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Biomedical subjects

Iain B McInnes

Publications and source records attributed to Iain B McInnes.

At least 19 recordsLinked to original sources
PubMed2007

Interleukin-18 as a potential therapeutic target in chronic autoimmune/inflammatory conditions.

Interleukin-18 (IL-18), a recently identified immunoregulatory and inflammatory cytokine, has attracted a profound interest as a potential therapeutic target in autoimmune/inflammatory disorders. In this review the authors focus on: IL-18 biology as an important link between innate and adaptive immunity; evidence of its pro-inflammatory role in several human autoimmune and chronic inflammatory disorders; and data indicating that IL-18 blockade in animal models results in prevention/amelioration of the disease process and preservation of the target tissue integrity and function. Finally, the authors analyse strategies presently under development to block IL-18 function and potential pitfalls resulting from IL-18 blockade that should be considered in ongoing/future clinical trials.

Animals↗
PubMed2006

Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study.

BACKGROUND: Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. AIM: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP. METHODS: A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS. RESULTS: At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy. CONCLUSIONS: In this "true-to-life" study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies.

Adolescent↗
PubMed2006

Expression and alternative processing of IL-18 in human neutrophils.

Interleukin-18 (IL-18), a member of the IL-1 cytokine superfamily, is an important regulator of both innate and acquired immune responses. We demonstrate here constitutive expression of IL-18 by human neutrophils. Unexpectedly, we observed that neutrophils from peripheral blood or rheumatoid synovial compartments contained not only pro and mature IL-18, but also several novel smaller-molecular-weight IL-18-derived species. Using specific protease inhibitors, and serine protease gene-targeted mice, we demonstrate that these IL-18-derived products arose through caspase-independent cleavage events mediated by the serine proteases, elastase and cathepsin G. Moreover, we report that the net effect of elastase treatment of mature recombinant IL-18 was to reduce its IFN-gamma-inducing activity. Thus, human neutrophils contain IL-18 and IL-18-derived molecular species that can arise through novel enzymatic processing pathways. Through cytosolic, membrane or secretory expression of such processing enzymes, together with generation of IL-18 itself, neutrophils likely play a critical role in regulating IL-18 activities during early innate immune responses.

Animals↗
PubMed2006

New cytokine targets in inflammatory rheumatic diseases.

With the advent of biological therapies, considerable advances have been achieved in the treatment of inflammatory arthritis. These have arisen primarily from studies elucidating mechanisms of pathophysiology and are best exemplified in the wide use of tumour necrosis factor (TNF) blockade in several rheumatic diseases. The identification of additional pro-inflammatory factors in rheumatic diseases and an understanding of their effector function, now offers major possibilities for the generation of novel therapeutics. To address unmet clinical need, such interventions will ideally fulfil several of the following criteria: (1) control of inflammation, (2) modulation of underlying immune dysfunction - promoting the re-establishment of immune tolerance, (3) protection of targeted tissues such as bone and cartilage - this should encompass promoting healing of previously damaged tissues, (4) preservation of host immune capability - to avoid profound immune suppression and (5) amelioration of co-morbidity associated with underlying inflammatory arthritis. This short review will consider those novel cytokine activities that represent optimal utility as therapeutic targets. Since we wish to reflect the current predominant research effort, we will focus primarily on rheumatoid arthritis (RA) based studies.

Animals↗
PubMed2006

Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis.

Dendritic cells (DCs) comprise heterogeneous subsets of professional antigen-presenting cells, linking innate and adaptive immunity. Analysis of DC subsets has been hampered by a lack of specific DC markers and reliable quantitation assays. We characterised the immunophenotype and functional characteristics of psoriatic arthritis (PsA)-derived and rheumatoid arthritis (RA)-derived myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to evaluate their potential role in arthritis. Circulating peripheral blood (PB) pDC numbers were significantly reduced in PsA patients (P = 0.0098) and RA patients (P = 0.0194), and mDCs were significantly reduced in RA patients (P = 0.0086) compared with healthy controls. The number of circulating mDCs in RA PB was significantly inversely correlated to C-reactive protein (P = 0.021). The phenotype of both DC subsets in PsA PB and RA PB was immature as compared with healthy controls. Moreover, CD62L expression was significantly decreased on both mDCs (PsA, P = 0.0122; RA, P = 0.0371) and pDCs (PsA, P = 0.0373; RA, P = 0.0367) in PB. Both mDCs and pDCs were present in PsA synovial fluid (SF) and RA SF, with the mDC:pDC ratio significantly exceeding that in matched PB (PsA SF, P = 0.0453; RA SF, P = 0.0082). pDCs isolated from RA SF and PsA SF displayed an immature phenotype comparable with PB pDCs. RA and PsA SF mDCs, however, displayed a more mature phenotype (increased expression of CD80, CD83 and CD86) compared with PB mDCs. Functional analysis revealed that both SF DC subsets matured following toll-like receptor stimulation. pDCs from PB and SF produced interferon alpha and tumour necrosis factor alpha on TLR9 stimulation, but only SF pDCs produced IL-10. Similarly, mDCs from PB and SF produced similar tumour necrosis factor alpha levels to TLR2 agonism, whereas SF mDCs produced more IL-10 than PB controls. Circulating DC subset numbers are reduced in RA PB and PsA PB with reduced CD62L expression. Maturation is incomplete in the inflamed synovial compartment. Immature DCs in SF may contribute to the perpetuation of inflammation via sampling of the inflamed synovial environment, and in situ presentation of arthritogenic antigen.

Arthritis, Psoriatic↗
PubMed2005

Inhibition of neutrophil function by the Kaposi's sarcoma-associated herpesvirus vOX2 protein.

Kaposi's sarcoma is multifactorial, involving Kaposi's sarcoma-associated herpesvirus (KSHV) infection and immune dysfunction. A KSHV protein (vOX2), fused with the Fc domain of human immunoglobulin G1 to create vOX2:Fc, suppressed neutrophil oxidative burst and inhibited the production of pro-inflammatory chemokines (IL-8 and monocyte chemoattractant protein 1) by monocyte/macrophage cells. vOX2:Fc suppressed the acute inflammatory response in mice in which neutrophil-mediated inflammation was induced by carrageenan. The data suggest that vOX2 can contribute to immune dysfunction and could have anti-inflammatory therapeutic potential.

Animals↗
PubMed2005

Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?

Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.

Animals↗
PubMed2005

Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study.

OBJECTIVE: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA. METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study. RESULTS: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%). CONCLUSION: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.

Adult↗
PubMed2005

Prior elevation of IL-18 promotes rapid early IFN-gamma production during staphylococcal infection.

Systemic Staphylococcus aureus infection is associated with significant morbidity and mortality arising from both bacterial and host immune factors. IL-18 is a pro-inflammatory cytokine of the IL-1 superfamily that exhibits broad functional effects in innate and acquired immune responses and which has been found in high levels in several chronic inflammatory and autoimmune diseases. Over-expression of IL-18 may promote early resolution of infection or could promote a detrimental exaggerated immune response. This was explored in a model of S. aureus infection. We report increased mortality in Swiss mice that were given recombinant IL-18 prior to inoculation with S. aureus LS-1. IL-18 administration prior to infection induced preferentially enhanced IFN-gamma mRNA expression in peripheral blood leukocytes and spleen, especially splenic NK cells. This correlated with increased IFN-gamma protein detection in serum, and leukocyte and spleen cultures at subsequent discrete time points. These data suggest that increased mortality following gram-positive infection in autoimmune diseases could in part reflect the impact of high levels of pleiotropic pro-inflammatory cytokines such as IL-18 present prior to the onset of infection.

Animals↗
PubMed2005

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.

Arthritis, Rheumatoid↗
PubMed2005

TNF-blocking therapies: an alternative mode of action?

Despite expanding use of drugs blocking tumour necrosis factor (TNF), their precise mechanisms of action remain unclear. Early assumptions that they act by direct neutralization of the toxic inflammatory effects of TNF might be too simplistic because they explain neither the range of effects observed nor the varying properties of different TNF-blocking agents. Recent studies have demonstrated a key role for mast cell-derived TNF in the increase in lymph node size and the organizational complexity that accompanies a developing immune response. Regulation of this phenomenon might comprise a novel mode of action for TNF-directed therapy: by preventing this lymph node hyperplasia, TNF blockade could modulate immune responses, ameliorating pathology in autoimmune diseases, such as rheumatoid arthritis.

Antirheumatic Agents↗
PubMed2005

Cytokine networks--towards new therapies for rheumatoid arthritis.

Success achieved so far in the blockade of tumor necrosis factor and interleukin (IL)-1 in rheumatoid arthritis exemplifies the feasibility and potential therapeutic application of antagonizing cytokine signaling. Despite these advances, there remains a considerable unmet clinical need in this field. A number of preclinical development programs are ongoing to target a variety of cytokines that are central to immune regulation and tissue-matrix destruction in rheumatoid arthritis. Evidence indicates that IL-6 antagonists might represents a useful approach and preliminary data similarly identify IL-15 as an intriguing target. Numerous additional cytokines are under investigation at the preclinical stage, including IL-12-IL-23, IL-17 and IL-18. As therapeutic goals move from disease control towards remission induction, development of the capacity for cytokine targeting to modify the underlying immune dysregulation remains a major priority.

Antirheumatic Agents↗
PubMed2005

Vascular comorbidity in rheumatoid arthritis: potential mechanisms and solutions.

PURPOSE OF REVIEW: To summarise recent evidence for elevated risk of coronary heart disease (CHD) in rheumatoid arthritis (RA) and explore explanatory mechanisms and modalities that may lessen such risk. RECENT FINDINGS: Evidence for elevated CHD risk in RA is convincing. On current estimates, individuals who have had RA for several years have around a twofold higher risk for CHD compared with non-RA persons after taking account of most traditional risk factors. Such excess risk appears to be driven by systemic inflammation both directly via its deleterious effects on blood vessels (endothelial dysfunction inclusive of myocardial microvascular abnormalities) and indirectly by its accentuation of multiple risk pathways including lipid abnormalities. Established therapies that lessen RA disease activity and systemic inflammation will likely lessen CHD risk, although there remains considerable scope for more robust studies employing better measures of vascular disease (e.g., carotid intima-media thickening). Other emerging evidence indicates statins may have dual effects in RA, with a modest disease-modifying effect (requiring confirmation) and significant lipid-lowering action. The latter finding is particularly important because extrapolation of data from all statin endpoint trials suggests that the extent of low-density lipoprotein cholesterol reduction may account for most statin clinical benefit. SUMMARY: Systemic inflammation is the major driver for excess vascular comorbidity in RA. Controlling systemic inflammation should lessen vascular risk but complete, long-term suppression of articular inflammation is rarely achieved. Thus, the use of conventional CHD risk reduction strategies, in particular statins, should be considered in patients with RA with prevalent CHD or at elevated risk.

Arthritis, Rheumatoid↗
PubMed2005

Synovial tissue analysis in clinical trials.

Synovial tissue analysis has considerable potential for future randomized controlled trials (RCT). The synovial membrane is the target tissue in treatment strategies of rheumatoid arthritis and other arthropathies. Effective modulation of synovitis is critical when attempting to control symptoms and signs, to prevent joint damage, and to maintain function. In RCT, the systematic evaluation of changes in synovial tissue after commencing treatment enables identification of an early therapeutic effect, using relatively small numbers of patients. This special interest group is working on establishing the evidence to have this endpoint meet the OMERACT filter criteria.

Antirheumatic Agents↗
PubMed2004

Interleukin-18: a therapeutic target in rheumatoid arthritis?

Interleukin 18 (IL-18), a member of the IL-1 superfamily of cytokines has been demonstrated to be an important mediator of both innate and adaptive immune responses. Several reports have implicated its role in the pathogenesis of rheumatoid arthritis (RA). Although biologic therapy is firmly established in the treatment of a number of inflammatory diseases including RA, partial and non-responder patients constitute residual unmet clinical need. The aim of this article is to briefly review the biology of, and experimental approaches to IL-18 neutralisation, together with speculation as to the relative merits of IL-18 as an alternative to existing targets.

Animals↗
PubMed2004

Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjögren's syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate.

IL-18, an immunoregulatory and proinflammatory cytokine, has been shown to play an important pathogenic role in Th1-driven autoimmune disorders. In this study, we evaluated the circulating levels and salivary-gland expression of IL-18 in patients with Sjögren's syndrome (SS), a mainly Th1-mediated disease. IL-18 serum levels were measured by ELISA in 37 patients with primary SS, 42 with rheumatoid arthritis, and 21 normal controls. We demonstrated high IL-18 serum levels in SS, similar to those in rheumatoid arthritis patients and significantly higher than in controls (P < 0.01). In addition, IL-18 serum concentrations were significantly higher in anti-SSA/Ro+ and anti-SSB/La+ than in anti-SSA/Ro- and anti-SSB/La- SS patients (respectively, P = 0.01, P < 0.01). Serum IL-18 correlated strongly with anti-SSA/Ro (P = 0.004) and anti-SSB/La (P = 0.01) titers. Salivary gland IL-18 expression was investigated by single/double immunohistochemistry in 13 patients with primary SS and in 10 with chronic sialoadenitis, used as controls. The expression of IL-18 was also examined in periductal inflammatory foci in relation to the acquisition of features of secondary lymphoid organs such as T-B compartmentalization, formation of follicular dendritic cell networks, and presence of germinal-center-like structures. IL-18 expression in SS salivary glands was detected in 28 of 32 periductal foci of mononuclear cells (87.5%), while no IL-18 production by infiltrating cells was detected in patients with chronic sialoadenitis. Within the inflammatory foci, IL-18 immunoreactivity co-localized almost exclusively with CD68+ macrophages. In addition, IL-18 was found in 15 of 19 foci (78.9%) with no evidence of T-B cell compartmentalization (nonsegregated) but in 100% of the segregated aggregates, both in T- and B-cell-rich areas. Strikingly, IL-18 was strongly expressed by CD68+ tingible body macrophages in germinal-centre-like structures both in SS salivary glands and in normal lymph nodes. IL-18 expression was observed in the ducts of all SS biopsies but in only 4 of 10 patients with nonspecific chronic sialoadenitis (P < 0.01). This study provides the first evidence of increased circulating levels and salivary gland expression of IL-18 in SS, suggesting an important contribution of this cytokine to the modulation of immune inflammatory pathways in this condition.

Adult↗
PubMed2004

Abnormal cytokine levels in non-pregnant women with a history of recurrent miscarriage.

OBJECTIVE: To compare cytokine levels in serum from non-pregnant women with a history of recurrent miscarriage with those found in non-pregnant women with no such history. STUDY DESIGN: Two patient groups were enrolled into the study. Group 1 comprised 25 non-pregnant women with no history of recurrent miscarriage. Group 2 comprised 50 non-pregnant women who had a history of at least three previous miscarriages. Fifteen of these women have since become pregnant again--10 had a successful pregnancy and five miscarried. Serum levels of IL-4, IFN gamma, IL-12 and IL-18 were measured. RESULTS: Results showed IFN gamma ( 0.68 +/- 0.72 versus 0.45 +/- 0.29 P < 0.05) and IL-12 levels (66 +/- 25 versus 51 +/- 24 P < 0.05) were significantly higher in Group 2 compared to Group 1. Levels of IL-18 were significantly lower in Group 2 patients (318 +/- 140 versus 246 +/- 219 P < 0.05). Of the 15 women who became pregnant, those who miscarried again had significantly higher IL-18 levels when not pregnant than those women whose next pregnancies went successfully to term (547 +/- 20 versus 274 +/- 129 P < 0.05). CONCLUSION: These results suggest that women with a history of recurrent miscarriage can have abnormal cytokine expression even when not pregnant. This may influence the potential for future successful immune modulatory therapy.

Abortion, Habitual↗