyGMPGood Manufacturing PracticeIgEImmunoglobulin EIgGImmunoglobulin GILITIntralymphatic immunotherapyMPLMonophosphoryl lipid AODNoligodeoxynucleotideOITOral immunotherapyPBMCPeripheral blood mononuclear cellspDCplasmacytoid dendritic cellPEGPolyethylenglycolSCITSubcutaneous immunotherapySLITSublingual immunotherapySPTSkin prick testTFH cellsT follicular helper cellsTFR cellsT follicular regulatory cellsTHT helperTLRToll\like receptorVITVenom immunotherapyVLPVirus\like particleVNPVirus\like nanoparticle 1.?INTRODUCTION IgE\associated allergy, the most common immunologically mediated hypersensitivity disease, is based on the formation of IgE antibodies against per se harmless and mainly environmental antigens, termed allergens. 1 Subjects with a genetic predisposition for allergy (ie, atopic subjects) produce IgE antibodies against allergens in their environment. 2 IgE binds to mast cells and basophils via high\affinity receptors for IgE Pomalidomide-C2-NH2 so that subsequent allergen contact can induce mast cell and basophil activation by cross\linking of cell\bound IgE. This leads to release of inflammatory mediators and cytokines and thus immediate allergic inflammation. 3 , 4 Antigen\presenting cells, especially B cells and dendritic cells can bind IgE via the low\ or high\affinity receptor for IgE, and via IgE\facilitated allergen presentation cause T\cell activation and secretion of inflammatory Th2 cytokines leading to activation of eosinophils and formation of innate Th2\like immune cells such as group 2 innate lymphoid cells (ILC2s). 5 , 6 In contrast to allergic patients, nonallergic subjects produce allergen\specific IgG antibodies without experiencing allergic inflammation upon allergen contact. 7 , 8 While anti\inflammatory treatment based on pharmacotherapy and biologics which neutralize allergen\specific IgE or inflammatory cytokines can ameliorate allergic inflammation, only AIT represents a causative treatment. 9 In fact, AIT induces a protective immunity in allergic patients consisting of allergen\specific IgG antibodies which serve as blocking antibodies. They prevent IgE from binding to the allergens and thus the complete consecutive downstream cascade of allergic inflammation induced by IgE allergen immune complexes. 10 , 11 AIT also profoundly affects allergen\specific cellular responses which may be also due to the effects of blocking IgG antibodies and direct, not yet fully understood, effects on cells of the adaptive and innate immune system such as allergen\specific Treg cells and other immune regulatory components. Cell types receiving current attention in the context of AIT are T follicular helper cells, follicular regulatory T cells, and B regulatory cells. T follicular helper (TFH) cells are defined by the CXCR5?surface receptor and help in B\cell maturation and immunoglobulin class switching. CXCR5+FoxP3+ Treg cells are a subset of Tregs, called follicular regulatory T (TFR) cells, which are capable of suppressing T\ and B\cell responses by migrating to germinal centers of lymph nodes. 12 , 13 A study by grass pollen immunotherapy has shown a significant decrease in memory TFH cell numbers after immunotherapy. 14 Additionally, TFR cells were found to produce more IL\10 compared with TFH cells. A possible plasticity between TFH and TFR cells has been suggested in the same study, indicating that TFR cells may play important roles in suppressing TH2 responses during AIT. 14 IL\10\secreting allergen\specific Breg cells which may be capable of suppressing allergen\specific CD4?+?T cells and producing allergen\specific IgG4 antibodies have been identified in bee venomCtolerant beekeepers and patients having received venom AIT 15 as well as in house dust mite allergen immunotherapy. 16 Additionally, Breg cells may have inhibitory capacity by producing IL\35 and TGF\. 17 Apart from Treg and Breg cells, IL\10\secreting natural killer regulatory cells have also been shown to suppress allergen\stimulated T\cell proliferation in humans and may be important in tolerance induction as other regulatory cell types. 18 All these aspects and their relevance for AIT are currently being investigated. Major advantages of AIT are that, conceptually, AIT is a therapeutic vaccination which induces a protective allergen\specific immune response. Only small amounts of Pomalidomide-C2-NH2 the disease\causing allergen or allergen derivatives are needed for generating and maintaining the protective immune response. Like other vaccination approaches, costs for treatment are affordable. 19 Usually, after 3?years of AIT treatment beneficial effects Rabbit polyclonal to FosB.The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2.These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. continue for a few years, even when AIT has been discontinued. 20 These long\term effects may be attributed to the persistence of high\affinity and functional allergen\specific IgG4 antibodies. 21 , 22 , 23 However, boosting of antibody responses may become necessary after discontinuation. One of the most important aspects of AIT is that it seems to halt the progression of mild symptoms toward severe symptoms as has been.