Malaghan Institute of Medical Research

Wellington, New Zealand

Malaghan Institute of Medical Research

Wellington, New Zealand
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Harvie M.,Queensland University of Technology | Camberis M.,Malaghan Institute of Medical Research | Gros G.L.,Malaghan Institute of Medical Research
Frontiers in Immunology | Year: 2013

Of all the microbial infections relevant to mammals the relationship between parasitic worms and what constitutes and regulates a host protective immune response is perhaps the most complex and evolved. Nippostrongylus brasiliensis is a tissue migrating parasitic roundworm of rodents that exemplifies many of the salient features of parasitic worm infection, including parasite development through sequential larval stages as it migrates through specific tissue sites. Immune competent hosts respond to infection by N. brasiliensis with a rapid and selective development of a profound Th2 immune response that appears able to confer life long protective immunity against reinfection. This review details how the lung can be the site of migrating nematode immune killing and the gut a site of rapid immune mediated clearance of worms. Furthermore it appears that N. brasiliensis induced responses in the lung are sufficient for conferring immunity in lung and gut while infection of the gut only confers immunity in the gut. This review also covers the role of IL-4, STAT6, and the innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin in the generation of CD4-mediated immunity against N. brasiliensis reinfection and discusses what cytokines might be involved in mediated killing or expulsion of helminth parasites. © 2013 Harvie, Camberis and Le Gros.

Martin W.J.,Malaghan Institute of Medical Research | Harper J.L.,Malaghan Institute of Medical Research
Immunology and Cell Biology | Year: 2010

Acute gout is an inflammatory arthritis that is controlled by the innate arm of the immune response. Although the causative feature of gout has long been recognized, it is surprising that the cellular activities that underpin the initiation and resolution of acute gout remain poorly described. This review article summarizes what are currently thought to be the key cellular mechanisms at play during an inflammatory episode of acute gout. The emerging role of mononuclear phagocytes is highlighted as having a central role in both the initiation and resolution of acute gout, and the interplay between monocytes and other elements of the innate immune response, including neutrophils, and complement protein activation are discussed. © 2010 Australasian Society for Immunology Inc. All rights reserved.

Shaw O.M.,Malaghan Institute of Medical Research | Harper J.L.,Malaghan Institute of Medical Research
Biochemical and Biophysical Research Communications | Year: 2011

The aim of this study was determine the effect of bradykinin receptor antagonism on MSU crystal-induced chemokine production and leukocyte recruitment. Mice were injected intraperitoneally with monosodium urate (MSU) crystals. ±. bradykinin B1- or B2 receptor antagonists, Des-Arg-HOE-140 and HOE-140, respectively. MSU crystal-induced chemokine production and leukocyte recruitment in the peritoneum were measured over 24. h and B1 and B2 receptor expression on leukocytes and peritoneal membrane was determined by flow cytometry and fluorescence microscopy.Data analysis showed that only B2 receptor antagonism decreased monocyte and neutrophil infiltration 24. h post MSU crystal administration. Decreased leukocyte infiltration was associated with reduced monocyte (CCL2) chemokine levels. MSU crystal-induced damage to the surrounding visceral membrane was also attenuated in the presence of B2 receptor antagonism. Together, these data show that bradykinin receptor 2 plays a role in maintaining MSU crystal-induced leukocyte infiltration and membrane permeability and identify the B2 receptor as a potential therapeutic target for managing inflammation in gout. © 2011 Elsevier Inc..

Prendergast K.A.,Malaghan Institute of Medical Research | Kirman J.R.,University of Otago
Tuberculosis | Year: 2013

Anti-mycobacterial immunity is guided by specialised antigen presenting cells known as dendritic cells, which are essential for both initiating and maintaining T cell immune responses during infection. The dendritic cell population can be divided into functionally distinct subsets that differ in their ability to present antigen and produce key TH1 cytokines, such as IL-12. This review discusses recent studies, in murine models, investigating which dendritic cell populations are important for mycobacterial control. © 2012 Elsevier Ltd. All rights reserved.

Min B.,Cleveland Clinic | Brown M.A.,Northwestern University | Legros G.,Malaghan Institute of Medical Research
Immunology | Year: 2012

Early studies that used parasite-infected interleukin-4 (IL-4) reporter animals led us to identify basophils as the primary source of IL-4 and hence propose the hypothesis that basophils trigger the development of antigen-specific T helper type 2 (Th2) immune responses in vivo. These findings appeared to resolve a long-standing puzzle underlying Th2 immunity, that is, 'what is the source of the initial IL-4 necessary for CD4 T-cell differentiation into Th2 effector cells?'. However, results from extensive investigations of the contribution of basophils to Th2 immunity unveiled some controversial data that cast doubt on the initial hypothesis. In this review, the consensus and the controversy regarding the roles of basophils in infection and immunity, as well as outstanding questions for the future, are discussed. © 2011.

Steiger S.,Malaghan Institute of Medical Research | Harper J.L.,Malaghan Institute of Medical Research
Arthritis and Rheumatism | Year: 2013

Objective To identify macrophage-independent sources of transforming growth factor β1 (TGFβ1) production during monosodium urate monohydrate (MSU) crystal-induced inflammation and to determine how TGFβ1 alters MSU crystal-recruited neutrophil functions. Methods C57BL/6J mice were injected intraperitoneally with MSU crystals with or without TGFβ1-neutralizing antibody. MSU crystal-recruited peritoneal and blood neutrophils were purified and cultured ex vivo. Peritoneal neutrophils were treated with the caspase inhibitor Q-VD-OPh, anti-TGFβ1 antibody, or fluorochrome-labeled apoptotic neutrophils. Neutrophils were analyzed for expression of annexin V, caspase 3, and TGFβ1 by flow cytometry or fluorescence microscopy, for superoxide production using the redox-sensitive dye water-soluble tetrazolium 1, and for TGFβ1 and interleukin-1β (IL-1β) production by enzyme-linked immunosorbent assay. Results Eighteen hours after MSU crystal administration in vivo, TGFβ1 levels were elevated in peritoneal lavage fluids, and a significant number of peritoneal neutrophils were TGFβ1+. Purified blood or peritoneal neutrophils cultured ex vivo showed TGFβ1+ neutrophils coexpressing the apoptosis marker caspase 3 and increased TGFβ1 production, both of which dropped following inhibition of apoptosis. Live neutrophils that had phagocytosed apoptotic neutrophils showed greatest TGFβ1 expression. Superoxide production by purified MSU crystal-recruited neutrophils ex vivo was enhanced by anti-TGFβ1 antibody treatment. Neutrophils purified from the peritoneum of MSU crystal-challenged mice treated with anti-TGFβ1 antibody produced elevated levels of superoxide, but neutrophil IL-1β production was unaffected. Conclusion Neutrophil cannibalism and TGFβ1 production have the potential to make a significant contribution to the controlled resolution of neutrophil-driven inflammatory diseases such as gout. © 2013 by the American College of Rheumatology.

Steiger S.,Malaghan Institute of Medical Research | Harper J.L.,Malaghan Institute of Medical Research
Current Rheumatology Reports | Year: 2014

Acute gout is an auto-inflammatory disease characterized by self-limiting inflammation in response to the deposition of monosodium urate (MSU) crystals in the joints or tissues. Recognition of MSU triggers activation of the NLRP3 inflammasome, release of active interleukin (IL)-1β, and amplification of the inflammatory response by the surrounding tissue followed by recruitment and activation of inflammatory leukocytes. The shutdown of this inflammatory response is linked to a number of regulatory events ranging from crystal coating and apoptotic cell clearance through to pro-inflammatory cytokine regulation and transforming growth factor β1 (TGFβ1) production. This review will highlight mechanisms that limit acute inflammation triggered by MSU crystals and suggests areas for further research. © 2013 Springer Science+Business Media New York.

Tan A.S.,Malaghan Institute of Medical Research | Berridge M.V.,Malaghan Institute of Medical Research
Free Radical Biology and Medicine | Year: 2010

2,3-Dimethoxy 1,4-naphthoquinone (DMNQ), which redox cycles via two-electron reduction, mediates reduction of the cell-impermeative tetrazolium dye WST-1 in kidney epithelial cells (MDCK), which express high levels of NQO1, but not in HL60 or CHO cells, which are NQO1 deficient. DMNQ-dependent WST-1 reduction by MDCK cells was strongly inhibited by low concentrations of the NQO1 inhibitor dicoumarol and was also inhibited by diphenyleneiodonium, capsaicin, and superoxide dismutase (SOD), but not by the uncoupler FCCP or the complex IV inhibitor cyanide. This suggests that DMNQ-dependent WST-1 reduction by MDCK cells is catalyzed by NQO1 via redox cycling and plasma membrane electron transport (PMET). Interestingly, we observed an association between DMNQ/WST-1 reduction and extracellular H2O2 production as determined by Amplex red. Exposure of MDCK cells to DMNQ for 48 h caused cellular toxicity that was extensively reversed by co-incubation with dicoumarol or exogenous SOD, catalase, or N-acetylcysteine. No effects were observed in NQO1-deficient CHO and HL60 cells. In conclusion, we have developed a simple real-time cellular assay for NQO1 and show that PMET plays a significant role in DMNQ redox cycling via NQO1, leading to cellular toxicity in cells with high NQO1 levels. © 2009 Elsevier Inc. All rights reserved.

Hunn M.K.,Malaghan Institute of Medical Research | Hermans I.F.,Victoria University of Wellington
OncoImmunology | Year: 2013

Invariant natural killer T (iNKT) cells have the capacity to amplify adaptive immune responses by licensing antigenpresenting cells. A simple vaccine consisting of whole tumor cells pulsed with an iNKT-cell agonist efficiently delivers antigens plus adjuvants to endogenous dendritic cells and has potential for clinical applications. © 2013 Landes Bioscience.

Tan A.S.,Malaghan Institute of Medical Research | Baty J.W.,Malaghan Institute of Medical Research | Berridge M.V.,Malaghan Institute of Medical Research
Biochimica et Biophysica Acta - General Subjects | Year: 2014

Background Tumor formation and spread via the circulatory and lymphatic drainage systems is associated with metabolic reprogramming that often includes increased glycolytic metabolism relative to mitochondrial energy production. However, cells within a tumor are not identical due to genetic change, clonal evolution and layers of epigenetic reprogramming. In addition, cell hierarchy impinges on metabolic status while tumor cell phenotype and metabolic status will be influenced by the local microenvironment including stromal cells, developing blood and lymphatic vessels and innate and adaptive immune cells. Mitochondrial mutations and changes in mitochondrial electron transport contribute to metabolic remodeling in cancer in ways that are poorly understood. Scope of Review This review concerns the role of mitochondria, mitochondrial mutations and mitochondrial electron transport function in tumorigenesis and metastasis. Major Conclusions It is concluded that mitochondrial electron transport is required for tumor initiation, growth and metastasis. Nevertheless, defects in mitochondrial electron transport that compromise mitochondrial energy metabolism can contribute to tumor formation and spread. These apparently contradictory phenomena can be reconciled by cells in individual tumors in a particular environment adapting dynamically to optimally balance mitochondrial genome changes and bioenergetic status. General Significance Tumors are complex evolving biological systems characterized by genetic and adaptive epigenetic changes. Understanding the complexity of these changes in terms of bioenergetics and metabolic changes will permit the development of better combination anticancer therapies. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. © 2013 Elsevier B.V.

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