Prevalence and incidence of IgE-mediated allergic diseases have increased over the past years in developed and developing countries. Allergen-specific immunotherapy (AIT) is currently the only ...curative treatment available for allergic diseases that has long-term efficacy. Although AIT has been proven successful as an immunomodulatory therapy since its beginnings, it still faces several unmet needs and challenges today. For instance, some patients can experience severe side effects, others are non-responders, and prolonged treatment schedules can lead to lack of patient adherence and therapy discontinuation. A common strategy to improve AIT relies on the use of adjuvants and immune modulators to boost its effects and improve its safety. Among the adjuvants tested for their clinical efficacy, CpG oligodeoxynucleotide (CpG-ODN) was investigated with limited success and without reaching phase III trials for clinical allergy treatment. However, recently discovered immune tolerance-promoting properties of CpG-ODN place this adjuvant again in a prominent position as an immune modulator for the treatment of allergic diseases. Indeed, it has been shown that the CpG-ODN dose and concentration are crucial in promoting immune regulation through the recruitment of pDCs. While low doses induce an inflammatory response, high doses of CpG-ODN trigger a tolerogenic response that can reverse a pre-established allergic milieu. Consistently, CpG-ODN has also been found to stimulate IL-10 producing B cells, so-called B regulatory cells (Bregs). Accordingly, CpG-ODN has shown its capacity to prevent and revert allergic reactions in several animal models showing its potential as both preventive and active treatment for IgE-mediated allergy. In this review, we describe how CpG-ODN-based therapies for allergic diseases, despite having shown limited success in the past, can still be exploited further as an adjuvant or immune modulator in the context of AIT and deserves additional attention. Here, we discuss the past and current knowledge, which highlights CpG-ODN as a potential adjuvant to be reevaluated for the enhancement of AIT when used in appropriate conditions and formulations.
Class-switch recombination (CSR) is an integral part of B cell maturation. Here we present sciCSR (pronounced 'scissor', single-cell inference of class-switch recombination), a computational pipeline ...that analyzes CSR events and dynamics of B cells from single-cell RNA sequencing (scRNA-seq) experiments. Validated on both simulated and real data, sciCSR re-analyzes scRNA-seq alignments to differentiate productive heavy-chain immunoglobulin transcripts from germline 'sterile' transcripts. From a snapshot of B cell scRNA-seq data, a Markov state model is built to infer the dynamics and direction of CSR. Applying sciCSR on severe acute respiratory syndrome coronavirus 2 vaccination time-course scRNA-seq data, we observe that sciCSR predicts, using data from an earlier time point in the collected time-course, the isotype distribution of B cell receptor repertoires of subsequent time points with high accuracy (cosine similarity ~0.9). Using processes specific to B cells, sciCSR identifies transitions that are often missed by conventional RNA velocity analyses and can reveal insights into the dynamics of B cell CSR during immune response.
The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate ...lymphoid cells (IL-10+ ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1+ but not KLRG1– ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10+ ILC2s in the disease-modifying effect by allergen immunotherapy.
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•A thorough characterization of IL-10-producing type 2 innate lymphoid cell (ILC2s)•IL-10-producing ILC2s restore epithelial cell integrity and suppress Th2 responses•Symptom severity inversely correlates with IL-10-producing ILC2s after immunotherapy•IL-10-producing ILC2s play a critical role in tolerance induction to aeroallergens
Underpinning mechanisms of immune tolerance following allergen immunotherapy is not well understood. Golebski et al. characterized IL-10-producing type 2 innate lymphoid cell and report that these cells with regulatory properties are induced following immunotherapy suggesting that they play an essential role in immune tolerance to aeroallergens in upper respiratory disease.
Background
The prevalence of allergy to cat is expanding worldwide. Allergen‐specific immunotherapy (AIT) has advantages over symptomatic pharmacotherapy and promises long‐lasting disease control in ...allergic patients. However, there is still a need to improve cat AIT regarding efficacy, safety, and adherence to the treatment. Here, we aim to boost immune tolerance to the major cat allergen Fel d 1 by increasing the anti‐inflammatory activity of AIT with the established immunomodulatory adjuvant CpG, but at a higher dose than previously used in AIT.
Methods
Together with CpG, we used endotoxin‐free Fel d 1 as therapeutic allergen throughout the study in a BALB/c model of allergy to Fel d 1, thus mimicking the conditions of human AIT trials. Multidimensional immune phenotyping including mass cytometry (CyTOF) was applied to analyze AIT‐specific immune signatures.
Results
We show that AIT with high‐dose CpG in combination with endotoxin‐free Fel d 1 reverts all major hallmarks of allergy. High‐dimensional CyTOF analysis of the immune cell signatures initiating and sustaining the AIT effect indicates the simultaneous engagement of both, the pDC‐Treg and B‐cell axis, with the emergence of a systemic GATA3+ FoxP3hi biTreg population. The regulatory immune signature also suggests the involvement of the anti‐inflammatory TNF/TNFR2 signaling cascade in NK and B cells at an early stage and in Tregs later during AIT.
Conclusion
Our results highlight the potential of CpG adjuvant in a novel formulation to be further exploited for inducing allergen‐specific tolerance in patients with cat allergy or other allergic diseases.
AIT adjuvanted with a high and safe dose of CpG reverts major hallmarks of cat allergy without inducing any Th1/Th17 profile. The use of endotoxin‐free Fel d 1 and B‐Type CpG in AIT induces a tolerance‐promoting immune reaction through an early pDC‐NK cell‐Breg‐Treg axis, characterized by a sustained TNFR2 expression. A novel double positive FoxP3+ GATA3+ Treg subpopulation appears upon AIT.
Abbreviations: AHR, airway hyperreactivity; AIT, allergen‐specific immunotherapy; biTreg, double‐positive FoxP3+ GATA3+ Treg; CyTOF, cytometry by time‐of‐flight; CpG, oligodeoxynucleotides containing unmethylated CpG motifs; Fel d 1, Felis domesticus 1, major cat allergen; TNFR2, tumor necrosis factor receptor 2.
Background
Food challenges carry a burden of safety, effort and resources. Clinical reactivity and presentation, such as thresholds and symptoms, are considered challenging to predict ex vivo.
Aims
...To identify changes of peripheral immune signatures during oral food challenges (OFC) that correlate with the clinical outcome in patients with peanut allergy (PA).
Methods
Children with a positive (OFC+, n = 16) or a negative (OFC−, n = 10) OFC‐outcome were included (controls, n = 7). Single‐cell mass cytometry/unsupervised analysis allowed unbiased immunophenotyping during OFC.
Results
Peripheral immune profiles correlated with OFC outcome. OFC+‐profiles revealed mainly decreased Th2 cells, memory Treg and activated NK cells, which had an increased homing marker expression signifying immune cell migration into effector tissues along with symptom onset. OFC−‐profiles had also signs of ongoing inflammation, but with a signature of a controlled response, lacking homing marker expression and featuring a concomitant increase of Th2‐shifted CD4+ T cells and Treg cells. Low versus high threshold reactivity‐groups had differential frequencies of intermediate monocytes and myeloid dendritic cells at baseline. Low threshold was associated with increased CD8+ T cells and reduced memory cells (central memory CM CD4+ Th2 T cells, CM CD8+ T cells, Treg). Immune signatures also discriminated patients with preferential skin versus gastrointestinal symptoms, whereby skin signs correlated with increased expression of CCR4, a molecule enabling skin trafficking, on various immune cell types.
Conclusion
We showed that peripheral immune signatures reflected dynamics of clinical outcome during OFC with peanut. Those immune alterations hold promise as a basis for predictive OFC biomarker discovery to monitor disease outcome and therapy of PA.
Changes of peripheral immune profiles through oral food challenge‐course distinguish negative from positive outcome based on T helper cell (Th)2/non‐Th2 phenotypes. Symptom development correlates with inflammatory immune cell decrease and tissue migration characterized by homing marker expression. Discriminatory immune signatures reflect clinical endotypes of threshold dose reactivity and organ involvement.Abbreviations: GigaSOM, computational analysis tool for unsupervised clustering and dimension reduction; NK, natural killer cell; OFC, oral food challenge; Th, T helper cell; Treg, regulatory T cell
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