Biomedical subjects

D T Umetsu

Publications and source records attributed to D T Umetsu.

At least 19 recordsLinked to original sources

PubMed2005

Allergen immunotherapy with heat-killed Listeria monocytogenes alleviates peanut and food-induced anaphylaxis in dogs.

BACKGROUND: Heat-killed Listeria monocytogenes (HKL) potently stimulates interferon (IFN)-gamma production in CD4 T-lymphocytes, and when used as adjuvant for immunotherapy, reduces immunoglobulin (Ig)E production and reverses established allergen-induced airway hyperreactivity (AHR) in a murine model of asthma. We asked if such treatment could decrease established peanut-induced anaphylaxis or cow's milk-induced food allergy in highly food-allergic dogs. METHODS: We therefore studied four 4-year-old atopic colony dogs extremely allergic to peanut (Group I), as well as five 7-year-old dogs very allergic to wheat, milk and other foods (Group II). All dogs experienced marked allergic symptoms, including vomiting and diarrhea on oral challenge with the relevant foods. The dogs were then vaccinated once subcutaneously with peanut or milk and wheat with HKL emulsified in incomplete Freund's adjuvant. RESULTS: Following vaccination of the allergic dogs with HKL and allergen, oral challenges with peanut (Group I) or milk (Group II) elicited only minor or no symptoms. In addition, skin test end-point titrations showed marked reductions for >10 weeks after treatment, and levels of Ara h 1-specific IgE in serum of peanut sensitive dogs, as demonstrated by immunoblotting, were greatly reduced by treatment with HKL plus peanut allergen. CONCLUSIONS: Thus, HKL plus allergen treatment markedly improved established food allergic responses in dogs, suggesting that such an immunotherapy strategy in humans might greatly improve individuals with food allergy and anaphylaxis.

Allergens↗

PubMed2001

Critical role for IL-13 in the development of allergen-induced airway hyperreactivity.

Airway hyperresponsiveness to a variety of specific and nonspecific stimuli is a cardinal feature of asthma, which affects nearly 10% of the population in industrialized countries. Eosinophilic pulmonary inflammation, eosinophil-derived products, as well as Th2 cytokines IL-13, IL-4, and IL-5, have been associated with the development of airway hyperreactivity (AHR), but the specific immunological basis underlying the development of AHR remains controversial. Herein we show that mice with targeted deletion of IL-13 failed to develop allergen-induced AHR, despite the presence of vigorous Th2-biased, eosinophilic pulmonary inflammation. However, AHR was restored in IL-13(-/-) mice by the administration of recombinant IL-13. Moreover, adoptive transfer of OVA-specific Th2 cells generated from TCR-transgenic IL-13(-/-) mice failed to induce AHR in recipient SCID mice, although such IL-13(-/-) Th2 cells produced high levels of IL-4 and IL-5 and induced significant airway inflammation. These studies definitively demonstrate that IL-13 is necessary and sufficient for the induction of AHR and that eosinophilic airway inflammation in the absence of IL-13 is inadequate for the induction of AHR. Therefore, treatment of human asthma with antagonists of IL-13 may be very effective.

Adoptive Transfer↗

PubMed2001

Il-18 gene transfer by adenovirus prevents the development of and reverses established allergen-induced airway hyperreactivity.

We examined the role of IL-18 in preventing the development of and in reversing established allergen-induced airway inflammation and airway hyperreactivity (AHR), the cardinal features of asthma. IL-18, which potently induces IFN-gamma, was administered into the respiratory tract as cDNA in a replication-deficient adenovirus (Adv). Treatment of OVA-sensitized mice with the IL-18-expressing Adv reduced allergen-specific IL-4 production, airway eosinophilia, and mucus production, increased IFN-gamma production, and prevented the development of AHR. The effects of the IL-18 Adv treatment were dependent on the presence of IFN-gamma and IL-12. Moreover, administration of the IL-18 Adv to mice with established AHR greatly reduced AHR and IL-4 production and increased IFN-gamma production. These results demonstrate that IL-18, when administered by Adv into the respiratory tract, effectively reduces AHR and replaces an established Th2-biased immune response with a Th1-biased response.

Adenoviridae↗

PubMed2001

Vaccination with allergen-IL-18 fusion DNA protects against, and reverses established, airway hyperreactivity in a murine asthma model.

Vaccination with naked DNA encoding a specific allergen has been shown previously to prevent, but not reverse, the development of allergen-induced airway hyperresponsiveness (AHR). To enhance the effectiveness of DNA vaccine therapies and make possible the treatment of established AHR, we developed a DNA vaccination plasmid containing OVA cDNA fused to IL-18 cDNA. Vaccination of naive mice either with this fusion DNA construct or with an OVA cDNA-containing plasmid protected the mice from the subsequent induction of AHR. Protection from AHR correlated with increased IFN-gamma production and reduced OVA-specific IgE production. The protection appeared to be mediated by IFN-gamma and CD8(+) cells because treatment of mice with neutralizing anti-IFN-gamma mAb or with depleting anti-CD8 mAb abolished the protective effect. Moreover, vaccination of mice with preexisting AHR with the OVA-IL-18 fusion DNA, but not with the OVA cDNA plasmid, reversed established AHR, reduced allergen-specific IL-4, and increased allergen-specific IFN-gamma production. Thus, combining IL-18 cDNA with OVA cDNA resulted in a vaccine construct that protected against the development of AHR, and that was unique among cDNA constructs in its capacity to reverse established AHR.

Allergens↗

PubMed2001

Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen.

Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperreactivity and asthma. However, the specific mechanisms by which tolerance is induced by respiratory allergen are not clear. We report here that pulmonary dendritic cells (DCs) from mice exposed to respiratory antigen transiently produced interleukin 10 (IL-10). These phenotypically mature pulmonary DCs, which were B-7(hi) as well as producing IL-10, stimulated the development of CD4(+) T regulatory 1--like cells that also produced high amounts of IL-10. In addition, adoptive transfer of pulmonary DCs from IL-10(+/+), but not IL-10(-/-), mice exposed to respiratory antigen induced antigen-specific unresponsiveness in recipient mice. These studies show that IL-10 production by DCs is critical for the induction of tolerance, and that phenotypically mature pulmonary DCs mediate tolerance induced by respiratory exposure to antigen.

Animals↗

PubMed2001

Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family.

To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.

Amino Acid Sequence↗

PubMed2001

Human alveolar macrophages induce functional inactivation in antigen-specific CD4 T cells.

BACKGROUND: Alveolar macrophages (AMCs) are the most abundant phagocytic cells in the lung, but they present antigen poorly to T cells. OBJECTIVES: The objectives of our studies were to more clearly define the mechanisms by which AMCs present antigen to T cells and to determine whether AMCs actively inhibit T-cell activation. METHODS: We studied purified human CD4 T cells and compared the capacity of allogeneic AMCs and peripheral blood monocytes to induce T-cell proliferation and cytokine production. RESULTS: We previously demonstrated that human AMCs fail to upregulate expression of B7-1 and B7-2 on stimulation with IFN-gamma. We now demonstrate that AMCs actively induce T-cell unresponsiveness (functional inactivation) in an antigen-specific manner and reduce the capacity of CD4 T cells to respond on secondary stimulation. The induction of unresponsiveness was reversed by the addition of CD28 costimulation or IL-2. However, interruption of Fas/Fas ligand interactions or of B7/CTLA-4 interactions did not prevent unresponsiveness, indicating that neither CTLA-4 triggering nor Fas-induced apoptosis was involved in the induction of T-cell unresponsiveness. CONCLUSIONS: These studies indicate that AMCs actively tolerize CD4 T cells in an antigen-specific fashion. We propose that AMCs mediate a form of immune privilege in the lungs that effectively limits immune responses in the pulmonary compartment but has little effect on systemic immunity.

Abatacept↗

PubMed2000

Allergen-induced airway hyperreactivity is diminished in CD81-deficient mice.

We demonstrated previously that CD81(-/-) mice have an impaired Th2 response. To determine whether this impairment affected allergen-induced airway hyperreactivity (AHR), CD81(-/-) BALB/c mice and CD81(+/+) littermates were sensitized i.p. and challenged intranasally with OVA. Although wild type developed severe AHR, CD81(-/-) mice showed normal airway reactivity and reduced airway inflammation. Nevertheless, OVA-specific T cell proliferation was similar in both groups of mice. Analysis of cytokines secreted by the responding CD81(-/-) T cells, particularly those derived from peribronchial draining lymph nodes, revealed a dramatic reduction in IL-4, IL-5, and IL-13 synthesis. The decrease in cytokine production was not due to an intrinsic T cell deficiency because naive CD81(-/-) T cells responded to polyclonal Th1 and Th2 stimulation with normal proliferation and cytokine production. Moreover, there was an increase in T cells and a decrease in B cells in peribronchial lymph nodes and in spleens of immunized CD81(-/-) mice compared with wild-type animals. Interestingly, OVA-specific Ig levels, including IgE, were similar in CD81(-/-) and CD81(+/+) mice. Thus, CD81 plays a role in the development of AHR not by influencing Ag-specific IgE production but by regulating local cytokine production.

Administration, Intranasal↗

PubMed2000

Respiratory infection with influenza A virus interferes with the induction of tolerance to aeroallergens.

Viral respiratory infections have been implicated in influencing allergen sensitization and the development of asthma, but their exact role remains controversial. Because respiratory exposure to Ag normally engenders T cell tolerance and prevents the development of airway hyperreactivity (AHR) and inflammation, we examined the effects of influenza A virus infection on tolerance induced by exposure to intranasal (i.n.) OVA and the subsequent development of AHR. We found that concurrent infection with influenza A abrogated tolerance induced by exposure to i.n. OVA, and instead led to the development of AHR accompanied by the production of OVA-specific IgE, IL-4, IL-5, IL-13, and IFN-gamma. When both IL-4 and IL-5 were neutralized in this system, AHR was still induced, suggesting that influenza-induced cytokines such as IL-13, or mechanisms unrelated to cytokines, might be responsible for the development of AHR. The length of time between influenza A infection and i.n. exposure to OVA was crucial, because mice exposed to i.n. OVA 15-30 days after viral inoculation developed neither AHR nor OVA-specific tolerance. These mice instead acquired Th1-biased OVA-specific immune responses associated with vigorous OVA-induced T cell proliferation, and reduced production of OVA-specific IgE. The protective effect of influenza A on AHR was dependent on IFN-gamma, because protection was abrogated with a neutralizing anti-IFN-gamma mAb. These results suggest that viral respiratory infection interferes with the development of respiratory allergen-induced tolerance, and that the time interval between viral infection and allergen exposure is critical in determining whether viral infection will enhance, or protect against, the development of respiratory allergen sensitization and AHR.

Administration, Intranasal↗

PubMed2000

Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D.

Muscarinic cholinergic signaling plays an essential role in the control of the normal airway functions and in the development of pulmonary pathologies including asthma. In this paper we demonstrate that the airways of mice deficient in a cAMP-specific phosphodiesterase (PDE4D) are no longer responsive to cholinergic stimulation. Airway hyperreactivity that follows exposure to antigen was also abolished in PDE4D(-/-) mice, despite an apparently normal lung inflammatory infiltration. The loss of cholinergic responsiveness was specific to the airway, not observed in the heart, and was associated with a loss of signaling through muscarinic receptors with an inability to decrease cAMP accumulation. These findings demonstrate that the PDE4D gene plays an essential role in cAMP homeostasis and cholinergic stimulation of the airway, and in the development of hyperreactivity. In view of the therapeutic potentials of PDE4 inhibitors, our findings provide the rationale for novel strategies that target a single PDE isoenzyme.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2000

Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18.

Asthma is a respiratory disorder characterized by airway hyperreactivity (AHR) and inflammation and is associated with high serum IgE and overproduction of IL-4, IL-5, and IL-13 by allergen-specific Th2 cells. Our previous studies demonstrated that heat-killed Listeria monocytogenes (HKL) as an adjuvant in immunotherapy successfully reversed ongoing Ag-specific Th2-dominated responses toward Th1-dominated responses, but it was unclear if such immune modulation could reverse ongoing, established disease in target organs such as the lung. In this paper we show that a single dose of Ag plus HKL as adjuvant significantly reduced AHR in a murine model for asthma and reversed established AHR when given late after allergen sensitization. HKL as adjuvant also dramatically inhibited airway inflammation, eosinophilia, and mucus production, significantly reduced Ag-specific IgE and IL-4 production, and dramatically increased Ag-specific IFN-gamma synthesis. The inhibitory effect of HKL on AHR depended on the presence of IL-12 and CD8+ T cells and was associated with an increase of IL-18 mRNA expression. Thus, our results demonstrate that HKL as an adjuvant for immunotherapy mediates immune deviation from a pathological Th2-dominated response toward a protective immune response in peripheral lymphoid tissues and in the lungs and may be clinically effective in the treatment of patients with established asthma and allergic disease.

Adjuvants, Immunologic↗

PubMed2000

Allergen immunotherapy: novel approaches in the management of allergic diseases and asthma.

Currently available pharmacotherapies for allergic diseases and asthma, which are serious public health problems, are aimed primarily at neutralizing effector molecules and inflammatory mediators such as histamine and leukotrienes or at inhibiting the function of inflammatory cells such as eosinophils and Th2 lymphocytes. While this approach is effective in controlling symptoms, these therapies have a limited capacity to alter the natural course of allergic diseases and asthma, and discontinuation of medications results in the redevelopment of symptoms on reexposure to the offending allergens. In contrast, immune-based allergen immunotherapies modify and correct the underlying pathological immune responses in allergy and asthma in an antigen-specific manner. These immunotherapies replicate the regulatory processes that occur in nonallergic individuals and allow patients to tolerate exposure to allergens. Current and future methodologies for immunotherapy involve immunization with allergen, modified allergen, peptides of allergen, cDNA of allergen, with adjuvants, including immunostimulatory DNA sequences, cytokines, and bacterial products such as Listeria monocytogenes. This form of therapy can provide a long-lasting cure for allergic diseases without the need for continuous therapeutic intervention and without causing generalized immunosuppression or immune augmentation.

Allergens↗

PubMed2000

Mechanisms preventing allergen-induced airways hyperreactivity: role of tolerance and immune deviation.

BACKGROUND: Aeroallergens continuously enter the respiratory tract of atopic individuals and provoke the development of asthma characterized by airway hyperreactivity (AHR) and inflammation. By contrast, nonatopic individuals are exposed to the same aeroallergens, but airway inflammation does not develop. However, the mechanisms that prevent allergen-induced respiratory diseases in nonatopic subjects are poorly characterized. OBJECTIVE: In this study we compared the role of allergen-specific T-cell tolerance and immune deviation in conferring protection against the development of allergen-induced AHR. METHODS: We exposed mice to intranasal ovalbumin (OVA) to induce T-cell tolerance and examined its effects on the subsequent development of AHR and inflammation. RESULTS: We demonstrated that exposure of mice to intranasal OVA resulted in peripheral CD4(+) T-cell unresponsiveness that very efficiently prevented not only the development of AHR but also greatly inhibited airway inflammation and OVA-specific IgE production. The induction of peripheral T-cell tolerance and protection against AHR were not dependent on the presence of IFN-gamma or IL-4. The development of AHR was also prevented by an OVA-specific T(H)1-biased immune response induced by inhalation of OVA in the presence of IL-12. However, the OVA-specific T(H)1 response was associated with a significant degree of pulmonary inflammation. CONCLUSION: These results indicate that both allergen-specific T-cell tolerance and T(H)1-biased immune deviation prevent the development of AHR, but T(H)1 responses are associated with significantly greater inflammation in the lung than is associated with T-cell unresponsiveness. Therefore CD4(+) T-cell unresponsiveness critically regulates immune responses to aeroallergens and protects against the development of allergic disease and asthma.

Allergens↗

PubMed2000

Immunotherapy of asthma and allergic diseases.

The goals of therapy for allergic disease and asthma, which have increased dramatically during the past 2 decades, are to relieve and prevent symptoms. Currently, allergen immunotherapy is the only available treatment that can reduce symptoms, alter the natural course of disease, and induce long-term clinical remission effectively and safely in patients with allergic rhinitis, asthma, and insect venom anaphylaxis. Allergen immunotherapy may even prevent the evolution towards polysensitization and prevent the development of asthma in allergic children. In the long run, it is more cost-effective than pharmacotherapy and environmental control measures alone. Future developments, such as using alternate routes of administration, peptide fragments of allergen, adjuvants, and DNA vaccines, may improve its efficiency in inducing long-term clinical relief of symptoms.

Asthma↗

PubMed2000

CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation.

T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-beta abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-beta in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-beta was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-beta-secreting Th cells was antigen-specific and was reversed by neutralization of TGF-beta. Our results demonstrate that T cells secreting TGF-beta in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-beta-producing T cells play an important regulatory role in asthma.

Allergens↗

PubMed1999

Intranasal exposure to protein antigen induces immunological tolerance mediated by functionally disabled CD4+ T cells.

In this study we examined the immunological parameters underlying the natural immunity to inhaled nonpathogenic proteins. We addressed this question by examining the effect of intranasal exposure to OVA in both wild-type mice and mice reconstituted with OVA-TCR transgenic CD4+ T cells. Intranasal administration of OVA induced an initial phase of activation during which CD4+ T cells were capable of proliferating and producing cytokines. Although many of the OVA-specific CD4+ T cells were subsequently depleted from the lymphoid organs, a stable population of such T cells survived but remained refractory to antigenic rechallenge. The unresponsive state was not associated with immune deviation due to selective secretion of Th1- or Th2-type cytokines, and the presence of regulatory CD8+ T cells was not required. Moreover, neutralization of the immunosuppressive cytokines IL-10 and TGF-beta did not abrogate the induction of tolerance. Inhibition of the interaction of T cells with CD86, but not CD80, at the time of exposure to intranasal Ag prevented the development of unresponsiveness, while selective blockade of CTLA-4 had no effect. Our results suggest that intranasal exposure to Ags results in immunological tolerance mediated by functionally impaired CD4+ T cells via a costimulatory pathway that requires CD86.

Abatacept↗

PubMed1999

The safety and efficacy of ALLERVAX CAT in cat allergic patients.

Conventional immunotherapy for cat allergy is effective in reducing cat allergy symptoms in many patients, but this type of immunotherapy can cause severe reactions, including anaphylaxis, and often requires years of injections for successful desensitization. To improve the efficacy of immunotherapy for cat allergic patients, synthetic cat allergen peptides (ALLERVAX CAT) were generated, based on analysis of the immunodominant T cell epitopes of cat allergen. These peptides lack the tertiary structure of native Fel d1 and possess a significantly reduced capacity to bind to Fel d1-specific IgE. Using these peptides, we performed a multicenter, randomized, double-blind, placebo-controlled study of 133 cat allergic patients chronically exposed to cats or who had failed previous conventional cat immunotherapy. We evaluated the safety of ALLERVAX CAT treatment and determined whether ALLERVAX CAT treatment improved tolerance to cat allergen, as measured by symptom analysis and pulmonary function testing. Three of the ALLERVAX CAT-treated patients required systemic epinephrine for adverse reactions, but the frequency of all adverse reactions in both groups was not statistically different from that of the placebo group. The majority of adverse events were "late" events, most commonly associated with respiratory symptoms, and these events declined with successive injections. ALLERVAX CAT given at a dose of 750 microg/dose improved pulmonary function in patients with reduced baseline FEV1, and global evaluation of the subjects' ability to tolerate cats improved significantly in the actively treated groups relative to placebo. Thus, although therapy with ALLERVAX CAT is associated with some adverse events in patients with severe cat sensitivity, such therapy is an effective approach for the management of cat allergy, since it improves tolerance to cats and improves pulmonary function in cat allergic patients with reduced FEV1.

Adolescent↗

PubMed1999

The kinetics of change in cytokine production by CD4 T cells during conventional allergen immunotherapy.

BACKGROUND: The effect of conventional allergen immunotherapy on allergen-specific T lymphocyte cytokine production is incompletely understood, particularly during the initial phase of treatment. OBJECTIVE: The purpose of this study was to prospectively follow the kinetics of change in CD4(+) T cell cytokine secretion during the course of conventional immunotherapy. METHODS: Six allergic individuals were treated with extracts of Dermatophagoides farinae/Dermatophagoides pteronyssinus or with rye grass pollen (Lolium perenne) allergen, but not both, by using an internally controlled conventional immunotherapy protocol. CD4(+) T cells from peripheral blood were examined in vitro at varying intervals after the initiation of immunotherapy by stimulation with D farinae or L perenne group I antigen. The quantity of IL-4 and IFN-gamma produced and its relationship to clinical improvement was determined. RESULTS: The ratio of allergen-specific IL-4/IFN-gamma production by CD4(+) T cells from 4 of 6 individuals receiving immunotherapy greatly increased during the period when the dose of allergen was increasing. However, after high-dose maintenance therapy was achieved, this ratio decreased in subjects responding clinically to, but not in those failing, immunotherapy. In addition, late-phase skin reactions and allergen-specific IgE levels in responding, but not in nonresponding, subjects diminished over the course of immunotherapy. CONCLUSION: Conventional immunotherapy may initially exacerbate allergic disease by increasing allergen-specific IL-4 and allergen-specific IgE production. Later clinical improvement is associated with a reduction in allergen-specific IL-4 production and in allergen-specific serum IgE.

Adult↗