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Dive into the research topics where Ian G. Young is active.

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Featured researches published by Ian G. Young.


Immunity | 1996

IL-5-Deficient Mice Have a Developmental Defect in CD5+ B-1 Cells and Lack Eosinophilia but Have Normal Antibody and Cytotoxic T Cell Responses

Manfred Kopf; Frank Brombacher; Philip D. Hodgkin; Alistair J. Ramsay; Elizabeth A. Milbourne; Wen J Dai; K.S. Ovington; Carolyn A. Behm; Georges Köhler; Ian G. Young; Klaus I. Matthaei

Mice deficient in interleukin-5 (IL-5-/- mice) were generated by gene targeting in embryonal stem cells. Contrary to previous studies, no obligatory role for IL-5 was demonstrated in the regulation of conventional B (B-2) cells, in normal T cell-dependent antibody responses or in cytotoxic T cell development. However, CD5+ B cells (B-1 cells) in the peritoneal cavity were reduced by 50%-80% in 2-week-old IL-5-/- mice, returning to normal by 6-8 weeks of age. The IL-5-/- mice did not develop blood and tissue eosinophilia when infected with the helminth Mesocestoides corti, but basal levels of eosinophils with normal morphology were produced in the absence of IL-5. IL-5 deficiency did not affect the worm burden of infected mice, indicating that increased eosinophils do not play a significant role in the host defence in this parasite model.


Journal of Clinical Investigation | 1997

Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice.

Arne W. Mould; Klaus I. Matthaei; Ian G. Young; Paul S. Foster

The mechanism of cooperation between IL-5 and eotaxin for the selective accumulation of eosinophils at sites of allergic inflammation is unknown. In this investigation we have used IL-5 deficient mice to define the relationship between this cytokine and eotaxin in the regulation of blood eosinophilia and eosinophil homing and tissue accumulation. Both IL-5 and eotaxin could independently induce a rapid and pronounced blood eosinophilia in wild type mice when administered systemically. In contrast, only eotaxin induced a pronounced blood eosinophilia in IL-5 deficient mice. The eosinophilic response induced by intravenous eotaxin in wild type mice did not correlate with a significant reduction in the level of bone marrow eosinophils, whereas intravenous IL-5 resulted in depletion of this store. These results suggest the existence of two mechanisms by which eosinophils can be rapidly mobilized in response to intravenous eosinophil chemoattractants; first, mobilization of an IL-5 dependent bone marrow pool, and second, an eotaxin-induced sequestration of eosinophils from tissues into the blood. Subcutaneous injection of eotaxin induced a local tissue eosinophilia in wild type mice but not in IL-5 deficient mice. Furthermore, tissue eosinophilia in wild type mice, but not in IL-5 deficient mice, was enhanced by adoptive transfer of eosinophils or the administration of intravenous IL-5. However, pretreatment of IL-5 deficient mice with intraperitoneal IL-5 for 72 h restored eosinophil homing and tissue accumulation in response to subcutaneous eotaxin. We propose that eotaxin secreted from inflamed tissue may play an important role in initiating both blood and tissue eosinophilia in the early phases of allergic inflammation. Furthermore, IL-5 is not only essential for mobilizing eosinophils from the bone marrow during allergic inflammation, but also plays a critical role in regulating eosinophil homing and migration into tissues in response to eotaxin and possibly other specific chemotactic stimuli.


Journal of Experimental Medicine | 2002

Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma

Joerg Mattes; Ming Yang; Surendran Mahalingam; Joachim Kuehr; Dianne C. Webb; Ljubov Simson; Simon P. Hogan; Aulikki Koskinen; Andrew N. J. McKenzie; Lindsay A. Dent; Marc E. Rothenberg; Klaus I. Matthaei; Ian G. Young; Paul S. Foster

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti–IL-5 or anti–IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin−/−) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4+ T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin−/− mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.


Immunological Reviews | 1988

Molecular and Cellular Biology of Eosinophil Differentiation Factor (Interleukin‐5) and its Effects on Human and Mouse B Cells

Colin J. Sanderson; Hugh D. Campbell; Ian G. Young

Eosinophils are found only infrequently in the blood and tissues of normal individuals and animals, but are characteristic of allergic responses and infection by helminths. Their distinctive morphology led to descriptive reports of their presence in the blood and tissues in these and other diseases well before the turn of this century. However, compared to neutrophils and macrophages they are relatively inactive in standard phagocytosis assays and so little has been known about their biological activity and they remained, until recently, largely a hematological curiosity. These early descriptive reports both illustrated the magnitude of the eosinophil response, by showing that in particular circumstances they can become the predominant blood and tissue leukocyte, and established a clear association between the development of an eosinophilia and increased levels of IgE antibody. An important development which has led to an increased understanding of the biological role of the eosinophil was the development of techniques for their purification, firstly from human peripheral blood (Butterworth 1975), which made possible the observation that human eosinophils were capable of killing schistosomula of Schistosoma mansoni. This was followed by a series of reports indicating that human eosinophils could kill a wide variety of helminthic larvae (reviewed by Butterworlh 1984). Later techniques for purifying eosinophils from the peritoneal exudate of experimental animals made it clear that their cytotoxic capability was not limited to helminths. They were shown to have potent activity


Immunological Reviews | 2001

Elemental signals regulating eosinophil accumulation in the lung

Paul S. Foster; Arne W. Mould; Ming Yang; Jason R. MacKenzie; Joerg Mattes; Simon P. Hogan; Surendran Mahalingam; Andrew N. J. McKenzie; Marc E. Rothenberg; Ian G. Young; Klaus I. Matthaei; Dianne C. Webb

Summary: In this review we identify the elemental signals that regulate eosinophil accumulation in the allergic lung. We show that there are two interwoven mechanisms for the accumulation of eosinophils in pulmonary tissues and that these mechanisms are linked to the development of airways hyperreactivity (AHR). Interleukin‐(IL)‐5 plays a critical role in the expansion of eosinophil pools in both the bone marrow and blood in response to allergen provocation of the airways. Secondly, IL‐4 and IL‐13 operate within the allergic lung to control the transmigration of eosinophils across the vascular bed into pulmonary tissues. This process exclusively promotes tissue accumulation of eosinophils. IL‐13 and IL‐4 probably act by activating eosinophil‐specific adhesion pathways and by regulating the production of IL‐5 and eotaxin in the lung compartment. IL‐5 and eotaxin co‐operate locally in pulmonary tissues to selectively and synergistically promote eosinophilia. Thus, IL‐5 acts systemically to induce eosinophilia and within tissues to promote local chemotactic signals. Regulation of IL‐5 and eotaxin levels within the lung by IL‐4 and IL‐13 allows Th2 cells to elegantly co‐ordinate tissue and peripheral eosinophilia. Whilst the inhibition of either the IL‐4/IL‐13 or IL‐5/ eotaxin pathways resulted in the abolition of tissue eosinophils and AHR, only depletion of IL‐5 and eotaxin concurrently results in marked attenuation of pulmonary inflammation. These data highlight the importance of targeting both IL‐5 and CCR3 signalling systems for the resolution of inflammation and AHR associated with asthma.


Cell | 2001

Structure of the Complete Extracellular Domain of the Common beta Subunit of the Human GM-CSF, IL-3, and IL-5 Receptors Reveals a Novel Dimer Configuration

Paul D. Carr; Sonja E. Gustin; Alice P. Church; James M. Murphy; Sally C. Ford; David A. Mann; Donna Woltring; Ian Walker; David L. Ollis; Ian G. Young

The receptor systems for the hemopoietic cytokines GM-CSF, IL-3, and IL-5 consist of ligand-specific alpha receptor subunits that play an essential role in the activation of the shared betac subunit, the major signaling entity. Here, we report the structure of the complete betac extracellular domain. It has a structure unlike any class I cytokine receptor described thus far, forming a stable interlocking dimer in the absence of ligand in which the G strand of domain 1 hydrogen bonds into the corresponding beta sheet of domain 3 of the dimer-related molecule. The G strand of domain 3 similarly partners with the dimer-related domain 1. The structure provides new insights into receptor activation by the respective alpha receptor:ligand complexes.


Laboratory Investigation | 2000

Dissociation of Inflammatory and Epithelial Responses in a Murine Model of Chronic Asthma

Paul S. Foster; Yang Ming; Klaus I Matthei; Ian G. Young; Jason Temelkovski; Rakesh K. Kumar

To study pathogenetic mechanisms in chronic asthma, we employed a novel experimental model that replicates characteristic features of the human disease. Chronic inflammation and epithelial changes, specifically localized to the airways, were induced by repeated exposure of systemically sensitized BALB/c mice to low mass concentrations of aerosolized ovalbumin for 6 weeks. The contribution of Th2 cytokine-driven inflammation to the development of airway lesions and hyperreactivity was assessed in cytokine-deficient mice. In interleukin-5-deficient animals, intraepithelial eosinophils and chronic inflammatory cells in the lamina propria of the airways were markedly decreased; however, these animals developed epithelial hypertrophy and subepithelial fibrosis comparable with that observed in sensitized wild type mice. Airway hyperreactivity to inhaled methacholine did not develop in interleukin-5-deficient mice. In contrast, interleukin-4-deficient mice exhibited no decrease in airway inflammation, but had significantly greater epithelial hypertrophy and subepithelial fibrosis, as well as exaggerated hyperreactivity to methacholine. We conclude that interleukin-5, but not interleukin-4, plays a central role in the development of chronic inflammation of the airways and the induction of airway hyperreactivity. Furthermore, chronic epithelial and fibrotic changes occur independently of interleukin-5 and are not required for the development of airway hyperreactivity. The dissociation between airway wall remodeling and airway hyperreactivity has important implications for therapeutic approaches to chronic asthma.


The Journal of Steroid Biochemistry and Molecular Biology | 1993

Sex hormones and dexamethasone modulate interleukin-5 gene expression in T lymphocytes

Y. Wang; Hugh D. Campbell; Ian G. Young

The ability of the sex hormones progesterone, testosterone and estradiol-17 beta and the glucocorticoid dexamethasone to modulate expression of the interleukin-5 (IL-5) gene in T cell lines has been investigated. The T cell lines used show analogous regulation of IL-5 gene expression to that occurring in T-lymphocytes, in that IL-5 mRNA levels are undetectable unless the cells are induced with phorbol myristate acetate (PMA). Progesterone and testosterone were as effective as PMA in inducing IL-5 mRNA levels in the T cell hybrid NIMP-TH1 and induced IL-5, -3 and -2 mRNA accumulation in the T cell lymphoma EL-4. Estradiol-17 beta also induced IL-5 mRNA accumulation but less effectively than testosterone. Nuclear run-on experiments suggested that the effects of progesterone, testosterone and PMA on IL-5 gene expression were mediated at the level of transcription. The presence of the protein synthesis inhibitor cycloheximide completely prevented PMA-induced synthesis of IL-5 mRNA by both NIMP-TH1 and EL-4 cells, indicating that induction of IL-5 mRNA via PMA stimulation requires de novo synthesis of a presumptive trans-acting factor(s). PMA-, testosterone- and progesterone-induced expression of the IL-5 gene was completely blocked by the anti-inflammatory steroid dexamethasone. Stimulation of IL-5 expression by PMA was relatively resistant to the immuno- suppressive drug cyclosporin A although inhibition did occur at very high levels. Testosterone- and progesterone-induced IL-5 gene expression was not inhibited by cyclosporin A. The in vivo significance of these findings are not yet clear but the results show that sex hormones have the potential to regulate cytokine gene expression in cells possessing the appropriate steroid receptors.


Trends in Molecular Medicine | 2002

Interleukin-5 and eosinophils as therapeutic targets for asthma

Paul S. Foster; Simon P. Hogan; Ming Yang; Joerg Mattes; Ian G. Young; Klaus I. Matthaei; Rakesh K. Kumar; Surendran Mahalingam; Dianne C. Webb

Extensive clinical investigations have implicated eosinophils in the pathogenesis of asthma. In a recent clinical trial, humanized monoclonal antibody to interleukin (IL)-5 significantly limited eosinophil migration to the lung. However, treatment did not affect the development of the late-phase response or airways hyperresponsiveness in experimental asthma. Although IL-5 is a key regulator of eosinophilia and attenuation of its actions without signs of clinical improvement raises questions about the contribution of these cells to disease, further studies are warranted to define the effects of anti-IL-5 in the processes that lead to chronic asthma. Furthermore, eosinophil accumulation into allergic tissues should not be viewed as a process that is exclusively regulated by IL-5 but one in which IL-5 greatly contributes. Indeed, data on anti-IL-5 treatments (human and animal models) are confounded by the failure of this approach to completely resolve tissue eosinophilia and the belief that IL-5 alone is the critical molecular switch for eosinophil development and migration. The contribution of these IL-5-independent pathways should be considered when assessing the role of eosinophils in disease processes.


Immunology | 1998

Intestinal IgA plasma cells of the B1 lineage are IL‐5 dependent

Shisan Bao; Kenneth W. Beagley; A. M. Murray; V. Caristo; Klaus I. Matthaei; Ian G. Young; Alan J. Husband

Two lineages of B cells, designated B1 and B2 cells, have been identified based upon their origins, anatomical distribution, cell surface markers, antibody repertoire and self‐replenishing potential. B1 cells are maintained by self‐renewal of cells resident in the peritoneal cavity (PerC) and they utilize a limited repertoire of germline V‐region genes, mostly directed against ubiquitous bacterial antigens such as phosphoryl choline (PC). B2 cells are replenished from bone marrow precursors and use a larger repertoire of immunoglobulin V‐region genes. Whereas most immunoglobulin A (IgA) plasma cells in the intestine derive from B2 lineage precursors in the Peyer’s patch, a subpopulation of Per C‐derived B1 cells populate the intestinal lamina propria where they mature into IgA plasma cells. In previous in vivo studies we have shown that whereas IgA+ B2 cells are interleukin (IL)‐6 dependent, B1 cells are IL‐6 independent. In view of the in vitro evidence that IL‐5 is also involved in IgA expression, in the studies reported here we have used IL‐5‐deficient mice to evaluate the role of IL‐5 in vivo in IgA expression in the gut. The results demonstrate that although total IgA cell numbers are only marginally depressed in IL‐5‐deficient mice, there is a marked selective depletion of IgA+ cells of the B1 lineage in the gut and a corresponding depression in the capacity of these mice to mount an intestinal response to a B1 antigen (PC) but not to a B2 antigen (oralbumin; OVA), reflecting intact B2‐derived IgA cell function but a defect in the B1 cell contribution to IgA responses in IL‐5 deficient mice. Collectively these data demonstrate differential cytokine regulation of subsets of IgA+ cells in the gut in that IgA+ cells of the B2 lineage are IL‐6 dependent but IL‐5 independent, but B1‐derived IgA+ cells are IL‐5 dependent and IL‐6 independent.

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Hugh D. Campbell

Australian National University

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Klaus I. Matthaei

Australian National University

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Sally C. Ford

Australian National University

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Simon P. Hogan

Cincinnati Children's Hospital Medical Center

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David L. Ollis

Australian National University

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Jinglong Chen

Australian National University

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Shamaruh Mirza

Australian National University

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