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1.
Anim Microbiome ; 6(1): 4, 2024 Feb 02.
Article in English | MEDLINE | ID: mdl-38308359

ABSTRACT

Poor efficiency of dietary fibre utilization not only limits global pork production profit margin but also adversely affects utilization of various dietary nutrients. Poor efficiency of dietary nutrient utilization further leads to excessive excretion of swine manure nutrients and results in environmental impacts of emission of major greenhouse gases (GHG), odor, nitrate leaching and surface-water eutrophication. Emission of the major GHG from intensive pork production contributes to global warming and deteriorates heat stress to pigs in tropical and sub-tropical swine production. Exogenous fibre enzymes of various microbial cellulases, hemicellulases and pectinases have been well studied and used in swine production as the non-nutritive gut modifier feed enzyme additives in the past over two decades. These research efforts have aimed to improve growth performance, nutrient utilization, intestinal fermentation as well as gut physiology, microbiome and health via complementing the porcine gut symbiotic microbial fibrolytic activities towards dietary fibre degradation. The widely reported exogenous fibre enzymes include the singular use of respective cellulases, hemicellulases and pectinases as well as their multienzyme cocktails. The currently applied exogenous fibre enzymes are largely limited by their inconsistent in vivo efficacy likely due to their less defined enzyme stability and limited biochemical property. More recently characterized monomodular, multifunctional and processive endoglucanases have the potential to be more efficaciously used as the next-generation designer fibre biocatalysts. These newly emerging multifunctional and processive endoglucanases have the potential to unleash dietary fibre sugar constituents as metabolic fuels and prebiotics, to optimize gut microbiome, to maintain gut permeability and to enhance performance in pigs under a challenged environment as well as to parallelly unlock biomass to manufacture biofuels and biomaterials.

2.
Allergy ; 79(4): 924-936, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37984453

ABSTRACT

BACKGROUND: RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD). METHODS: This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. RESULTS: In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures. CONCLUSIONS: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.


Subject(s)
Dermatitis, Atopic , Humans , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Skin/pathology , Th2 Cells/pathology , Treatment Outcome , Double-Blind Method , Severity of Illness Index , Receptors, CCR4/therapeutic use
3.
ACR Open Rheumatol ; 4(10): 903-911, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35899378

ABSTRACT

OBJECTIVE: To assess the safety and biological activity of rozibafusp alfa, a first-in-class bispecific antibody-peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). METHODS: This phase 1b, double-blind, placebo-controlled, multiple ascending dose study included 34 patients (18-75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints-C-reactive protein [DAS28-CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow-up. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28-CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease). RESULTS: TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t1/2  = 4.6-9.5 days) and dose-related, reversible PD (>90% ICOSL receptor occupancy in 210- and 420-mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti-rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210- and 420-mg cohorts. CONCLUSION: Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease.

4.
Sci Rep ; 12(1): 9135, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35650308

ABSTRACT

Development of highly efficacious exogenous fibre degradation enzymes can enhance efficiency of dietary fibre utilization and sustainability of global pork production. The objectives of this study were to investigate in vitro stability for two processive endoglucanases, referred to as GH5-tCel5A1 and GH5-p4818Cel5_2A that were overexpressed in CLEARCOLIBL21(DE3). Three-dimensional models predicted presence of Cys residues on the catalytic site surfaces of GH5-tCel5A1 and GH5-p4818Cel5_2A; and time course experimental results shown that both cellulases were susceptible to auto-oxidation by airborne O2 and were unstable. Furthermore, we examined these endoglucanases' stability under the mimicked in vitro porcine gastric and the small intestinal pH and proteases' conditions. Eadie-Hofstee inhibition kinetic analyses showed that GH5-tCel5A1 and GH5-p4818Cel5_2A respectively lost 18 and 68% of their initial activities after 2-h incubations under the gastric conditions and then lost more than 90% of their initial activities after 2-3 h of incubations under the small intestinal conditions. Therefore, further enzyme protein engineering to improve resistance and alternatively post-fermentation enzyme processing such as coating to bypass the gastric-small intestinal environment will be required to enable these two processive endoglucanases as efficacious exogenous fibre enzymes in pig nutrition application.


Subject(s)
Cellulase , Cellulases , Animals , Catalytic Domain , Cellulase/metabolism , Cellulases/metabolism , Cellulose/metabolism , Dietary Fiber , Swine
5.
Front Immunol ; 12: 782788, 2021.
Article in English | MEDLINE | ID: mdl-34970265

ABSTRACT

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.


Subject(s)
Antibodies, Bispecific/adverse effects , Antibody Formation , Antigen-Antibody Complex/immunology , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/etiology , Immune Tolerance , Antibodies, Bispecific/immunology , Antibodies, Bispecific/pharmacokinetics , Antibodies, Bispecific/therapeutic use , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Biomarkers/blood , Drug-Related Side Effects and Adverse Reactions/blood , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Immunoassay , Isoantibodies/immunology , Protein Binding/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
6.
Arthritis Rheumatol ; 70(7): 1071-1076, 2018 07.
Article in English | MEDLINE | ID: mdl-29513931

ABSTRACT

OBJECTIVE: To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis. METHODS: In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169. CONCLUSION: AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Arthritis/drug therapy , Inducible T-Cell Co-Stimulator Ligand/immunology , Lupus Erythematosus, Systemic/drug therapy , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Antibodies, Monoclonal, Humanized/immunology , Arthritis/immunology , Arthritis/pathology , Double-Blind Method , Female , Humans , Immunosuppressive Agents/therapeutic use , Joints/drug effects , Joints/pathology , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/pathology , Male , Middle Aged , Severity of Illness Index , Treatment Outcome , Young Adult
7.
Proc Natl Acad Sci U S A ; 113(6): 1612-7, 2016 Feb 09.
Article in English | MEDLINE | ID: mdl-26802121

ABSTRACT

Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.


Subject(s)
DNA-Binding Proteins/metabolism , I-kappa B Kinase/chemistry , I-kappa B Kinase/metabolism , Inflammation/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , NF-kappa B/metabolism , Nuclear Proteins/metabolism , Case-Control Studies , Cell Line , Cell Nucleus/metabolism , Cytokines/biosynthesis , Deubiquitinating Enzyme CYLD , Female , Gene Expression Regulation , Humans , I-kappa B Kinase/genetics , Immunity, Innate , Inflammation/immunology , Inflammation/pathology , Male , Monocytes/metabolism , Mutant Proteins/metabolism , Mutation/genetics , Pedigree , Phenotype , Polyubiquitin/metabolism , Protein Structure, Tertiary , Protein Transport , Receptors, Tumor Necrosis Factor/metabolism , T-Lymphocytes/metabolism , Toll-Like Receptors/metabolism , Tumor Necrosis Factor alpha-Induced Protein 3 , Tumor Suppressor Proteins/metabolism , Ubiquitination
9.
PLoS One ; 10(3): e0118513, 2015.
Article in English | MEDLINE | ID: mdl-25789765

ABSTRACT

Mast cells (MC) and myeloid dendritic cells (DC) act proximally in detecting and processing antigens and immune insults. We sought to understand their comparative dynamic behavior with respect to the airway epithelium in the steady state and in response to an allergic stimulus in mouse trachea. We devised methods to label MC in living trachea and to demonstrate that MC and DC occupy distinct layers of the tracheal mucosa, with DC being closer to the lumen. DC numbers doubled after allergen challenge, but MC numbers remained stable. MC and DC migrated minimally in either steady state or allergen-challenge conditions, and their interactions with one another appeared to be stochastic and relatively infrequent. While DC, unlike MC, exhibited probing behaviors involving dendrites, these projections did not cross the epithelium into the airway lumen. MC typically were located too far from the epithelial surface to contact the tracheal lumen. However, MC had protrusions toward and into blood vessels, likely to load with IgE. Thus, DC and MC occupy distinct niches and engage in sessile surveillance in the mouse trachea. Little or no access of these cell types to the airway lumen suggests that trans-epithelial transport of proteins in the steady state would be required for them to access luminal antigens.


Subject(s)
Allergens/immunology , Blood Vessels/immunology , Blood Vessels/pathology , Cell Surface Extensions/immunology , Mast Cells/cytology , Mast Cells/immunology , Trachea/immunology , Animals , Cell Movement , Dendritic Cells/immunology , Imaging, Three-Dimensional , Immunoglobulin E/immunology , Mice, Inbred C57BL , Ovalbumin/immunology , Reproducibility of Results , Staining and Labeling
10.
J Exp Med ; 212(4): 513-24, 2015 Apr 06.
Article in English | MEDLINE | ID: mdl-25779634

ABSTRACT

Vertebrate immunity has evolved a modular architecture in response to perturbations. Allergic inflammation represents such a module, with signature features of antigen-specific IgE and tissue eosinophilia, although the cellular and molecular circuitry coupling these responses remains unclear. Here, we use genetic and imaging approaches in models of IgE-dependent eosinophilic dermatitis to demonstrate a requisite role for basophils. After antigenic inflammation, basophils initiate transmigration like other granulocytes but, upon activation via their high-affinity IgE receptor, alter their migratory kinetics to persist at the endothelium. Prolonged basophil-endothelial interactions, in part dependent on activation of focal adhesion kinases, promote delivery of basophil-derived IL-4 to the endothelium and subsequent induction of endothelial vascular cell adhesion molecule-1 (VCAM-1), which is required for eosinophil accumulation. Thus, basophils are gatekeepers that link adaptive immunity with innate effector programs by altering access to tissue sites by activation-induced interactions with the endothelium.


Subject(s)
Basophils/immunology , Endothelial Cells/immunology , Eosinophils/immunology , Immunoglobulin E/immunology , Transendothelial and Transepithelial Migration/immunology , Animals , Basophils/pathology , Cell Communication , Dermatitis/immunology , Dermatitis/pathology , Endothelial Cells/metabolism , Eosinophils/pathology , Immunity, Innate/genetics , Interleukin-4/genetics , Interleukin-4/immunology , Mice , Mice, Knockout , Transendothelial and Transepithelial Migration/genetics , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/immunology
12.
Cold Spring Harb Perspect Biol ; 7(3): a016352, 2014 Nov 20.
Article in English | MEDLINE | ID: mdl-25414367

ABSTRACT

Allergic inflammation is associated closely with parasite infection but also asthma and other common allergic diseases. Despite the engagement of similar immunologic pathways, parasitized individuals often show no outward manifestations of allergic disease. In this perspective, we present the thesis that allergic inflammatory responses play a primary role in regulating circadian and environmental inputs involved with tissue homeostasis and metabolic needs. Parasites feed into these pathways and thus engage allergic inflammation to sustain aspects of the parasitic life cycle. In response to parasite infection, an adaptive and regulated immune response is layered on the host effector response, but in the setting of allergy, the effector response remains unregulated, thus leading to the cardinal features of disease. Further understanding of the homeostatic pressures driving allergic inflammation holds promise to further our understanding of human health and the treatment of these common afflictions.


Subject(s)
Circadian Rhythm/physiology , Homeostasis/physiology , Hypersensitivity/complications , Immunity, Humoral , Inflammation/immunology , Metabolic Networks and Pathways/physiology , Parasitic Diseases/complications , Humans , Hypersensitivity/immunology , Inflammation/etiology
13.
Nature ; 502(7470): 245-8, 2013 Oct 10.
Article in English | MEDLINE | ID: mdl-24037376

ABSTRACT

Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago, and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins mediate eosinophil development and survival, and tissue recruitment, respectively, the processes underlying the basal regulation of these signals remain unknown. Here we show that serum IL-5 levels are maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 cells secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, ILC2 cells co-express IL-5 and IL-13; this co-expression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide also stimulates ILC2 cells through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.


Subject(s)
Eosinophils/metabolism , Homeostasis , Lymphocytes/metabolism , Animals , Cells, Cultured , Circadian Rhythm , Collagen/metabolism , Eosinophils/immunology , Eosinophils/parasitology , Female , Gene Expression Regulation , Interleukin-13/genetics , Interleukin-13/metabolism , Interleukin-5/blood , Interleukin-5/genetics , Interleukin-5/metabolism , Lung/immunology , Lung/metabolism , Lung/parasitology , Lymphocytes/immunology , Lymphocytes/parasitology , Male , Mice , Mice, Inbred C57BL , Nippostrongylus/physiology , Strongylida Infections/immunology
14.
J Exp Med ; 210(3): 535-49, 2013 Mar 11.
Article in English | MEDLINE | ID: mdl-23420878

ABSTRACT

Eosinophils in visceral adipose tissue (VAT) have been implicated in metabolic homeostasis and the maintenance of alternatively activated macrophages (AAMs). The absence of eosinophils can lead to adiposity and systemic insulin resistance in experimental animals, but what maintains eosinophils in adipose tissue is unknown. We show that interleukin-5 (IL-5) deficiency profoundly impairs VAT eosinophil accumulation and results in increased adiposity and insulin resistance when animals are placed on a high-fat diet. Innate lymphoid type 2 cells (ILC2s) are resident in VAT and are the major source of IL-5 and IL-13, which promote the accumulation of eosinophils and AAM. Deletion of ILC2s causes significant reductions in VAT eosinophils and AAMs, and also impairs the expansion of VAT eosinophils after infection with Nippostrongylus brasiliensis, an intestinal parasite associated with increased adipose ILC2 cytokine production and enhanced insulin sensitivity. Further, IL-33, a cytokine previously shown to promote cytokine production by ILC2s, leads to rapid ILC2-dependent increases in VAT eosinophils and AAMs. Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation.


Subject(s)
Eosinophils/physiology , Intra-Abdominal Fat/cytology , Macrophages/physiology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Helminthiasis/immunology , Immunity, Innate , Insulin Resistance , Interleukin-13/physiology , Interleukin-33 , Interleukin-5/physiology , Interleukins/pharmacology , Intestinal Diseases, Parasitic/immunology , Lymphocyte Activation , Macrophage Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
15.
Immunity ; 38(1): 166-75, 2013 Jan 24.
Article in English | MEDLINE | ID: mdl-23290520

ABSTRACT

Mast cells are tissue-resident immune cells that play a central role in allergic disease. These contributions are largely dependent on the acquisition of antigen-specific immunoglobulin E (IgE). Despite this requirement, studies of mast cell and IgE interactions have overlooked the mechanism by which mast cells acquire IgE from the blood. To address this gap, we developed reporter IgE molecules and employed imaging techniques to study mast cell function in situ. Our data demonstrate that skin mast cells exhibit selective uptake of IgE based on perivascular positioning. Furthermore, perivascular mast cells acquire IgE by extending cell processes across the vessel wall to capture luminal IgE. These data demonstrate how tissue mast cells acquire IgE and reveal a strategy by which extravascular cells monitor blood contents to capture molecules central to cellular function.


Subject(s)
Immunoglobulin E/immunology , Mast Cells/immunology , Skin/immunology , Animals , Cell Tracking , Immunoglobulin E/metabolism , Immunophenotyping , Mast Cells/metabolism , Mice , Peritoneal Cavity/cytology , Peritoneum/immunology , Protein Binding/immunology , Receptors, IgE/immunology , Receptors, IgE/metabolism , Skin/metabolism
16.
Nat Immunol ; 12(6): 527-35, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21552267

ABSTRACT

Contributions by basophils to allergic and helminth immunity remain incompletely defined. Using sensitive interleukin 4 (Il4) reporter alleles, we demonstrate here that basophil IL-4 production occurs by a CD4(+) T cell-dependent process restricted to the peripheral tissues affected. We genetically marked and achieved specific deletion of basophils and found that basophils did not mediate T helper type 2 (T(H)2) priming in vivo. Two-photon imaging confirmed that basophils did not interact with antigen-specific T cells in lymph nodes but engaged in prolonged serial interactions with T cells in lung tissues. Although targeted deletion of IL-4 and IL-13 in either CD4(+) T cells or basophils had a minimal effect on worm clearance, deletion from both lineages demonstrated a nonredundant role for basophil cytokines in primary helminth immunity.


Subject(s)
Basophils/immunology , Interleukin-4/immunology , Lung/immunology , Strongylida Infections/immunology , Animals , Basophils/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Female , Flow Cytometry , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Helminthiasis, Animal/immunology , Helminthiasis, Animal/metabolism , Helminthiasis, Animal/parasitology , Host-Parasite Interactions/immunology , Humans , Interleukin-13/genetics , Interleukin-13/immunology , Interleukin-13/metabolism , Interleukin-4/genetics , Interleukin-4/metabolism , Liver/immunology , Liver/metabolism , Liver/parasitology , Lung/metabolism , Lung/parasitology , Lung Diseases, Parasitic/immunology , Lung Diseases, Parasitic/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microscopy, Fluorescence, Multiphoton , Nippostrongylus/immunology , Nippostrongylus/physiology , Schistosoma mansoni/immunology , Schistosoma mansoni/physiology , Strongylida Infections/metabolism , Strongylida Infections/parasitology
17.
J Immunol ; 185(9): 5040-7, 2010 Nov 01.
Article in English | MEDLINE | ID: mdl-20870945

ABSTRACT

The manifestations of allergic disorders are closely tied to the biologic effects of IgE activation with Ag. In immediate hypersensitivity reactions, IgE effector function requires prior binding to innate immune cells, primarily mast cells and basophils, with the blood acting as a reservoir for unbound IgE. As the severity of allergic disease is proportional to the size of this unbound IgE pool, we hypothesized that cellular mechanisms exist to limit the size and/or enhance the clearance of free IgE molecules. We examined this in mice by engineering a reporter IgE molecule that allowed us to track the fate of IgE molecules in vivo. The absence of FcεRI-expressing cells did not affect serum IgE levels, but B cells regulated serum IgE by controlling the size of the free IgE pool. B cells captured IgE by direct binding to the low-affinity IgE receptor, CD23. These data indicate a mechanism regulating serum IgE and additionally clarify the role of CD23 in this process.


Subject(s)
B-Lymphocytes/immunology , Hypersensitivity, Immediate/blood , Immunoglobulin E/blood , Receptors, IgE/immunology , Animals , B-Lymphocytes/metabolism , Cell Separation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Hypersensitivity, Immediate/immunology , Immunoglobulin E/immunology , Immunoglobulin E/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, IgE/metabolism
18.
Clin Immunol ; 132(1): 124-31, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19375390

ABSTRACT

The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are increasingly well understood, little is known about autoimmune manifestations in NEMO patients. We therefore sought to examine serologic markers of systemic inflammation and intestinal pathology in a kindred of patients with the NEMO syndrome. We observed persistent elevation of erythrocyte sedimentation rates in five patients, and two were symptomatic, with a chronic but atypical enterocolitis. Though pathologic lesions in these two patients were consistent with acute inflammation, sustained clinical improvement was only achieved with systemic and/or topical glucocorticoid therapy. Our data suggest that some patients with the NEMO syndrome exhibit persistent elevation of inflammatory markers similar to systemic autoimmune diseases and may subsequently develop an atypical enterocolitis.


Subject(s)
Enterocolitis/etiology , Immunologic Deficiency Syndromes/complications , Inflammation/etiology , Adolescent , Blood Sedimentation , Child , Child, Preschool , Colonoscopy , Enterocolitis/blood , Enterocolitis/pathology , Female , Humans , Immunologic Deficiency Syndromes/blood , Immunologic Deficiency Syndromes/pathology , Infant , Inflammation/blood , Inflammation/pathology , Male , Pedigree
19.
J Immunol ; 169(9): 4990-7, 2002 Nov 01.
Article in English | MEDLINE | ID: mdl-12391213

ABSTRACT

CD8(+) T cells respond to IL-2 produced both endogenously and by CD4(+) Th during an antiviral response. However, IL-2R signals can potentially promote CD8(+) T cell death as well as proliferation, making it unclear whether IL-2R signals provide a predominantly positive or negative effect upon CD8(+) T cell responses to viral infection. To more precisely define the direct role of IL-2R signaling on CD8(+) T cells during the response to a virus, we examined the effect of delivering augmented IL-2R signals selectively to CD8(+) T cells responding to lymphocytic choriomeningitis virus infection. Although naive CD8(+) T cells are competent to produce IL-2, CD8(+) T cells lose this capacity upon differentiation into effector CD8(+) T cells. However, effector CD8(+) T cells do retain the capacity to produce GM-CSF upon Ag stimulation. Thus, to deliver enhanced autocrine IL-2R signals to CD8(+) T cells, we established a transgenic mouse strain expressing a chimeric GM-CSF/IL-2R (GMIL2R). As GM-CSF production is Ag dependent, the GMIL2R delivers an augmented IL-2R signal exclusively to CD8(+) T cells responding to Ag. Following lymphocytic choriomeningitis virus infection, GMIL2R transgenic mice exhibited an increase in both the peak CD8(+) T cell response achieved and the size of the resulting memory pool established. Upon secondary viral challenge, the GMIL2R also enhanced the proliferative response of memory CD8(+) T cells. Thus, our findings indicate that IL-2 delivery to responding CD8(+) T cells is a limiting factor in both the acute and memory antiviral responses.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Immunologic Memory , Lymphocytic choriomeningitis virus/immunology , Receptors, Interleukin-2/physiology , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/virology , Acute Disease , Adjuvants, Immunologic/genetics , Adjuvants, Immunologic/physiology , Animals , Antigens, Viral/immunology , Autocrine Communication/genetics , Autocrine Communication/immunology , CD8-Positive T-Lymphocytes/cytology , Cell Division/genetics , Cell Division/immunology , Epitopes, T-Lymphocyte/immunology , Glycoproteins/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Hybridomas , Immunologic Memory/genetics , Lymphocyte Count , Lymphocytic Choriomeningitis/genetics , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/pathology , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Lymphoid Tissue/virology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Interleukin-2/biosynthesis , Receptors, Interleukin-2/genetics , Signal Transduction/genetics , Splenomegaly/genetics , Splenomegaly/immunology , Splenomegaly/virology , T-Lymphocyte Subsets/cytology , Viral Proteins/immunology
20.
J Exp Med ; 195(11): 1407-18, 2002 Jun 03.
Article in English | MEDLINE | ID: mdl-12045239

ABSTRACT

CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon gamma. This split tolerance was accompanied by inhibition of Ca(2+) flux, ERK1/2, and Jun kinase phosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.


Subject(s)
Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immune Tolerance/immunology , Animals , Antigens, Neoplasm/genetics , Calcium/metabolism , Cell Division , Cell Extracts , Flow Cytometry , Gene Expression , Interferon-gamma/metabolism , Interleukin-2/metabolism , JNK Mitogen-Activated Protein Kinases , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Signal Transduction , Spleen/cytology , Spleen/metabolism , Tumor Necrosis Factor-alpha/metabolism , fas Receptor/metabolism , ras Proteins/metabolism
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