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1.
Mucosal Immunol ; 9(1): 240-53, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26153764

ABSTRACT

Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1(-/-) mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.


Subject(s)
Idiopathic Pulmonary Fibrosis/immunology , Interleukin-13 Receptor alpha1 Subunit/immunology , Interleukin-13/immunology , Lung Injury/immunology , Adult , Animals , Bleomycin , Case-Control Studies , Female , Gene Expression Regulation , Homeostasis/immunology , Humans , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Interleukin-13/genetics , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Lung/immunology , Lung/pathology , Lung Injury/chemically induced , Lung Injury/genetics , Lung Injury/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Protein Isoforms/genetics , Protein Isoforms/immunology , Receptors, Interleukin-4/genetics , Receptors, Interleukin-4/immunology , Signal Transduction , Transcription, Genetic
2.
Mucosal Immunol ; 8(4): 863-73, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25465099

ABSTRACT

Allergic asthma is a chronic, inflammatory lung disease. Some forms of allergic asthma are characterized by T helper type 2 (Th2)-driven eosinophilia, whereas others are distinguished by Th17-driven neutrophilia. Stimulation of Toll-like receptor 4 (TLR4) on hematopoietic and airway epithelial cells (AECs) contributes to the inflammatory response to lipopolysaccharide (LPS) and allergens, but the specific contribution of TLR4 in these cell compartments to airway inflammatory responses remains poorly understood. We used novel, conditionally mutant Tlr4(fl/fl) mice to define the relative contributions of AEC and hematopoietic cell Tlr4 expression to LPS- and allergen-induced airway inflammation. We found that Tlr4 expression by hematopoietic cells is critical for neutrophilic airway inflammation following LPS exposure and for Th17-driven neutrophilic responses to the house dust mite (HDM) lysates and ovalbumin (OVA). Conversely, Tlr4 expression by AECs was found to be important for robust eosinophilic airway inflammation following sensitization and challenge with these same allergens. Thus, Tlr4 expression by hematopoietic and airway epithelial cells controls distinct arms of the immune response to inhaled allergens.


Subject(s)
Asthma/genetics , Asthma/immunology , Eosinophils/metabolism , Gene Expression , Neutrophils/metabolism , Toll-Like Receptor 4/genetics , Animals , Asthma/metabolism , Asthma/pathology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Models, Animal , Eosinophils/immunology , Eosinophils/pathology , Epithelial Cells/metabolism , Immunity, Innate , Lipopolysaccharides/immunology , Lung/immunology , Lung/metabolism , Lung/pathology , Mice , Mice, Knockout , Neutrophils/immunology , Neutrophils/pathology , Pyroglyphidae/immunology , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Toll-Like Receptor 4/metabolism
3.
Cancer Chemother Pharmacol ; 73(6): 1307-13, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24771103

ABSTRACT

PURPOSE: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase. PATIENTS AND METHODS: The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy. RESULTS: Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients. CONCLUSIONS: These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.


Subject(s)
Asparaginase/administration & dosage , Asparaginase/therapeutic use , Adolescent , Asparaginase/adverse effects , Child , Dickeya chrysanthemi/enzymology , Drug Hypersensitivity/etiology , Escherichia coli/enzymology , Female , Humans , Male , Polyethylene Glycols/adverse effects , Polyethylene Glycols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
4.
Proc Natl Acad Sci U S A ; 105(20): 7240-5, 2008 May 20.
Article in English | MEDLINE | ID: mdl-18480254

ABSTRACT

IL-13 and IL-4 are central T helper 2 (Th2) cytokines in the immune system and potent activators of inflammatory responses and fibrosis during Th2 inflammation. Recent studies using Il13ra1(-/-) mice have demonstrated a critical role for IL-13 receptor (IL-13R) alpha1 in allergen-induced airway responses. However, these observations require further attention especially because IL-4 can induce similar lung pathology to IL-13, independent of IL-13, and is still present in the allergic lung. Thus, we hypothesized that IL-13Ralpha1 regulates IL-4-induced responses in the lung. To dissect the role of IL-13Ralpha1 and the type I and II IL-4Rs in experimental asthma, we examined lung pathology induced by allergen, IL-4, and IL-13 challenge in Il13ra1(-/-) mice. We report that IL-13Ralpha1 is essential for baseline IgE production, but Th2 and IgE responses to T cell-dependent antigens are IL-13Ralpha1-independent. Furthermore, we demonstrate that increased airway resistance, mucus, TGF-beta, and eotaxin(s) production, but not cellular infiltration, are critically dependent on IL-13Ralpha1. Surprisingly, our results identify a CCR3- and IL-13Ralpha1-independent pathway for lung eosinophilia. Global expression profiling of lungs from mice stimulated with allergen or IL-4 demonstrated that marker genes of alternatively activated macrophages are differentially regulated by the type I and type II IL-4R. Taken together, our data provide a comprehensive mechanistic analysis of the critical role by which IL-13Ralpha1 mediates allergic lung pathology and highlight unforeseen roles for the type II IL-4R.


Subject(s)
Asthma/pathology , Gene Expression Profiling , Interleukin-13/physiology , Interleukin-4/physiology , Receptors, Interleukin-13/metabolism , Receptors, Interleukin-4/metabolism , Animals , Chemokine CCL11/metabolism , Eosinophils/metabolism , Inflammation , Lung/metabolism , Lung/pathology , Mice , Mice, Transgenic , Models, Biological , Th2 Cells/metabolism
5.
Allergy ; 63(1): 35-7, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18053014

ABSTRACT

Effector mechanisms in anaphylaxis were reviewed. Current approaches to confirmation of the clinical diagnosis were discussed. Improved methods for distinguishing between allergen sensitization (which is common in the general population) and clinical risk of anaphylaxis (which is uncommon) were deliberated. Innovative techniques that will improve risk assessment in anaphylaxis in the future were described.


Subject(s)
Anaphylaxis/diagnosis , Practice Guidelines as Topic/standards , Risk Assessment , Consensus Development Conferences as Topic , Europe , Female , Humans , Hypersensitivity/diagnosis , Male , Prognosis , Sensitivity and Specificity , United States
6.
Eur J Immunol ; 31(11): 3355-60, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11745353

ABSTRACT

Interleukin-2 is an immunotherapeutic agent for the treatment of metastatic tumors. Administration of recombinant human IL-2 (rhIL-2) in vivo activates lymphocytes and cell-mediated immune responses. In mice, we have recently observed a dramatic increase of serum IFN-gamma levels in response to in vivo administration of rhIL-2, which was necessary for the observed protective effects of IL-2 against the development of collagen-induced arthritis. To explore further the basis of this phenomenon, the kinetics and source of IFN-gamma in response to IL-2 was investigated. Highest serum levels of IFN-gamma were observed within 3 h of IL-2 administration, with levels decreasing over time. Anti-IL-2 receptor beta antibody blocked this IFN-gamma induction. Multiple doses of rhIL-2 resulted in corresponding increases in circulating IFN-gamma. IFN-gamma induction was dose-dependent between doses of 240 to 30,000 U of rhIL-2. Analysis of the cellular source of IFN-gamma secretion using NK- and T cell-deficient mice demonstrated that NK cells are the likely source of IFN-gamma. Furthermore, IFN-gamma secretion in response to IL-2 administration was not affected by the absence of IL-12, the pivotal cytokine for determination of Th1 responses. These results suggest that effects of IL-2 on immune responses in vivo may be mediated by IFN-gamma.


Subject(s)
Interferon-gamma/biosynthesis , Interleukin-2/pharmacology , Killer Cells, Natural/metabolism , Animals , Autoimmune Diseases/etiology , Dose-Response Relationship, Drug , Interleukin-12/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Inbred DBA , Recombinant Proteins/pharmacology
7.
J Immunol ; 167(12): 6821-6, 2001 Dec 15.
Article in English | MEDLINE | ID: mdl-11739498

ABSTRACT

Neutralization of TNF-alpha in humans with rheumatoid arthritis or Crohn's disease has been associated with the development of humoral autoimmunity. To determine the effect of TNF-alpha neutralization on cell-mediated and humoral-mediated responses, we administered anti-TNF-alpha mAb to mice undergoing acute graft-vs-host disease (GVHD) using the parent-into-F(1) model. In vivo neutralization of TNF-alpha blocked the lymphocytopenic features characteristic of acute GVHD and induced a lupus-like chronic GVHD phenotype (lymphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable antihost CTL activity and required the presence of anti-TNF-alpha mAb for the first 4 days after parental cell transfer, indicating that TNF-alpha plays a critical role in the induction of CTL. Moreover, an in vivo blockade of TNF-alpha preferentially inhibited the production of IFN-gamma and blocked IFN-gamma-dependent up-regulation of Fas; however, cytokines such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest that a therapeutic TNF-alpha blockade may promote humoral autoimmunity by selectively inhibiting the induction of a CTL response that would normally suppress autoreactive B cells.


Subject(s)
Antibodies, Antinuclear/biosynthesis , Autoimmunity , T-Lymphocytes, Cytotoxic/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Acute Disease , Animals , Antibodies, Monoclonal/pharmacology , Cells, Cultured , Cytotoxicity Tests, Immunologic , DNA/immunology , Graft vs Host Disease/immunology , Interferon-gamma/biosynthesis , Kinetics , Lupus Erythematosus, Systemic/immunology , Lymphocyte Activation , Male , Mice , Mice, Inbred C57BL , Neutralization Tests , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/physiology , fas Receptor/biosynthesis
8.
J Immunol ; 167(11): 6078-81, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11714764

ABSTRACT

Expulsion of two gastrointestinal nematode parasites, Nippostrongylus brasiliensis and Trichinella spiralis, is similar in that both require IL-4Ralpha expression, but different in that T cells and mast cells are required for IL-4-induced expulsion of T. spiralis but not N. brasiliensis. To examine the role of IL-4Ralpha signaling in immunity to these parasites, we studied worm expulsion in chimeric mice that selectively expressed IL-4Ralpha on bone marrow-derived or non-bone marrow-derived cells. N. brasiliensis was expelled by mice that expressed IL-4Ralpha only on non-bone marrow-derived cells, but not by mice that expressed IL-4Ralpha only on bone marrow-derived cells. Although T. spiralis expulsion required IL-4Ralpha expression by both bone marrow- and non-bone marrow-derived cells, IL-4 stimulation eliminated the requirement for IL-4Ralpha expression by bone marrow-derived cells. Thus, direct IL-4Ralpha signaling of nonimmune gastrointestinal cells may be generally required to induce worm expulsion, even when mast cell and T cell responses are also required.


Subject(s)
Bone Marrow Cells/immunology , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/parasitology , Mast Cells/immunology , Nippostrongylus/immunology , Receptors, Interleukin-4/biosynthesis , T-Lymphocytes/immunology , Trichinella spiralis/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Bone Marrow Cells/metabolism , Bone Marrow Cells/parasitology , Female , Gastrointestinal Diseases/prevention & control , Interleukin-4/physiology , Lymphopenia/genetics , Lymphopenia/immunology , Lymphopenia/parasitology , Mast Cells/metabolism , Mast Cells/pathology , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Nude , Mice, SCID , Receptors, Interleukin-4/deficiency , Receptors, Interleukin-4/genetics , Strongylida Infections/immunology , Strongylida Infections/parasitology , Strongylida Infections/prevention & control , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Trichinellosis/immunology , Trichinellosis/parasitology , Trichinellosis/prevention & control
9.
J Immunol ; 167(4): 2234-9, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11490010

ABSTRACT

IL-4 and IL-13 promote gastrointestinal worm expulsion, at least in part, through effects on nonlymphoid cells, such as intestinal epithelial cells. The role of IL-4/IL-13 in the regulation of intestinal epithelial function during Heligmosomoides polygyrus (Hp) infection was investigated in BALB/c mice infected with Hp or treated with a long-lasting formulation of recombinant mouse IL-4/alphaIL-4 complexes (IL-4C) for 7 days. Separate groups of BALB/c mice were drug-cured of initial infection and later reinfected and treated with anti-IL-4R mAb, an antagonist of IL-4 and IL-13 receptor binding, or with a control mAb. Segments of jejunum were mounted in Ussing chambers, and short circuit current responses to acetylcholine, histamine, serotonin, PGE2, and glucose were determined. Although only modest changes in epithelial cell function were observed during primary Hp infection, IL-4C or a secondary Hp infection each induced more dramatic changes, including increased mucosal permeability, reduced sodium-linked glucose absorption, and increased Cl- secretory response to PGE2. Some, but not all, effects of IL-4C and Hp infection were dependent on enteric nerves. Hp-induced changes in epithelial function were attenuated or prevented by anti-IL-4R mAb. Thus, IL-4/IL-13 mediate many of the effects of Hp infection on intestinal epithelial cell function and do so both through direct effects on epithelial cells and through indirect, enteric nerve-mediated prosecretory effects. These immune system-independent effector functions of IL-4/IL-13 may be important for host protection against gastrointestinal nematodes.


Subject(s)
Heligmosomatoidea/immunology , Interleukin-4/physiology , Intestinal Mucosa/immunology , Intestinal Mucosa/parasitology , Animals , Antibodies, Blocking/administration & dosage , Antibodies, Monoclonal/administration & dosage , Dinoprostone/pharmacology , Female , Histamine/pharmacology , Interleukin-13/antagonists & inhibitors , Interleukin-13/biosynthesis , Interleukin-4/antagonists & inhibitors , Interleukin-4/biosynthesis , Intestinal Diseases, Parasitic/immunology , Intestinal Diseases, Parasitic/pathology , Intestinal Mucosa/cytology , Intestinal Mucosa/innervation , Mice , Mice, Inbred BALB C , Neurons/immunology , Receptors, Interleukin-4/immunology , Receptors, Interleukin-4/physiology , Strongylida Infections/immunology , Strongylida Infections/pathology
10.
J Allergy Clin Immunol ; 107(5): 772-80, 2001 May.
Article in English | MEDLINE | ID: mdl-11344341

ABSTRACT

Although T(H)2 cytokine involvement in allergy makes these cytokines attractive therapeutic targets, they protect against ectoparasites and gastrointestinal worms and suppress inflammation induced by T(H)1 cytokines. T(H)2 cytokines induce mastocytosis, eosinophilia, IgE synthesis, and mucus production. Each element of this response protects against some worms; however, different worms are protected against by different elements of the total response. The induction of the entire response by most parasitic worms suggests that it is safer for the immune system to make a stereotyped worm-protective response than to attempt to match a more specific response to a particular worm. In contrast, the reciprocal antagonism between T(H)1 and T(H)2 cytokines suggests that it is safer for the immune system to limit immunopathology by suppressing inflammatory effector mechanisms not required for host protection against a particular pathogen class than to make an all-purpose inflammatory response. This, in turn, implies that innate immunity can distinguish different classes of parasites (eg, worms vs protozoa) but has limited ability to distinguish individual parasites within a class (eg, different worms). Although these considerations suggest that T(H)2 cytokine antagonists may increase the risk and severity of worm infections and T(H)1 cytokine-mediated inflammatory disorders, such therapy should be relatively safe if it is restricted to areas in which worm infections are rare and commonsense precautions are taken to minimize the risk of inducing T(H)1 cytokine-related inflammatory disease.


Subject(s)
Helminthiasis/immunology , Interleukins/physiology , Nematode Infections/immunology , Protozoan Infections/immunology , Th2 Cells/metabolism , Animals , Asthma/immunology , Asthma/therapy , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Eosinophilia/etiology , Helminthiasis/parasitology , Helminthiasis/prevention & control , Host-Parasite Interactions/immunology , Humans , Immunoglobulin E/immunology , Inflammation/immunology , Interleukin-13/physiology , Interleukin-4/physiology , Interleukin-5/physiology , Interleukin-9/physiology , Interleukins/antagonists & inhibitors , Intestinal Diseases, Parasitic/immunology , Intestinal Diseases, Parasitic/parasitology , Intestinal Diseases, Parasitic/prevention & control , Mast Cells/physiology , Mice , Mice, Inbred C57BL , Nematode Infections/parasitology , Nematode Infections/prevention & control , Protozoan Infections/parasitology , Protozoan Infections/prevention & control , Stomach Diseases/immunology , Stomach Diseases/parasitology , Stomach Diseases/prevention & control , Th1 Cells/metabolism
11.
Int Immunol ; 13(3): 285-95, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11222497

ABSTRACT

In the classic 'two-signal' model for B cell activation, signal 1 through the antigen receptor plus signal 2 through lymphokine receptors and CD40 leads to proliferation, but signal 1 alone leads to tolerance or anergy. In a protocol designed to deliver signal 1 in vitro with anti-delta without signal 2, purified small dense B cells from untreated mice exposed to any of three monoclonal anti-delta antibodies or to polyclonal anti-delta in vitro showed modest S phase entry at 50 microg/ml. In contrast, at low doses (0.1-0.5 microg/ml) of anti-delta, there was no cell cycle entry at 64 h, but apoptosis was accelerated at 16 h. Polyclonal anti-mu and three monoclonal anti-mus did not show this early apoptosis induction. Anti-CD40 and IL-4 inhibited apoptosis in B cells treated with 0.5 microg/ml anti-delta and increased S phase entry at 10 microg/ml anti-delta. Low-dose anti-delta (but not anti-mu) induced increased B7-2 and class II MHC expression on a subset of B cells, many of which were in apoptosis. Larger transient increases in c-Myc and Egr-1 expression were seen with low-dose anti-delta than with anti-mu, followed by an abrupt fall below baseline, a sequence previously linked to apoptosis. There was no change in Bcl-2, Bcl-x(L) or Bax. These data suggest a functional difference between delta and mu cross-linking on resting spleen B cells. A BCR stimulus sufficient for early activation events, but insufficient for full G1 entry, may lead to apoptosis.


Subject(s)
Apoptosis/immunology , B-Lymphocytes/immunology , Immunoglobulin D/immunology , Immunoglobulin M/immunology , Receptors, Antigen, B-Cell/immunology , Animals , Antibodies, Anti-Idiotypic/immunology , Antibodies, Anti-Idiotypic/pharmacology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , B7-2 Antigen , CD40 Antigens/immunology , Cell Cycle , Histocompatibility Antigens Class II/biosynthesis , Immunologic Capping , Interleukin-4/pharmacology , Membrane Glycoproteins/immunology , Mice , Mice, Inbred BALB C , Specific Pathogen-Free Organisms
12.
J Immunol ; 165(10): 5839-46, 2000 Nov 15.
Article in English | MEDLINE | ID: mdl-11067944

ABSTRACT

The generation of tissue eosinophilia is governed in part by chemokines; initial investigation has identified three chemokines in the human genome with eosinophil selectivity, referred to as eotaxin-1, -2, and -3. Elucidation of the role of these chemokines is dependent in part upon analysis of murine homologues; however, only one murine homologue, eotaxin-1, has been identified. We now report the characterization of the murine eotaxin-2 cDNA, gene and protein. The eotaxin-2 cDNA contains an open reading frame that encodes for a 119-amino acid protein. The mature protein, which is predicted to contain 93 amino acids, is most homologous to human eotaxin-2 (59.1% identity), but is only 38.9% identical with murine eotaxin-1. Northern blot analysis reveals three predominant mRNA species and highest constitutive expression in the jejunum and spleen. Additionally, allergen challenge in the lung with Aspergillus fumigatus or OVA revealed marked induction of eotaxin-2 mRNA. Furthermore, eotaxin-2 mRNA was strongly induced by both transgenic over-expression of IL-4 in the lung and administration of intranasal IL-4. Analysis of eotaxin-2 mRNA expression in mice transgenic for IL-4 but genetically deficient in STAT-6 revealed that the IL-4-induced expression was STAT-6 dependent. Recombinant eotaxin-2 protein induced dose-dependent chemotactic responses on murine eosinophils at concentrations between 1-1000 ng/ml, whereas no activity was displayed on murine macrophages or neutrophils. Functional analysis of recombinant protein variants revealed a critical role for the amino terminus. Thus, murine eotaxin-2 is a constitutively expressed eosinophil chemokine likely to be involved in homeostatic, allergen-induced, and IL-4-associated immune responses.


Subject(s)
Allergens/administration & dosage , Chemokines, CC/biosynthesis , Chemokines, CC/genetics , Eosinophils/immunology , Interleukin-4/physiology , Administration, Intranasal , Amino Acid Sequence , Animals , Antigens, Fungal/administration & dosage , Aspergillus fumigatus/immunology , Base Sequence , Chemokine CCL24 , Chemokines, CC/chemistry , Chemokines, CC/isolation & purification , DNA, Complementary/chemistry , DNA, Complementary/isolation & purification , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Transgenic , Molecular Sequence Data , Ovalbumin/administration & dosage , Ovalbumin/immunology , Peptide Fragments/chemistry , Peptide Fragments/physiology , RNA, Messenger/biosynthesis , STAT6 Transcription Factor , Signal Transduction/genetics , Signal Transduction/immunology , Structure-Activity Relationship , Trans-Activators/physiology
13.
J Immunol ; 165(3): 1557-63, 2000 Aug 01.
Article in English | MEDLINE | ID: mdl-10903764

ABSTRACT

IL-2 is generally considered a pro-inflammatory cytokine that exacerbates Th1-mediated disease states, such as autoimmune arthritis. Consistent with this role for IL-2, recent studies from our laboratory demonstrate that IL-2 mRNA is markedly increased during the acute stage of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. To further define the role of IL-2 in CIA, the levels of IL-2 protein and its receptor and the effects of IL-2 administration were analyzed during CIA. IL-2 protein and IL-2R were preferentially expressed at disease onset, compared with later stages of disease. Administration of recombinant human IL-2 (rhIL-2) at, or just before, disease onset exacerbated disease; surprisingly, rhIL-2 given before disease onset inhibited CIA, associated with reduced cellular and humoral responses to type II collagen. Determination of in vivo serum levels of Th1 and Th2 cytokines in response to rhIL-2 treatment demonstrated that IFN-gamma, but not IL-4, was markedly up-regulated in response to IL-2. In mice treated with anti-IFN-gamma Ab, both early and late IL-2 administration exacerbated CIA. Thus, IL-2 can have two opposite effects on autoimmune arthritis, a direct stimulatory effect and an indirect suppressive effect that is mediated by IFN-gamma.


Subject(s)
Arthritis, Experimental/immunology , Collagen/immunology , Interleukin-2/immunology , Acute Disease , Animals , Arthritis, Experimental/etiology , Arthritis, Experimental/pathology , Arthritis, Experimental/prevention & control , B-Lymphocytes/immunology , Cattle , Chronic Disease , Humans , Immune Sera/administration & dosage , Immunosuppressive Agents/administration & dosage , Inflammation Mediators/administration & dosage , Injections, Intraperitoneal , Interferon-gamma/immunology , Interferon-gamma/physiology , Interleukin-2/administration & dosage , Interleukin-2/biosynthesis , Male , Mice , Mice, Inbred DBA , Receptors, Interleukin-2/biosynthesis , Recombinant Proteins/administration & dosage , T-Lymphocytes/immunology , Th1 Cells/immunology , Th1 Cells/metabolism
14.
J Immunol ; 164(11): 5704-12, 2000 Jun 01.
Article in English | MEDLINE | ID: mdl-10820247

ABSTRACT

We report that IL-4 causes a redistribution of B cells and modestly increases B cell life span. Intravenous injection of a long-acting formulation of IL-4 induces increases in both spleen cell number and the percentage of splenic B cells. These effects are observed within 1 day of IL-4 administration and plateau after approximately 3 days if IL-4 treatment is continued. The increase in splenic B cell number is IL-4 dose dependent, CD4+ T cell independent, FcgammaRII/FcgammaRIII independent, and Stat6 independent. Decreases in the number of B cells in the blood and the percentage of mature B cells in the bone marrow, concomitant with the increase in splenic B cell number, suggest that redistribution of circulating B cells to the spleen is partially responsible for IL-4 induction of splenic B cell hyperplasia. Considerable reduction in the effect of 5 days of IL-4 treatment on splenic B cell number when B lymphopoiesis is blocked with anti-IL-7 mAb suggests that generation of new B cells is also involved in IL-4-induced splenic B cell hyperplasia. 5-Bromo-2'-deoxyuridine labeling experiments demonstrate that IL-4 modestly prolongs the life span of newly generated splenic B cells, and experiments that measure B cell HSA (CD24) expression as an indicator of B cell age suggest that IL-4 may also prolong the life span of mature splenic B cells. Thus, IL-4 increases splenic B cell number through two Stat6-independent effects: increased net migration of circulating B cells to the spleen and increased B cell life span. Both effects may promote Ab responses to a systemic Ag challenge.


Subject(s)
B-Lymphocytes/immunology , Cell Movement/immunology , Interleukin-4/pharmacology , Spleen/cytology , Spleen/immunology , Animals , B-Lymphocytes/cytology , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Cell Survival/immunology , Dose-Response Relationship, Immunologic , Epitopes, B-Lymphocyte/analysis , Female , Injections, Intravenous , Interleukin-4/administration & dosage , Interleukin-7/physiology , Kinetics , Lymphocyte Count , Lymphopenia/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, IgG/physiology , STAT6 Transcription Factor , Signal Transduction/immunology , Trans-Activators/physiology
15.
J Immunol ; 164(6): 3035-46, 2000 Mar 15.
Article in English | MEDLINE | ID: mdl-10706692

ABSTRACT

To determine the effects of chronic Ag stimulation on B cell survival and phenotype, we compared survival and surface markers of hen egg lysozyme (HEL)-specific B cells in Ig transgenic (Tgn) mice, which lack HEL, and in HEL-Ig transgenic mice, which express soluble HEL. Serum HEL levels were maximized in HEL-Ig Tgn mice by feeding them zinc, which activates the metallothionein promoter that regulates HEL expression. B cell age was characterized by expression of heat-stable Ag, and B220 and B cell survival was studied by evaluating changes in B cell number when lymphopoiesis was suppressed with anti-IL-7 mAb and by identifying newly generated B cells through 5-bromo-2'-deoxyuridine incorporation. Our observations show that the mean B cell life span is considerably reduced in HEL-Ig Tgn compared with Ig Tgn mice, but also demonstrate that some HEL-Ig Tgn B cells survive to maturity. Some of these surviving B cells have undergone receptor editing (substitution of an endogenous Ig light chain for the transgenic Ig light chain), so that their ability to bind HEL is decreased or absent. Surviving HEL-Ig Tgn B cells that retain HEL specificity express decreased mIgD and little or no mIgM. mIgD expression progressively decreases with increasing HEL-Ig Tgn B cell age. These observations suggest that self Ag-specific B cells can survive in the presence of soluble self Ag by down-regulating mIg expression, which should limit B cell signaling by Ag that might otherwise cause deletion of these cells.


Subject(s)
B-Lymphocytes/cytology , B-Lymphocytes/immunology , Animals , Antibodies, Monoclonal/administration & dosage , B-Lymphocytes/metabolism , B-Lymphocytes/transplantation , Binding Sites, Antibody/genetics , Bromodeoxyuridine/metabolism , Cell Differentiation/genetics , Cell Differentiation/immunology , Cell Survival/genetics , Cell Survival/immunology , Female , Immunoglobulin D/biosynthesis , Immunoglobulin D/genetics , Immunoglobulin D/metabolism , Immunoglobulin M/biosynthesis , Immunoglobulin M/genetics , Immunoglobulin M/metabolism , Immunophenotyping , Injections, Intraperitoneal , Interleukin-7/immunology , Lymphocyte Depletion , Lymphopenia/genetics , Lymphopenia/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Muramidase/immunology , Muramidase/metabolism , Receptors, Antigen, B-Cell/biosynthesis , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/metabolism , Spleen/cytology , Spleen/immunology , Time Factors
16.
J Immunol ; 164(5): 2303-10, 2000 Mar 01.
Article in English | MEDLINE | ID: mdl-10679064

ABSTRACT

Although in vitro development of a Th2 response from naive CD4+ T cells is Stat6 dependent, mice immunized with a goat Ab to mouse IgD have been reported to produce a normal primary IL-4 response in Stat6-deficient mice. Experiments have now been performed with mice immunized with more conventional Ags or inoculated with nematode parasites to account for this apparent discrepancy. The ability of an immunogen to induce a primary in vivo IL-4 response in Stat6-deficient mice was found to vary directly with its ability to induce a strong type 2 cytokine-biased response in normal mice. Even immunogens, however, that induce strong primary IL-4 responses in Stat6-deficient mice induce poor memory IL-4 responses in these mice. Consistent with this, Stat6-deficient CD4+ T cells make relatively normal IL-4 responses when stimulated in vitro for 3 days with anti-CD3 and anti-CD28, but poor IL-4 responses if they are later restimulated with anti-CD3. Thus, Stat6 signaling enhances primary IL-4 responses that are made as part of a type 0 cytokine response (mixed type 1 and type 2) and is required for normal development or survival of Th2 memory cells.


Subject(s)
Interleukin-4/biosynthesis , Trans-Activators/physiology , Animals , Antibodies/physiology , Antibodies, Monoclonal/administration & dosage , CD3 Complex/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Chickens , Female , Goats , Immunoglobulin D/administration & dosage , Immunologic Memory , Injections, Intravenous , Interleukin-4/antagonists & inhibitors , Intestinal Diseases, Parasitic/immunology , Male , Mast Cells/immunology , Mast Cells/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Nematospiroides dubius/immunology , Nippostrongylus/immunology , Ovalbumin/administration & dosage , Ovalbumin/immunology , Receptors, Interleukin-4/deficiency , Receptors, Interleukin-4/genetics , STAT6 Transcription Factor , Signal Transduction/immunology , Strongylida Infections/immunology , Th2 Cells/immunology , Th2 Cells/metabolism , Trans-Activators/deficiency , Trans-Activators/genetics , Trichinella spiralis/immunology , Trichinellosis/immunology
17.
J Immunol ; 164(4): 1734-40, 2000 Feb 15.
Article in English | MEDLINE | ID: mdl-10657618

ABSTRACT

Injection of mice with a foreign anti-IgD Ab stimulates B and T cell activation that results in large cytokine and Ab responses. Because most anti-IgD-activated B cells die before they can be stimulated by activated T cells, and because IL-4 prolongs the survival of B cells cultured with anti-Ig, we hypothesized that treatment with IL-4 at the time of anti-IgD Ab injection would decrease B cell death and enhance anti-IgD-induced Ab responses. Instead, IL-4 treatment before or along with anti-IgD Ab suppressed IgE and IgG1 responses, whereas IL-4 injected after anti-IgD enhanced IgE responses. The suppressive effect of early IL-4 treatment on the Ab response to anti-IgD was associated with a rapid, short-lived increase in IFN-gamma gene expression but decreased CD4+ T cell activation and decreased or delayed T cell production of other cytokines. We examined the possibilities that IL-4 stimulation of IFN-gamma production, suppression of IL-1 or IL-2 production, or induction of TNF-alpha or Fas-mediated apoptosis could account for IL-4's suppressive effect. The suppressive effect of IL-4 was not reversed by IL-1, IL-2, or anti-TNF-alpha or anti-IFN-gamma mAb treatment, or mimicked by treatment with anti-IL-2Ralpha (CD25) and anti-IL-2Rbeta (CD122) mAbs. Early IL-4 treatment failed to inhibit anti-IgD-induced Ab production in Fas-defective lpr mice; however, the poor responsiveness of lpr mice to anti-IgD made this result difficult to interpret. These observations indicate that exposure to IL-4, while T cells are first being activated by Ag presentation, can inhibit T cells activation or promote deletion of responding CD4+ T cells.


Subject(s)
Immunoglobulin E/biosynthesis , Immunoglobulin G/biosynthesis , Immunosuppressive Agents , Interleukin-4/physiology , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Female , Goats , Immunoglobulin D/administration & dosage , Immunoglobulin E/blood , Immunoglobulin G/blood , Immunosuppressive Agents/administration & dosage , Injections, Intravenous , Interferon-gamma/immunology , Interleukin-1/antagonists & inhibitors , Interleukin-1/biosynthesis , Interleukin-2/antagonists & inhibitors , Interleukin-2/biosynthesis , Interleukin-4/administration & dosage , Male , Mice , Mice, Inbred BALB C , Mice, Inbred MRL lpr , Receptors, Interleukin-2/antagonists & inhibitors , Tumor Necrosis Factor-alpha/physiology
18.
J Immunol ; 164(4): 2046-52, 2000 Feb 15.
Article in English | MEDLINE | ID: mdl-10657657

ABSTRACT

Studies in mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis demonstrated that IL-4/IL-13 activation of Stat6 suppresses development of intestinal mastocytosis and does not contribute to IL-4/IL-13 production, but is still essential for parasite expulsion. Because expulsion of another gastrointestinal nematode, Trichinella spiralis, unlike N. brasiliensis expulsion, is mast cell dependent, these observations suggested that T. spiralis expulsion would be Stat6 independent. Instead, we find that Stat6 activation by IL-4/IL-13 is required in T. spiralis-infected mice for the mast cell responses that induce worm expulsion and for the cytokine responses that induce intestinal mastocytosis. Furthermore, although IL-4 induces N. brasiliensis expulsion in the absence of B cells, T cells, and mast cells, mast cells and T cells are required for IL-4 induction of T. spiralis expulsion. Thus, Stat6 signaling is required for host protection against N. brasiliensis and T. spiralis but contributes to expulsion of these two worms by different mechanisms. The induction of multiple effector mechanisms by Stat6 signaling provides a way for a cytokine response induced by most gastrointestinal nematode parasites to protect against most of these parasites, even though different effector mechanisms are required for protection against different nematodes.


Subject(s)
Mast Cells/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Trans-Activators/physiology , Trichinella spiralis/immunology , Trichinellosis/immunology , Animals , Cytokines/biosynthesis , Female , Immunity, Innate , Immunoglobulin G/biosynthesis , Interferon-gamma/physiology , Interleukin-13/physiology , Interleukin-4/physiology , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Nude , Receptors, Interleukin-4/metabolism , STAT6 Transcription Factor , Th2 Cells/immunology , Th2 Cells/metabolism , Trans-Activators/deficiency , Trans-Activators/genetics , Trichinella spiralis/physiology , Trichinellosis/parasitology , Trichinellosis/prevention & control
19.
J Immunol ; 164(8): 4250-6, 2000 Apr 15.
Article in English | MEDLINE | ID: mdl-10754322

ABSTRACT

B7 costimulation is a required component of many type 2 immune responses, including allergy and protective immunity to many nematode parasites. This response includes elevations in Th2 cytokines and associated effector functions including elevations in serum IgG1 and IgE and parasite expulsion. In studies of mice infected with Trichuris muris, blocking B7 ligand interactions inhibited protective immunity, suppressed IL-4 production, and enhanced IFN-gamma production, but unexpectedly did not inhibit production of the Th2 cytokine, IL-13. Blocking both IFN-gamma and B7 restored protective immunity, which was IL-13 dependent, but did not restore IL-4 or associated IgE responses. Although IL-13 was required for worm expulsion in mice in which both IFN-gamma and B7 were blocked, IL-4 could mediate expulsion in the absence of both IL-13 and IFN-gamma. These studies demonstrate that 1) B7 costimulation is required to induce IL-4, but not IL-13 responses; 2) IL-13 is elevated in association with the IFN-gamma response that occurs following inhibition of B7 interactions, but can only mediate IL-4-independent protection when IFN-gamma is also inhibited; and 3) increased IL-13 production, in the absence of increased IL-4 production, is not associated with an IgE response, even in the absence of IFN-gamma.


Subject(s)
B7-1 Antigen/physiology , Immunoconjugates , Interferon-gamma/physiology , Interleukin-13/physiology , Trichuriasis/immunology , Trichuris/immunology , Abatacept , Animals , Antigens, CD , Antigens, Differentiation/administration & dosage , B7-1 Antigen/metabolism , CTLA-4 Antigen , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Cytokines/therapeutic use , Female , Immunosuppressive Agents/administration & dosage , Injections, Intravenous , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Interleukin-13/biosynthesis , Interleukin-4/deficiency , Interleukin-4/genetics , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/parasitology , Ligands , Mice , Mice, Inbred AKR , Mice, Inbred BALB C , Mice, Knockout , Th2 Cells/immunology , Th2 Cells/metabolism , Trichuriasis/parasitology , Trichuris/growth & development
20.
Int Immunol ; 11(11): 1811-8, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10545485

ABSTRACT

The short in vivo lifespan of many cytokines can make measurement of in vivo cytokine production difficult. A method was developed to measure in vivo IL-4 and IFN-gamma production that eliminates this problem. Mice are injected with a biotin-labeled neutralizing IgG anti-IL-4 or anti-IFN-gamma mAb and bled 2-24 h later. Secreted cytokine is captured by the biotin-labeled mAb to produce a complex that has a relatively long in vivo half-life and consequently accumulates in serum. Serum concentrations of the complex are determined by ELISA, using wells coated with an antibody to a second epitope on the same cytokine to capture the complex. This technique is specific and increases sensitivity of detection of secreted IL-4 at least 1000-fold. The amount of cytokine measured is directly proportional to the amount produced and relatively independent of the site of cytokine production. Furthermore, because mice are injected with small quantities of biotin-labeled anti-cytokine mAb, which sample, rather than neutralize, all secreted cytokines, cytokine-dependent responses are not inhibited. The in vivo half-lives of the cytokine-anti-cytokine mAb complexes are sufficiently short to allow cytokine production to be measured every 2-3 days in the same mice. Thus, use of this assay provides a practical and relatively simple and inexpensive way to measure ongoing in vivo cytokine production. Furthermore, the techniques that have been developed to measure in vivo production of IL-4 and IFN-gamma can be applied to in vivo measurement of other molecules that have a short in vivo lifespan, including other cytokines.


Subject(s)
Cytokines/blood , Immunologic Techniques , Animals , Antibodies, Monoclonal , Enzyme-Linked Immunosorbent Assay , Interferon-alpha/biosynthesis , Interleukin-4/biosynthesis , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Th1 Cells/immunology , Th2 Cells/immunology
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