The gut microbiota plays a major role in the developmental biology and homeostasis of cells belonging to the adaptive and innate arms of the immune system. Alterations in its composition, which are ...known to be regulated by both genetic and environmental factors, can either promote or suppress the pathogenic processes underlying the development of various autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and rheumatoid arthritis, to just name a few. Cross-recognition of gut microbial antigens by autoreactive T cells as well as gut microbe-driven alterations in the activation and homeostasis of effector and regulatory T cells have been implicated in this process. Here, we summarize our current understanding of the positive and negative associations between alterations in the composition of the gut microbiota and the development of various autoimmune disorders, with a special emphasis on antigenic mimicry.
Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. ...Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.
IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity ST2) is a differentially expressed gene in pathogenic TH2 cells, but its role in ...T-cell effector function has not been elucidated.
We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses. We hypothesized that selective ST2 expression on allergen-specific CD4+ T cells would confer susceptibility to the effects of IL-33.
PBMCs from subjects with food allergy, inhalant allergy, and no allergy were obtained on the basis of clinical history and serum IgE level. A T-cell receptor–dependent CD154 upregulation assay and direct peptide major histocompatibility complex class II tetramer staining were used to profile allergen-specific CD4+ T cells by flow cytometry. Allergen-specific CD4+ T cell cytokine production was evaluated during IL-33 exposure. ST2 expression was also tracked by using a 2-color flow-based assay.
ST2 expression on peripheral allergen-specific CD4+ T cells was confined to subjects with allergy and restricted to TH2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of TH2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive TH2A cells. Allergen-induced ST2 expression on peripheral CD4+ T cells can be used to track allergen-reactive TH2A cells from donors with allergy.
ST2 expression on circulating CD4+ T cells represents a transient phenotype associated with TH2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic TH2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.
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Type 1 diabetes can be overcome by regulatory T cells (Treg) in NOD mice yet an efficient method to generate and maintain antigen-specific Treg is difficult to come by. Here, we devised a combination ...therapy of peptide/MHC tetramers and IL-2/anti-IL-2 monoclonal antibody complexes to generate antigen-specific Treg and maintain them over extended time periods. We first optimized treatment protocols conceived to obtain an improved islet-specific Treg/effector T cell ratio that led to the in vivo expansion and activation of these Treg as well as to an improved suppressor function. Optimized protocols were applied to treatment for testing diabetes prevention in NOD mice as well as in an accelerated T cell transfer model of T1D. The combined treatment led to robust protection against diabetes, and in the NOD model, to a close to complete prevention of insulitis. Treatment was accompanied with increased secretion of IL-10, detectable in total splenocytes and in Foxp3
CD4 T cells. Our data suggest that a dual protection mechanism takes place by the collaboration of Foxp3
and Foxp3
regulatory cells. We conclude that antigen-specific Treg are an important target to improve current clinical interventions against this disease.
Background
The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to ...peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut‐allergic individuals undergoing oral desensitization immunotherapy with AR101.
Methods
Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T‐cell reactivity to peanut.
Results
The absence of clinical reactivity to the entry double‐blinded placebo‐controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T‐cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut‐reactive TH2A cells were observed in many but not all peanut‐allergic patients and their level in peripheral blood correlates with T‐cell reactivity to peanut and with serum peanut‐specific IgE and IgG4 levels. POIT reshaped circulating peanut‐reactive T‐cell responses in a subset‐dependent manner. Changes in basophil and T‐cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut‐reactive Treg cell frequency was observed between groups.
Conclusion
Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut‐reactive T effector cell responses supporting its potential as an immunomodulatory therapy.
CRTH2+ pTeff cells and CCR6+ pTeff cells represent two mutually exclusive, nonoverlapping cellular and molecular entities involved in food‐allergic diseases. Circulating CRTH2+ pTeff cells are mostly restricted to peanut‐allergic individuals who react to the 100 mg DBPCFC compared to those with lower clinical sensitivity to peanut. Changes in basophil and T‐cell responses to peanut closely parallel clinical benefits to POIT and resemble responses in those that did not react to the baseline 100 mg DBPCFC.Abbreviations: BAT‐EC50, concentration of allergen corresponding to 50% of maximal activation of basophils in basophil activation test; CCR6, C‐C motif chemokine receptor 6; CRTH2, chemoattractant receptor‐homologous molecule expressed on Th2 cells; DBPCFC, double‐blinded placebo‐controlled peanut challenge; FOXP3, forkhead box P3; freq, frequency; GATA3, GATA binding protein 3; HPGDS, hematopoietic prostaglandin D synthase; IFNG, interferon gamma; IL, interleukin; PALISADE, Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults; POIT, peanut oral immunotherapy; PPARG, peroxisome proliferator activated receptor alpha; pTeff, peanut‐reactive T cell; RORC, RAR related orphan receptor C; ST2, suppression of tumorigenicity 2
Results Our data emphasize the heterogeneity of peanut-reactive effector T cell responses, with two mutually exclusive phenotypic entities (CCR6-CRTH2+ and CCR6+CRTH2-) associated with food allergy. ...While CRTH2+CCR6- peanut-specific T cell subset shared similar features with Th2A cell responses (i.e. IL33R+, IL25R+, IL-5), CCR6+CRTH2- T cell subset exhibit a Th17/Th1-related activity, suggesting a distinct pathway that may form the basis of a clinically relevant food allergy endotype.
Assembly of soluble peptide-major histocompatibility complex class II (pMHCII) monomers into multimeric structures enables the detection of antigen-specific CD4
T cells in biological samples and, in ...some configurations, their reprogramming in vivo. Unfortunately, current MHCII-αβ chain heterodimerization strategies are typically associated with low production yields and require the use of foreign affinity tags for purification, precluding therapeutic applications in humans. Here, we show that fusion of peptide-tethered or empty MHCII-αβ chains to the IgG1-Fc mutated to form knob-into-hole structures results in the assembly of highly stable pMHCII monomers. This design enables the expression and rapid purification of challenging pMHCII types at high yields without the need for leucine zippers and purification affinity tags. Importantly, this design increases the antigen-receptor signaling potency of multimerized derivatives useful for therapeutic applications and facilitates the detection and amplification of low-avidity T cell specificities in biological samples using flow cytometry.
Systemic delivery of nanoparticles (NPs) coated with mono-specific autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules can resolve organ inflammation in ...various disease models in a disease-specific manner without impairing normal immunity. These compounds invariably trigger the formation and systemic expansion of cognate pMHCII-specific T-regulatory type 1 (TR1) cells. By focusing on type 1 diabetes (T1D)-relevant pMHCII-NP types that display an epitope from the insulin B-chain bound to the same MHCII molecule (IA
) on three different registers, we show that pMHCII-NP-induced TR1 cells invariably co-exist with cognate T-Follicular Helper (TFH)-like cells of quasi-identical clonotypic composition and are oligoclonal, yet transcriptionally homogeneous. Furthermore, these three different TR1 specificities have similar diabetes reversal properties
despite being uniquely reactive against the peptide MHCII-binding register displayed on the NPs. Thus, pMHCII-NP treatment using nanomedicines displaying different epitope specificities results in the simultaneous differentiation of multiple antigen-specific TFH-like cell clones into TR1-like cells that inherit the fine antigenic specificity of their precursors while acquiring a defined transcriptional immunoregulatory program.
Targeting IL-33 in Food Allergy: Toward patient stratification Wambre, Erik R.; Garabatos Leitón, Nahir; Bajzik, Veronique ...
Journal of allergy and clinical immunology,
February 2018, 2018-02-00, 20180201, Letnik:
141, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Rationale Heterogeneity of peanut-specific memory T cell responses could be related to clinical treatment outcomes. Analyses of surface marker phenotype and the molecular and cytokine profile of ...these cells was performed to determine the impact of IL-33 in modulating T cell responses to food allergen.
Nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHCs) can blunt autoimmune diseases by re-programming cognate effector T-lymphocytes into ...disease-suppressing regulatory T-cells, followed by massive expansion. Here, a method to quantify the absolute amounts of the active drug product is developed, to understand the relationship between bioavailability and pharmacodynamics. Incubation with plasma results in the formation of a protein corona that stabilizes the directional pMHC coat, shielding it from proteolysis or anti-drug antibody recognition, without any appreciable loss in biological potency. A quantitative method that harnesses these features indicates that the half-life of these compounds in the circulation and organs is an order of magnitude shorter (minutes vs. hours) than that measured using commonly-used semi-quantitative methods. Extensive transmission electron microscopy-based organ scanning and flow cytometry-based enumeration of pMHCII-NP capturing cells confirmed that these compounds are rapidly captured (within 1 min) by liver sinusoidal endothelial cells, Kupffer cells, splenic phagocytes and cognate T-cells, leading to a fast decline in the circulation. Therefore, the powerful pharmacodynamic effects of these compounds are dissociated from long bioavailability, implying a hit-and-run event. Collectively, these data provide a detailed view of the life-cycle of a nanoimmunomedicine, and suggest that the real half-lives of intact nanomedicines may be much shorter than those estimated using indirect approaches.
A highly sensitive and specific method is developed to measure the true pharmacokinetic life-cycle of a nanoimmunomedicine that can revert complex autoimmune diseases by triggering the formation of disease-specific immunoregulatory cell networks. In combination with TEM-based organ scanning, this method reveals an unexpected dissociation between bioavailability and pharmacodynamic activity due to extremely rapid uptake by liver and splenic scavengers, implying hit-and-run-like biological effects. Display omitted
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