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Biomedical subjects

K G Tournoy

Publications and source records attributed to K G Tournoy.

16 recordsLinked to original sources

Animal models of allergen-induced tolerance in asthma: are T-regulatory-1 cells (Tr-1) the solution for T-helper-2 cells (Th-2) in asthma?

Non-specific anti-inflammatory medication is actually the treatment of choice for controlling the T-helper type 2 (Th-2) cell-driven airway inflammation in asthma. The induction of counterbalancing Th-1 cell clones, long considered a promising approach for immunotherapy, has failed to fulfil its promise because of potentially detrimental side-effects. This is therefore probably not a valid option for the treatment of asthma. With the increasing awareness that active immune mechanisms exist to control inflammatory responses, interest rises to investigate whether these can be exploited to control allergen-induced airway disease. The induction of antigen-specific T cells with suppressive characteristics (regulatory T cells) is therefore a potentially interesting approach. These regulatory T cells mediate tolerance in healthy, non-atopic individuals and have the potential of becoming an effective means of preventing allergen-induced airway inflammation and possibly of suppressing ongoing allergic immune responses. Here we review the available knowledge about allergen-induced suppressive immunity obtained from animal models taking into account the different developmental stages of allergic airway disease.

Adoptive Transfer↗

A case of recurrent non-small-cell lung carcinoma and paraneoplastic Cushing's syndrome.

Secretion of ectopic adrenocorticotropic hormone (ACTH) with consequently Cushing's syndrome is a rare paraneoplastic phenomenon. It has been described in a variety of malignancies, like bronchial carcinoids, small-cell lung carcinoma, thymoma, pancreatic carcinoma and other. In many cases of suspected ectopic ACTH secretion, it is difficult to histologically or cytochemically confirm the diagnosis. We present a 63-year-old woman with a recurrent poorly differentiated squamous cell lung carcinoma with clinical and biochemical features consistent with ectopic Cushing's syndrome. Immunocytochemical staining confirmed the secretion of ACTH by tumour cells.

ACTH Syndrome, Ectopic↗

Modulatory role of tachykinin NK1 receptor in cholinergic contraction of mouse trachea.

The role of the NK1 receptor in airway contraction induced by electrical field stimulation (EFS) was evaluated by comparing the response in NK1 receptor knockout mice (NK1R-/-) with that of NK1 receptor wild-type controls (WT). A frequency/response curve on tracheas from NK1R-/- mice and NK1R WT littermates was constructed. After incubation with [3H]choline, [3H]acetylcholine release upon EFS was measured by high-performance liquid chromatography and liquid scintillation counting. The effects of atropine (1 x 10(-6) M), tetrodotoxin (1 x 10(-6) M) and a specific NK1R antagonist (SR140333, 1 x 10(-8) M) were studied, as well as the effects of substance P (1 x 10(-5) M) on precontracted tracheas. Upon EFS, NK1R-/- mice had a significant lower trachea contractility than the NK1R WT animals, accompanied with less [3H]acetylcholine release. Pretreatment with atropine or tetrodotoxin abolished the EFS-induced contraction in both strains. Pretreatment with the NK1R antagonist SR140333 significantly reduced the contractility in the NK1R WT but not in the NK1R-/- mice. Substance P caused a small contraction in both NK1R WT and NK1R-/- mice. Substance P induced a relaxation in precontracted tracheas in NK1R WT but not in NK1R-/- mice. The data presented here provide direct evidence that the NK1 receptor augments cholinergic neurotransmission in mouse trachea.

Animals↗

The allergen-induced airway hyperresponsiveness in a human-mouse chimera model of asthma is T cell and IL-4 and IL-5 dependent.

The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-gamma after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype.

Allergens↗

Counterbalancing of TH2-driven allergic airway inflammation by IL-12 does not require IL-10.

BACKGROUND: Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma. OBJECTIVE: The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10. METHODS: C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both. RESULTS: IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity. CONCLUSIONS: These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology.

Adjuvants, Immunologic↗

New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5.

Asthma is currently defined as a chronic inflammatory disorder of the airways. The central role of allergen-specific Th2 cells in the regulation of this mucosal airway inflammation has been highlighted. Hence, there is large interest in the therapeutic potential of an anti-Th2 cell approach. One of the strategies which has been developed, is to inhibit the effect of interleukin (IL)-4 or IL-5, two main Th2 cell derived cytokines. Interleukin-4 is pivotal in the pathogenesis of allergic disorders through its wide range of effects. An important observation, especially during secondary antigen exposure, is the possible redundancy with IL-13. Both cytokines share common elements in their receptor and intracellular signalling pathway. As a result, compounds can be developed that selectively inhibit the effect of either IL-4 or IL-13, or alternatively, by interfering with the common pathway, inhibit the effect of both cytokines. Eosinophils are generally seen as a particularly harmful element in the allergic inflammation. The importance of IL-5 on eosinophil biology has clearly been established. Conversely, in man, the biological effects of IL-5 are largely limited to eosinophil function. Therefore, IL-5 antagonists offer the unique opportunity of selectively neutralizing the effect of eosinophils. Several strategies have now been developed that successfully inhibit the biological effect of interleukin-4 or interleukin-5. Some of these compounds have proven to be biologically active in man. The challenge now is to establish their therapeutic role in asthma.

Anti-Asthmatic Agents↗

Airway eosinophilia is not a requirement for allergen-induced airway hyperresponsiveness.

BACKGROUND: House dust mites (HDMs) are the major source of perennial allergens causing human allergic asthma. Animal models mimicking as closely as possible the allergic features observed in human asthma are therefore interesting tools for studying the immunological and pathophysiological mechanisms involved. Especially the role of eosinophils and allergen-specific immunoglobulin (Ig) E in the pathophysiology of airway hyperresponsiveness (AHR) remains a subject of intense debate. OBJECTIVE: To develop a mouse model of allergic airway inflammation and hyperresponsiveness based on the use of purified house dust mite allergen (Der p 1) as clinical relevant allergen. Furthermore, we studied the effects of low dose allergen exposure on the airway eosinophilia and AHR. METHODS: On day 0, C57Bl/6 mice were immunized with purified Der p 1 intraperitoneally. From day 14-20, the mice were exposed daily to a 30-min aerosol of different concentrations of house dust mite extract. RESULTS: Mice, actively immunized with Der p 1 and subsequently exposed to HDM aerosols, developed AHR, eosinophil infiltration of the airways and allergen-specific IgE. Moreover, lowering the concentration of the HDM aerosol also induced AHR and IgE without apparent eosinophil influx into the airways. Der p 1-sensitized mice exposed to PBS produced IgE, but did not show AHR or eosinophil influx. CONCLUSION: This in vivo model of HDM-induced allergic airway changes suggests that AHR is not related to either eosinophil influx or allergen-specific serum IgE, thereby reducing the importance of these factors as essential elements for allergic AHR.

Allergens↗

Endogenous interleukin-10 suppresses allergen-induced airway inflammation and nonspecific airway responsiveness.

BACKGROUND: The airway inflammation observed in asthma is orchestrated by activated Th-2 lymphocytes relevant for the induction of altered airway responsiveness. An increasing body of evidence is accumulating that not only the pro-inflammatory cytokines interleukin (IL)-4 and IL-5 but also the immunomodulating cytokines IL-12 and possibly IL-10 are crucial for regulating the allergic airway inflammation. OBJECTIVE: Since IL-10 is capable of downregulating a broad spectrum of pro-inflammatory cytokines, we wanted to address the role of endogenously produced IL-10 in vivo in allergic asthma. METHODS: Knockout (IL-10(-/-)) mice (C57BL/6-IL10tm1Cgn) and wild-type (WT) counterparts were immunized (day 0) and exposed (day 14-21) to ovalbumin (OVA). Airway inflammation and reactivity (AR), serum allergen-specific IgE responses and cytokine profiles in the bronchoalveolar lavage fluid (BALF) were studied. RESULTS: The IL-10(-/-) mice had more eosinophilic airway inflammation but comparable levels of allergen-specific serum IgE compared to the WT mice after allergen challenge. The AR was comparably increased in the OVA challenged WT and IL-10(-/-) mice vs sham-exposed WT, but not vs sham-exposed IL-10(-/-)mice since these showed a higher baseline AR. IFN gamma, IL-4 and IL-13 were comparable and IL-5 was even lower in the BALF of the in IL-10(-/-) mice compared to the similarly exposed WT mice. CONCLUSION: These results indicate that IL-10 plays an important and possibly direct role in the control of airway inflammation and responsiveness in an in vivo mouse model of allergy.

Allergens↗

Mouse strain and conditioning regimen determine survival and function of human leucocytes in immunodeficient mice.

The innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-beta1, a rat monoclonal antibody recognizing the mouse IL-2 receptor beta-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-beta1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-beta1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-beta1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-beta1. However, these animals died within 3 weeks post-grafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-beta1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-beta1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.

Animals↗

Murine IL-2 receptor beta chain blockade improves human leukocyte engraftment in SCID mice.

Severe combined immunodeficient (SCID) mice accept human xenografts and can act as a model for human immune functions. Murine natural killer cells (NK), however, represent an important barrier for the reconstitution of SCID mice with human peripheral blood leukocytes (Hu-PBL). We investigated the effect on Hu-PBL survival of pretreatment with TM-beta1, a rat monoclonal antibody for the mouse IL-2 receptor beta chain. TM-beta1 greatly improved the survival of Hu-PBL. Human lymphocytes, predominantly T cells, survived in the peritoneum and infiltrated spleen and lungs already 1 week after engraftment and liver and thymus from 2 weeks on. Secondary humoral responses were evaluated with Hu-PBL from a donor immune to hepatitis-B surface Ag (HBsAg) and tetanus toxoid (TT). TM-beta1 pretreatment enhanced the recall Ig response to HBsAg and did not affect the baseline anti-TT Ig production. In conclusion, TM-beta1 pretreatment of SCID mice significantly improves the survival and functionality of the Hu-PBL graft.

Animals↗

Cytokines and their receptors as therapeutic targets in asthma.

Cytokines are very potent pro-inflammatory agents. Several cytokines are present in abnormal quantities in asthmatic airway tissues. In vitro and in vivo experiments demonstrate that these cytokines have biological effects relevant to the pathogenesis of asthma. We review the evidence that interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), interleukin-12 (IL-12) and interferon-gamma (IFNgamma) have the potential of playing a key role in the pathogenesis of asthma. Inhibition of the activity of IL-4 or IL-5 and enhancing or mimicking the action of IL-10, IL-12 or IFNgamma are therapeutic options in asthma that warrant further investigations.

Administration, Inhalation↗

Genetic polymorphisms and erythrocyte sodium-lithium countertransport in essential hypertension.

Erythrocyte sodium-lithium countertransport (SLC) activity is elevated in essential arterial hypertension. With the growing attention to the genetic substrate of disturbed biochemical tests associated with essential arterial hypertension, we were particularly interested in the involvement of key genes for the regulation of SLC, possibly related to the pathophysiology of essential arterial hypertension. Consequently, the aim of the present study was to investigate SLC and its determining factors in essential hypertension. The influence of haptoglobin (Hp)-polymorphism, insertion/deletion polymorphism of angiotensin converting enzyme (ACE-I/D) and MNS blood group system on the regulation of SLC was studied. SLC activity was studied in a cross-sectional case-control study including 90 Caucasians: 60 patients with essential arterial hypertension who had been treated for at least 1 year and 30 normotensive controls. In essential hypertension, the SLC activity is significantly higher (P = 0.00005) than in controls. In normotensive patients, no differences in SLC are observed for the different polymorphisms studied. However, in the hypertensive group, SLC activity is higher (P = 0.003) in Hp 2-1 phenotype and independent of ACE-I/D genotyping and MNS blood group polymorphism. Multifactor analysis of variance in essential hypertension reveals significant (P = 0.001) differences in SLC activity for the presence or absence of Hp 2-1 phenotype and for body weight (P = 0.0003). Multivariate regression analysis shows the same parameters to be independent determining factors of SLC in essential arterial hypertension. No relation is found between SLC activity and target organ damage which includes coronary artery disease, peripheral arterial occlusive disease, left ventricular hypertrophy and cerebrovascular accident. We conclude that erythrocyte SLC activity is elevated despite pressure-lowering therapy. In essential arterial hypertension, individuals of Hp 2-1 phenotype show higher SLC activity than patients of other Hp-types, suggesting genetic heterogeneity of essential arterial hypertension. The presence or absence of Hp 2-1 phenotype is an independent determining factor of SLC activity whereas body weight codetermines SLC activity in essential hypertension.

Adult↗

Mycobacterium avium complex with a distinct clinical and iconographic presentation: the Lady Windermere syndrome.

Clinically significant pulmonary disease caused by non-tuberculous mycobacteria such as Mycobacterium avium Complex (MAC) usually occurs upon pre-existing lung diseases or immune-deficiency. In 1992, a particular presentation of pulmonary MAC, occuring in otherwise healthy middle-aged women, was described with pulmonary consolidations localized in lingula and middle lobe. For this specific, rare condition, the term Lady Windermere syndrome was introduced. We report a particular case of this syndrome, in which an otherwise healthy individual developed clinically significant disease upon MAC (subtype: Mycobacterium avium) infection of the right middle lobe and lingula of the lung. The patient did not have the classical risk factors for developing this syndrome (e.g. habitual cough suppression, long and narrow bronchi) indicating their modest contribution in the pathogenesis. In our case, guideline based therapy was found to be inadequate because of multi-drug resistance, so an alternative treatment regime was given with good clinical result.

Antitubercular Agents↗