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Biomedical subjects

Iain B McInnes

Publications and source records attributed to Iain B McInnes.

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

A novel therapy of murine collagen-induced arthritis with soluble T1/ST2.

Rheumatoid arthritis is characterized by chronic inflammatory infiltration of the synovium, leading to eventual cartilage and bone destruction. Previously, we have reported that soluble T1/ST2 (sST2), a member of the IL-1R gene family, inhibits LPS-induced macrophage proinflammatory cytokine production. In this study, we report the therapeutic effect of sST2-Fc in the murine model of collagen-induced arthritis. A short term administration of sST2-Fc fusion protein significantly attenuated disease severity compared with controls treated with normal IgG. Histological examination revealed that while control IgG-treated mice developed severe cellular infiltration in the joints, synovial hyperplasia, and joint erosion, this pathology was profoundly reduced in sST2-Fc-treated animals. Treatment of sST2-Fc also down-regulated serum levels of IL-6, IL-12, and TNF-alpha. Spleen cells from the sST2-Fc-treated mice produced significantly less IFN-gamma, TNF-alpha, IL-6, and IL-12 compared with cells from the control mice when cultured with collagen in vitro. Finally, pretreatment with ST2-Fc markedly inhibited the ability of human monocytic THP1 cells to release TNF-alpha when cocultured with peripheral blood T cells from rheumatoid patients. Together these results demonstrate that sST2-Fc may provide a novel approach in treating chronic autoimmune conditions by inhibiting the release of proinflammatory cytokines.

Animals↗
PubMed2004

Inducing experimental arthritis and breaking self-tolerance to joint-specific antigens with trackable, ovalbumin-specific T cells.

The importance of T cell Ag specificity and Th1 vs Th2 phenotype in synovial inflammation remains controversial. Using OVA-specific TCR transgenic T cells from DO11.10 mice, we demonstrate that mice receiving Th1, but not Th2, cells display a transient arthritis following immunization that is characterized by synovial hyperplasia, cellular infiltration, and cartilage erosion. OVA-specific T cells also accumulated in inflamed joints, suggesting that they could exert their inflammatory effect locally in the joint or in the draining lymph node. Importantly, this pathology was accompanied by a breakdown in self-tolerance, as evidenced by the induction of collagen-specific T and B cell responses. This model directly demonstrates a pivotal role for Th1 cells of an irrelevant specificity in the development of inflammatory arthritis. Furthermore, the ability to track these cells in vivo will make feasible studies revealing the dynamic role of T cells in arthritis.

Animals↗
PubMed2004

Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial.

BACKGROUND: Rheumatoid arthritis is characterised by inflammatory synovitis, articular destruction, and accelerated atherogenesis. HMG-CoA (3-hydroxy-3-methylglutarylcoenzyme A) reductase inhibitors (statins) mediate clinically significant vascular risk reduction in patients without inflammatory disease and might have immunomodulatory function. We postulated that statins might reduce inflammatory factors in rheumatoid arthritis and modify surrogates for vascular risk. METHODS: 116 patients with rheumatoid arthritis were randomised in a double-blind placebo-controlled trial to receive 40 mg atorvastatin or placebo as an adjunct to existing disease-modifying antirheumatic drug therapy. Patients were followed up over 6 months and disease activity variables and circulating vascular risk factors were measured. Coprimary outcomes were change in disease activity score (DAS28) and proportion meeting EULAR (European League Against Rheumatism) response criteria. Analysis was by intention to treat. FINDINGS: At 6 months, DAS28 improved significantly on atorvastatin (-0.5, 95% CI -0.75 to -0.25) compared with placebo (0.03, -0.23 to 0.28; difference between groups -0.52, 95% CI -0.87 to -0.17, p=0.004). DAS28 EULAR response was achieved in 18 of 58 (31%) patients allocated atorvastatin compared with six of 58 (10%) allocated placebo (odds ratio 3.9, 95% CI 1.42-10.72, p=0.006). C-reactive protein and erythrocyte sedimentation rate declined by 50% and 28%, respectively, relative to placebo (p<0.0001, p=0.005, respectively). Swollen joint count also fell (-2.69 vs -0.53; mean difference -2.16, 95% CI -3.67 to -0.64, p=0.0058). Adverse events occurred with similar frequency in patients allocated atorvastatin and placebo. INTERPRETATION: These data show that statins can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation.

Aged↗
PubMed2004

ES-62, a filarial nematode-derived immunomodulator with anti-inflammatory potential.

Arthropod-transmitted filarial nematodes can survive for in excess of a decade via modulation of the vertebrate host immune system. Although human infection can result in very severe pathology, most infected individuals show remarkably little evidence of this. Analysis of the anti-nematode response indicates that apparently pathology-free individuals have an anti-inflammatory immunological phenotype and it has been suggested that this favours maintenance of host good health. It is considered that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus investigated the properties of a filarial nematode glycoprotein secreted in some abundance, ES-62. This molecule shows a plethora of immunomodulatory activities that can be classified as anti-inflammatory. It has been observed in a number of studies that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are transmitted to humans. Furthermore, it has been speculated that these two observations are linked although molecular explanations for such an association have not been forthcoming. Although the aetiology of RA remains unknown a majority of data are consistent with it being mediated via excess pro-inflammatory cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might be able to counter the pathology associated with diseases like RA. Indeed, we found that exposure to ES-62 prevented initiation of collagen-induced arthritis (CIA) in a murine model and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects correlated with inhibition of TNF-alpha production and inhibition of collagen-specific TH-1 responses. The nematode product was also able to suppress pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus constitutes a pathogen-derived immunomodulator with significant therapeutic potential.

Animals↗
PubMed2004

A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma.

Statins, the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, are effective serum cholesterol-lowering agents in clinical practice, and they may also have anti-inflammatory properties. Asthma is characterized by chronic eosinophilic inflammation in the airways, which is thought to be regulated by the activity of T lymphocytes. We therefore examined the anti-inflammatory activity of simvastatin in a murine model of allergic asthma. In mice previously sensitized to OVA, simvastatin treatment, either orally or i.p., reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid in response to inhaled OVA challenge. Simvastatin therapy i.p. was also associated with a reduction in IL-4 and IL-5 levels in bronchoalveolar lavage fluid and, at higher doses, a histological reduction in inflammatory infiltrates in the lungs. OVA-induced IL-4, IL-5, IL-6, and IFN-gamma secretion was reduced in thoracic lymph node cultures from simvastatin-treated mice. Simvastatin treatment did not alter serum total IgE or OVA-specific IgG1 and IgG2a levels. These data demonstrate the therapeutic potential of statin-sensitive pathways in allergic airways disease.

Administration, Oral↗
PubMed2004

Targeting cytokines beyond tumor necrosis factor-alpha and interleukin-1 in rheumatoid arthritis.

Targeting tumor necrosis factor-a has proven of considerable value in treatment for rheumatoid arthritis, with substantial benefits achieved in a proportion of treated patients. However, a significant number of patients do not achieve sufficient improvement and as a result there remains considerable unmet clinical need. A number of cytokines have recently been described with proinflammatory activity in rheumatoid arthritis synovitis, including interleukin (IL) -6, IL-12, IL-15, and IL-18. We review recent data that support the notion that some or all of these moieties offer therapeutic potential. The possibility that some may be useful in partial responders to tumor necrosis factor blocking agents or in synergy with the latter is discussed.

Adalimumab↗
PubMed2004

Interleukin-15: a new cytokine target for the treatment of inflammatory diseases.

Interleukin (IL)-15 is a pleiotropic pro-inflammatory cytokine that is expressed in several inflammatory disorders, including rheumatoid arthritis, psoriasis and pulmonary inflammatory diseases. IL-15 promotes activation of T cells, neutrophils and macrophages, and is critical to dendritic cell function in several model systems. Recent emerging data suggest that IL-15 may serve as a useful therapeutic target across a range of disease states. Advances in the past year highlight the beneficial effect of IL-15 neutralisation in models of psoriasis and diabetes. Further evidence for IL-15 expression and effector function has emerged across a range of rheumatic disorders, including juvenile inflammatory arthritis, rheumatoid arthritis and Kawasaki disease. These data hold promise for therapeutic targeting in ongoing human studies and those in the near future.

Animals↗
PubMed2004

The anti-inflammatory potential of the filarial nematode secreted product, ES-62.

Filarial nematodes achieve long-term infection via modulation of the host immune system. Although human infection can result in severe pathology, the majority of infected individuals exhibit little evidence of this. Analysis of the immune response during infection indicates that the apparently healthy majority have an anti-inflammatory phenotype and it has been speculated that this may contribute to maintenance of host health. Recent data suggest that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus characterised a major filarial nematode secreted glycoprotein, ES-62. This molecule has been found to possess broad immunomodulatory activities that are in general, anti-inflammatory. It has long been recognised that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are endemic. Furthermore, it has been speculated that these two observations are causally linked. However, molecular explanations for such an association have not been forthcoming. Although the aetiology of RA is unknown most data suggest that it is mediated via a pro-inflammatory immune response associated with excess cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might possess activity against diseases like RA. Indeed we found that subcutaneous injection of ES-62 prevented initiation of collagen-induced arthritis (CIA) and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects were due to inhibition of TNF-alpha production and reversal of collagen specific TH-1 responses. The nematode product was also found to inhibit pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus represents a parasite-derived immunomodulator with significant therapeutic potential.

Anti-Inflammatory Agents↗
PubMed2003

Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis.

There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation-risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.

Arthritis, Rheumatoid↗
PubMed2003

A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62.

Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-alpha, IL-6, and IFN-gamma) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-alpha and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of "tolerance." ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.

Adjuvants, Immunologic↗
PubMed2003

IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4.

IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-alpha induction, which drives the production of leukotriene B(4) (LTB(4)), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB(4) and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB(4) synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB(4) production could also be blocked by a neutralizing anti-TNF-alpha Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55(-/-) mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease severity and reduced articular inflammation and joint destruction. Furthermore, MK-886-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Finally, we showed that IL-18-activated human peripheral blood neutrophils produced significant amounts of LTB(4) that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases.

Adjuvants, Immunologic↗
PubMed2003

A novel anti-inflammatory role for simvastatin in inflammatory arthritis.

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.

Animals↗
PubMed2003

Chemoattraction of human T cells by IL-18.

Cell locomotion is crucial to the induction of an effective immune response. We report here the chemoattraction of CD4(+) T cells by IL-18, a member of the IL-1 cytokine family. Recombinant IL-18 increased the proportion of T cells in polarized morphology in vitro and stimulated their subsequent invasion into collagen gels in an IL-18 concentration gradient-dependent manner. Immunofluorescent microscopy studies determined that the major cell type responding to IL-18 was IL-18R(+)CD4(+). Importantly, synovial CD4(+) T cells from patients with rheumatoid arthritis responded to IL-18, adopting polarized morphology and gel invasion without further activation ex vivo, indicating the physiologic relevance of our observations. Finally, injection of rIL-18 into the footpad of DBA/1 mice led to local accumulation of inflammatory cells. These data therefore demonstrate for the first time lymphocyte chemoattractant properties of a member of the IL-1 cytokine family and its relevance in inflammatory diseases.

Animals↗
PubMed2003

Interleukin-18.

Interleukin-18 (IL-18), a recently described member of the IL-1 cytokine superfamily, is now recognized as an important regulator of innate and acquired immune responses. IL-18 is expressed at sites of chronic inflammation, in autoimmune diseases, in a variety of cancers, and in the context of numerous infectious diseases. This short review will describe the basic biology of IL-18 and thereafter address its potential effector and regulatory role in several human disease states including autoimmunity and infection. IL-18, previously known as interferon-gamma (IFN-gamma)-inducing factor, was identified as an endotoxin-induced serum factor that stimulated IFN-gamma production by murine splenocytes [(1) ]. IL-18 was cloned from a murine liver cell cDNA library generated from animals primed with heat-killed Propionibacterium acnes and subsequently challenged with lipopolysaccharide [(2) ]. Nucleotide sequencing of murine IL-18 predicted a precursor polypeptide of 192 amino acids lacking a conventional signal peptide and a mature protein of 157 amino acids. Subsequent cloning of human IL-18 cDNA revealed 65% homology with murine IL-18 [(3) ] and showed that both contain an unusual leader sequence consisting of 35 amino acids at their N terminus.

Animals↗
PubMed2002

A novel dendritic cell-induced model of erosive inflammatory arthritis: distinct roles for dendritic cells in T cell activation and induction of local inflammation.

Transferring collagen-pulsed, bone marrow-derived dendritic cells (DCs) into congenic DBA/1 recipient mice produced arthritis in joints adjacent to the site of DC transfer and could be inhibited by treatment with TNF antagonists. Disease was Ag specific, as transfer of control, unpulsed DCs, or DCs pulsed with OVA did not produce arthritis. In contrast to other experimental arthritis models, DC-induced arthritis localized to the site of injection and did not spontaneously generalize to uninvolved joints, despite the demonstration of circulating collagen-reactive T cells. Similarly, transfer of T cells primed by collagen/DCs was not sufficient to produce arthritis in recipient mice. In collagen/DC-primed mice however, disease could be induced in uninvolved joints by local administration of noncollagen-pulsed DCs and this could be reduced through TNF inhibition. Similarly, injection of collagen/DC-primed mice with low-dose TNF also resulted in local induction of arthritis, as did administration of TNF to mice receiving T cells from collagen/DC but not OVA/DC-primed mice. Thus, we have demonstrated for the first time that administration of collagen-pulsed mature DCs is sufficient for the induction of arthritis. Furthermore, this disease process is mediated through both adaptive and innate effects of DCs; first, priming of autoreactive T cells and, second, induction of local inflammation via mediators such as TNF.

Animals↗
PubMed2002

Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice.

Lactoferrin (Lf) is an iron-binding protein of external secretions and neutrophil secondary granules with antimicrobial and immunomodulatory activities. To further define these properties of Lf, we have investigated the response to Staphylococcus aureus infection in transgenic mice carrying a functional human Lf gene. The transgenic mice cleared bacteria significantly better than congenic littermates, associated with a trend to reduced incidence of arthritis, septicemia, and mortality. We identified two pathways by which S. aureus clearance was enhanced. First, human Lf directly inhibited the growth of S. aureus LS-1 in vitro. Second, S. aureus-infected transgenic mice exhibited enhanced Th1 immune polarization. Thus, spleen cells from infected transgenic mice produced higher levels of TNF-alpha and IFN-gamma and less IL-5 and IL-10 upon stimulation ex vivo with the exotoxin toxic shock syndrome toxin-1 compared with congenic controls. To confirm that these effects of Lf transgene expression could occur in the absence of live bacterial infection, we also showed that Lf-transgenic DBA/1 mice exhibited enhanced severity of collagen-induced arthritis, an established model of Th1-induced articular inflammation. Higher levels of stainable iron in the spleens of transgenic mice correlated with human Lf distribution, but all other parameters of iron metabolism did not differ between transgenic mice and wild-type littermates. These results demonstrate that human Lf can mediate both antimicrobial and immunomodulatory activities with downstream effects on the outcome of immune pathology in infectious and inflammatory disease.

Adjuvants, Immunologic↗
PubMed2002

The role of innate mediators in inflammatory response.

Cytokines produced by innate immune response can profoundly influence the subsequent adaptive immunity. IL-15 and -18 are two of several mediators produced by macrophages that perform such a function. Here we present recent data mainly from our own laboratory illustrating the important role of IL-15 and -18 in the induction and perpetuation of chronic inflammation during experimental and clinical rheumatoid synovitis.

Animals↗