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Biomedical subjects

Dale T Umetsu

Publications and source records attributed to Dale T Umetsu.

At least 37 records · Page 2Linked to original sources
PubMed2004

Clinical efficacy of microencapsulated timothy grass pollen extract in grass-allergic individuals.

BACKGROUND: Conventional allergen immunotherapy is clinically effective in reducing the symptoms of allergic rhinitis and asthma. It differs from other pharmacotherapies in that it can induce long-term clinical remission of these diseases. However, it requires years of treatment and is associated with serious allergic reactions. OBJECTIVE: To evaluate the safety, clinical efficacy, and immunologic mechanisms of immunotherapy with an oral, microencapsulated form of timothy grass allergen. METHODS: In this double-blind, placebo-controlled study, 24 patients aged 19 to 55 years with grass pollen allergy were randomized to receive either microencapsulated timothy grass pollen extract or placebo once a day for 10 weeks. The dose of study drug was doubled weekly. Safety was evaluated through weekly visits, daily symptom diaries, and routine laboratory tests. Efficacy was evaluated by comparing medication use and symptoms scores during peak grass pollen season before and after treatment. Allergen-specific T-cell responses, cytokine production, and IgG, IgE, and skin reactivity were measured to evaluate immunologic mechanisms. RESULTS: Eleven of 12 patients in the active treatment group had a decrease in the combined medication and symptom score, but only 4 of 10 patients in the placebo group had a decrease in scores. The proliferative response to timothy grass was reduced by at least 30% in 9 of the 12 grass-treated patients, but only 3 of 11 placebo patients had a proliferative response reduction. Timothy grass-induced interleukin-5 messenger RNA was reduced in the active group, but not in the placebo group. There were no significant changes in either group in IgG, IgE, and skin reactivity. CONCLUSIONS: Oral immunotherapy with microencapsulated allergen induces a form of immunologic tolerance to the allergen and is a safe, efficient, and effective method of allergen immunotherapy.

Administration, Oral↗
PubMed2004

Role of regulatory dendritic cells in allergy and asthma.

PURPOSE OF REVIEW: Dendritic cells are the most efficient inducers of all immune responses, and are capable of inducing either productive immunity or maintaining the state of tolerance to self-antigens and allergens. The present review summarizes the emerging literature on dendritic cells, with the emphasis on regulatory function of dendritic cells in allergy and asthma. In particular we summarize recent data regarding the relationship between dendritic cell subsets and Th1, Th2 and regulatory T (TReg) cells. RECENT FINDINGS: The diverse functions of dendritic cells have been attributed to distinct lineages of dendritic cells, which arise from common immature precursor cells that differentiate in response to specific maturation-inducing or local microenvironment conditions. These subsets induce different lineages of T cells such as Th1, Th2 and TReg cells, including Th1Reg and Th2Reg cells, which regulate allergic diseases and asthma. SUMMARY: Subsets of dendritic cells regulate the induction of a variety of T-cell subtypes, which suppress the development of allergy and asthma, thus providing antiinflammatory responses and protective immunity.

Animals↗
PubMed2004

Regulation of tolerance in the respiratory tract: TIM-1, hygiene, and the environment.

In this chapter we will discuss the regulation of immune responses in the respiratory mucosal system, rather than in the gastrointestinal mucosal system. However, because the lung and gastrointestinal tracts derive developmentally from a common endoderm, immune mechanisms in the respiratory and gastrointestinal tracts are likely to be very similar. Therefore, concepts that are learned about the respiratory tract are likely to benefit the understanding of tolerance in the gastrointestinal tract. We will discuss the regulation of immune responses in asthma, the role of respiratory tolerance, mediated by dendritic cells and regulatory T cells in the lung. In addition, we will discuss a genetic approach to better understand respiratory tolerance and the discovery of the TIM gene family, which regulates the development of Th2 responses, asthma, and tolerance. Finally, we will discuss the association in humans of TIM-1 and atopy, and the relationship between TIM1, hygiene, and the environment.

Animals↗
PubMed2003

Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy.

OBJECTIVE: To explore whether acute destruction of hypocretin cells in a patient with narcolepsy could be detected and if the course of the disease could be reversed or altered by the use of prednisone for immunosuppression. DESIGN: Case report. SETTING: A sleep-clinic population in a tertiary-care hospital. PATIENT: An 8-year-old boy with a very acute recent (< 2 month) onset of sleepiness. METHODS: Sleep studies; fluid-attenuated inversion recovery and gadolinium magnetic resonance imaging studies with a focus on the hypothalamus; examinations of cerebrospinal fluid for cytology, protein, and hypocretin-1 levels; and HLA typing were performed. INTERVENTION: A 3-week regimen of 1 mg x kg(-1) x day(-1) of prednisone was administered in an attempt to modify the course of the disease. RESULTS AND CONCLUSION: Sleep evaluations were consistent with a diagnosis of narcolepsy. Hypocretin-1 was absent in the cerebrospinal fluid, and HLA-DQB1*0602 was present. All other results were within normal limits, and prednisone did not have any noticeable effects. Clinical manifestation of narcolepsy might occur when the hypocretin cell damage is too advanced to be reversible.

Acute Disease↗
PubMed2003

TIM-1, a novel allergy and asthma susceptibility gene.

Atopic diseases, including asthma, allergic rhinitis, and atopic dermatitis, are caused by environmental factors in genetically predisposed individuals. Although the prevalence of these diseases has risen dramatically over the past two decades, it has been difficult to identify the underlying causes of these diseases due to the complex interplay between the genetic and environmental factors involved. Using a congenic mouse model of asthma, we simplified this complex trait and identified the novel T cell immunoglobulin domain, mucin-like domain (TIM) gene family, that encodes transmembrane proteins expressed by CD4 T cells. Recent studies demonstrate that the TIM family, particularly TIM-1, plays a critical role in immune responses that regulate the development of atopic diseases. In humans, certain polymorphic variants of TIM-1 are strongly associated with protection against atopy, and this association occurs only in individuals who have had past infection with hepatitis A virus (HAV). Since TIM-1 functions as the cellular receptor for HAV, activation of T cells through TIM-1 by HAV or by its natural ligand may affect T cell differentiation and the development of Th2-driven allergic inflammatory responses. Epidemiologically, HAV infection is associated with a reduced risk of developing atopy, and because the incidence of HAV infection has been significantly reduced in industrialized countries over the past 30 years, the discovery of a genetic interaction between HAV and TIM-1 provides the first molecular genetic evidence for the hygiene hypothesis.

Animals↗
PubMed2003

Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.

Using natural killer T (NKT) cell-deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281(-/-) mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d(-/-) mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may be clinically effective in limiting the development of AHR and asthma.

Adoptive Transfer↗
PubMed2003

Role of regulatory T cells in allergy and asthma.

Th2 cells play a critical role in the pathogenesis of allergy and asthma. However, the immunological mechanisms that downmodulate and protect against the development of these disorders are poorly understood. A spectrum of CD4(+) T cells, including Th3 cells, T(R) cells, CD4(+)CD25(+) cells and NKT cells play a critical role in regulating these diseases. A better understanding of the role of regulatory cells in allergic diseases may lead to the identification of novel therapeutic targets.

Animals↗
PubMed2003

The TIM gene family: emerging roles in immunity and disease.

The search for cell-surface markers that can distinguish T helper 1 (T(H)1) cells from T(H)2 cells has led to the identification of a new gene family, encoding the T-cell immunoglobulin mucin (TIM) proteins, some of which are differentially expressed by T(H)1 and T(H)2 cells. The role of the TIM-family proteins in immune regulation is just beginning to emerge. Here, we describe the various TIM-family members in mice and humans, and discuss the genetic and functional evidence for their role in regulating autoimmune and allergic diseases.

Animals↗
PubMed2003

PDE4D plays a critical role in the control of airway smooth muscle contraction.

The airways of mice deficient in the cAMP phosphodiesterase PDE4D gene are refractory to muscarinic cholinergic stimulation. This study was undertaken to determine whether altered smooth muscle contractility causes the PDE4D-/- phenotype. A major disruption in contractility was observed in isolated PDE4D-/- tracheas, with a 60% reduction in maximal tension and a fivefold decrease in sensitivity to muscarinic cholinergic agonists. Conversely, responses to KCl or arginine vasopressin were unaffected. PDE4D is the predominant PDE4 form in tracheal extracts and PDE4D mRNA is expressed in smooth muscle where muscarinic binding sites are most abundant. Cyclic AMP accumulation in response to acute G(s)alpha-coupled receptor stimulation was increased up to fourfold in the airway of PDE4D-/- mice when compared with wild-type. This increase in cAMP was associated with an increased sensitivity to PGE2-induced relaxation of the PDE4D-/-tracheas. Furthermore, a blockade of prostanoid accumulation in PDE4D-/- tracheas restored the response to muscarinic cholinergic stimulation in vitro and in vivo. These results demonstrate that PDE4D plays a key role in balancing relaxant and contracting cues in airway smooth muscle, suggesting that natural mutations in the PDE4D gene have profound effects on airway tone.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Mucosal tolerance and immunity: regulating the development of allergic disease and asthma.

Allergic diseases and asthma are characterized by eosinophilic inflammation induced by Th2 lymphocytes. However, the immunological events and the molecular and cellular mechanisms that protect against and regulate these pathological immune responses are poorly understood. In this review, we discuss the role of immunological tolerance, regulatory T cells, and dendritic cells (DCs) in these protective processes. In addition, we discuss factors like the maturation state of DCs, source and effect of Il-10 production as well as specific combinations of costimulatory molecules in the antigen-presenting cell: T cell synapse, which determine whether tolerance or immunity develops in the respiratory mucosa in response to inhaled allergen.

Allergens↗
PubMed2003

Respiratory tolerance in the protection against asthma.

Understanding the pathways involved in the induction and maintenance of respiratory tolerance to airborne allergens is important in designing new therapies for asthma and other allergic diseases that not only control disease symptoms, but also change or potentially cure the disease. Respiratory tolerance, and mucosal immunity are maintained by a complex system of defense mechanisms. Most of the inhaled environmental load is eliminated by exclusion mechanisms, which include physical barriers, such as mucus, and cilia as well as a variety of mediators with anti-microbial and immunomodulatory properties. Blanket immunosuppression is provided by alveolar macrophages, which inhibit antigen presentation and T cell responses, in addition to their role in pathogen elimination. Furthermore, there is antigen specific unresponsiveness or tolerance. This tolerance is mediated by lung dendritic cells producing IL-10, which induce the development of CD4+ T regulatory cells. The development of respiratory tolerance also depends on co-stimulation (CD86, and the ICOS-ICOSL pathway). Although exposure of the respiratory mucosa to some pathogenic agents (especially virus, and endotoxin) is associated with asthma exacerbations, microbial exposure may also promote mucosal tolerance and protection against the development of allergic diseases, but the mechanisms involved are not very well understood. Mucosal-based immunotherapy has been already used as an alternative form of allergen delivery in immunotherapy, the only available treatment that is able to reverse established allergic disease. Strategies to further improve mucosal immunotherapy include the use of modified allergen derived peptides, and adjuvants like CpG motifs.

Animals↗
PubMed2003

Regulatory T cells control the development of allergic disease and asthma.

The role of T(H)2 cells in the pathogenesis of allergy and asthma has been well described. However, the immunologic mechanisms that downmodulate and protect against the development of these disorders are poorly characterized. A spectrum of CD4+ T cells, including T(H)1 cells, T(H)3 cells, regulatory T cells, CD25+ T cells, and natural killer T cells might play a critical role in regulating these diseases and are discussed in this review.

Asthma↗
PubMed2002

Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity.

Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (T(R)) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway. The T(R) cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, T(R) cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions. These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.

Allergens↗
PubMed2002

Asthma: an epidemic of dysregulated immunity.

The remarkable increase in asthma prevalence that has occurred over the last two decades is thought to be caused by changes in the environment due to improved hygiene and fewer childhood infections. However, the specific infections that limit T helper type 2 (T(H)2)-biased inflammation and asthma are not fully known. Infectious organisms, including commensal bacteria in the gastrointestinal tract and hepatitis A virus, may normally induce the development of regulatory T (T(R)) cells and protective immunity that limit airway inflammation and promote tolerance to respiratory allergens. In the absence of such infections, T(H)2 cells--which are developmentally related to T(R) cells--develop instead and coordinate the development of asthmatic inflammation.

Antigens, CD↗
PubMed2002

CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation.

BACKGROUND: T(H)2 cells play a critical role in the pathogenesis of asthma, but the precise immunologic mechanisms that inhibit T(H)2 cell function in vivo are not well understood. OBJECTIVE: The purpose of our studies was to determine whether T cells producing IL-10 regulate the development of asthma. METHODS: We used gene therapy to generate ovalbumin-specific CD4 T-helper cells to express IL-10, and we examined their capacity to regulate allergen-induced airway hyperreactivity. RESULTS: We demonstrated that the CD4 T-helper cells engineered to express IL-10 abolished airway hyperreactivity and airway eosinophilia in BALB/c mice sensitized and challenged with ovalbumin and in SCID mice reconstituted with ovalbumin-specific T(H)2 effector cells. The inhibitory effect of the IL-10-secreting T-helper cells was accompanied by the presence of increased quantities of IL-10 in the bronchoalveolar lavage fluid, was antigen-specific, and was reversed by neutralization of IL-10. Moreover, neutralization of IL-10 by administration of anti-IL-10 mAb in mice sensitized and challenged with ovalbumin seriously exacerbated airway hyperreactivity and airway inflammation. CONCLUSION: Our results demonstrate that T cells secreting IL-10 in the respiratory mucosa can indeed regulate T(H)2-induced airway hyperreactivity and inflammation, and they strongly suggest that IL-10 plays an important inhibitory role in allergic asthma.

Allergens↗