On the combined effect of statins and lycopene on cytokine production by human peripheral blood cells

Since both statins and lycopene exert immunomodulatory activities following incubation with human peripheral blood mononuclear cells (PBMC), the present work was designed to examine whether they may induce a synergistic or antagonistic effect on cytokine production while applied together. Peripheral blood mononuclear cells isolated from 15 healthy subjects were incubated for 24 h as follows: (1) without and with 0.125 or 0.25 μM lycopene, (2) without and with 10 or 50 mM pravastatin or simvastatin, and (3) with lycopene and with one of the statins together at the respective doses. The production of the following cytokines was assessed: interleukin (IL)-1β, IL-1ra, IL-2, and IL-10, as well as tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). The results showed that lycopene and simvastatin applied together reduced TNFα and IFNγ secretion, and abolished the increased production of the proinflammatory cytokine IL-1γ caused by incubation with simvastatin only, an observation suggesting that simultaneous administration of both substances may reduce inflammatory responses.     

Effect of stimulation by interferonγ and tumor necrosis factorα on CD54 expression and homotypic aggregation of blasts of acute lymphoblastic leukemias

 CD54 (intercellular adhesion molecule-1, ICAM-1) surface expression on the blasts in ten cases of acute lymphoblastic leukemia (ALL) and its up-regulation by human recombinant interferon-γ (IFNγ) and/or tumor necrosis factor-α (TNFα) were studied in a serum-free culture system. In addition, the function of CD54 was assessed by a cellular aggregation assay. Prior to in vitro culture, only 3/10 ALL cases had more than 20% CD54-positive blasts. A 24-h incubation in serum-free medium alone induced CD54 positivity in another two cases. In these two ALLs, stimulation with IFNγ and/or TNFα further enhanced CD54 positivity. In addition, TNFα induced CD54 expression in one further case. In the remaining four cases no CD54 expression was induced by either cytokine. Of the six cases with constitutive or inducible CD54 expression, only five displayed CD54-dependent cellular aggregation. Taken together, the ALLs studied were heterogeneous with respect to their constitutive and cytokine-driven CD54 expression, while TNFα seemed to be more effective than IFNγ. In most cases, the CD54 molecule was functionally active, in that CD54 expression was paralleled by CD54-dependent homotypic aggregation of the blasts. Received: 25 August 1997 / Accepted: 10 October 1997     

The biology and biochemistry of interferon-gamma and its receptor

Interferon-gamma (IFNγ) is an important immunomodulatory cytokine produced by activated T cells and NK cells that plays a pivotal role in promoting host defense. IFNγ is distinguished from IFNα and IFNβ by its ability to regulate a number of immune functions. IFNγ induces its biologic effects by interacting with a specific IFNγ receptor expressed at the cell surface. Recently, IFNγ receptors have been purified from human and murine cells and their cDNAs cloned and expressed. This work has revealed that IFNγ receptors are 90 kDa, single chain glycoproteins that bind ligand with high affinity in a species specific manner. There appears to be only a single type of IFNγ receptor that is expressed on nearly all cell types. Whereas this single polypeptide is sufficient to confer ligand binding and processing activity to transfected cells, a second, as yet undefined, component is required to form a functionally active IFNγ receptor. The identity of this second component is currently being investigated. In addition, recent work has revealed novel structure-function relationships that exist within the IFNγ receptor’s intracellular domain. This work has shown that distinct portions of the intracellular domain are differentially responsible for mediating different biologic activities of the receptor.     

Epidemiology of spondyloarthritis in North America

Many challenges have made it difficult to determine the prevalence of spondyloarthritis (SpA) in North America. They include the ethnic heterogeneity of the population, the lack of feasibility of applying current criteria (such as requirements for human leukocyte antigen-B27 testing and imaging studies such as pelvic radiographs and magnetic resonance imaging scanning) and the transient nature of some SpA symptoms (ie, peripheral arthritis and enthesitis). Current estimates of the prevalence of SpA in the United States range between 0.2% and 0.5% for ankylosing spondylitis, 0.1% for psoriatic arthritis, 0.065% for enteropathic peripheral arthritis, between 0.05% and 0.25% for enteropathic axial arthritis and an overall prevalence of SpA as high as >1%. With newer population-based instruments becoming available, the availability of the widely validated European Spondyloarthropathy Study Group criteria and the lower cost and greater feasibility of genetic testing, opportunities for true population-based studies of SpA are possible and will likely soon ensue.     

HMG-CoA Reductase Inhibitors (Statins) Activate Expression of PPARα/PPARγ and ABCA1 in Cultured Gallbladder Epithelial Cells

In gallbladder epithelial cells (GBEC), PPARα and PPARγ ligands modulate inflammation by suppression of TNFα production and prevent excessive accumulation of cholesterol by ABCA1 activation. Recently, HMG-CoA reductase inhibitors (statins) were shown to activate PPARα and PPARγ in various cells but no studies of their effects in GBEC have been conducted. The objective of this study was, therefore, to determine the effects of statins on PPAR and ABCA1 expression and the anti-inflammatory effect of statins in GBEC. Canine GBEC were cultured on Petri dishes. Expression of the proteins PPARα, PPARγ, and ABCA1 was measured by western blotting analysis after treatment with simvastatin, pravastatin, NO-pravastatin, PPARα ligand, or PPARγ ligand in the culture media. Expression of ABCA1 and LXRα mRNAs was estimated by RT-PCR. Expression of TNFα mRNA was measured by RT-PCR after 24 h pre-treatment with the statins, preceding 1 h of lipopolysaccharide (LPS) loading. Simvastatin, pravastatin, and NO-pravastatin increased expression of the proteins PPARα, PPARγ, and ABCA1, and expression of the mRNA of ABCA1 and LXRα in GBEC. Pre-treatment with simvastatin, pravastatin, and NO-pravastatin suppressed the production of TNFα mRNA induced by LPS. In conclusion, statins probably contribute to the preservation of GBEC function by activation of PPARα and PPARγ, which have anti-inflammatory effects by suppression of pro-inflammatory cytokines, and ABCA1 activation mediated by LXRα, which prevents the accumulation of cholesterol in GBEC.     

Immunological predictors of different responses to combination therapy with interferon α and ribavirin in patients with chronic hepatitis C

Background: This study aimed to investigate peripheral blood CD4+ T-helper (Th) and CD8+ cytotoxic T-lymphocyte (CTL) responses to combination treatment with interferon (IFN) α and ribavirin in 59 patients with chronic hepatitis C, and to correlate the results with the therapy outcome. Methods: The expression of activation molecules on the surface of CD8+ T cells and cytokine production by in-vitro activated CTLs and Th lymphocytes were examined before and at the end of the therapy, using flow cytometry. Results: There were 36 complete responders to the treatment and 23 transient responders who relapsed after withdrawal of the therapy. A significant increase in the production of Th1-type cytokines [IFNγ, interleukin 2 (IL2), and tumor necrosis factor-α (TNFα)] was found at the end of the treatment in complete responders compared with baseline values (P < 0.001). In contrast, transient responders had a marked decrease in the percentage of activated CD8+ T cells expressing CD28 or HLA-DR costimulatory molecules in peripheral blood, and a lower production of TNFα by CTLs and Th cells at the end of the therapy with respect to pretreatment values (P < 0.001). Conclusions: The efficacy of IFNα and ribavirin combination therapy for chronic hepatitis C is associated with a vigorous response of peripheral blood Th1 cells, whereas weak CTL responses at the end of the therapy might predict a further relapse of the disease. Received: March 26, 2002 / Accepted: August 30, 2002 Acknowledgments. This work was supported by grants MZd CzR 5740-3, 6015-3/00. Reprint requests to: R. Amaraa Editorial on page 302     

Lupus patients with pulmonary involvement have a pro-inflammatory cytokines profile

Objectives The literature on cytokine response in systemic lupus erythematosus (SLE) is confusing. It is possible that different disease phenotypes have different cytokine profiles. Our aim was to examine the levels of selected pro-inflammatory and anti-inflammatory cytokines in SLE patients with and without pulmonary involvement. Methods and subjects Patients with SLE were interviewed and were subjected to the pulmonary function test and high-resolution computed tomography studies. Serum levels of interleukin (IL)-6, IL-8, IL-10, Il-12, interferon (IFN) γ, and tumor necrosis factor (TNF) α were estimated by enzyme-linked immunosorbent assay. Results Forty-nine of the 61 SLE patients had pulmonary involvement. Median levels of IL-8, IFNγ, and TNFα were significantly higher in the pulmonary group as compared to the non-pulmonary group (p = 0.027, 0.027 and 0.002, respectively). Ratios of pro-inflammatory cytokines to anti-inflammatory cytokines were higher in the pulmonary group as compared to the non-pulmonary group as well as in the pulmonary restrictive subgroup compared to the obstructive subgroup. Conclusion Lupus patients with pulmonary involvement have a stronger pro-inflammatory cytokine bias than those without pulmonary involvement.     

Advances in the understanding of entheseal inflammation

The importance of enthesitis in the pathogenesis of spondyloarthropathy (SpA) is now well recognized. Several entheses comprise more than simply the insertion site, and they are part of a complex biomechanical organ to resist shear and compression. It is also evident that tendons that wrap around bony pulleys form an integral part of joint capsules, and share, along with imaging abnormalities and histopathologic changes, common anatomic, histologic, and biomechanical features with classically defined entheses. Researchers have called these regions of tendons functional entheses. Furthermore, certain synovial joints have much in common with classic entheses—most notably those lined with fibrocartilage rather than hyaline cartilage. These observations provide a unifying anatomic basis for SpA. Enthesitis is associated with underlying osteitis, whether mechanically induced or inflammatory-related—with the extent of osteitis determined by the human leukocyte antigen-B27 gene. Until recently, there was no effective therapy for resistant enthesitis, but it is now evident that enthesitis responds well to biologic blockade with anti-tumor necrosis factor. Unraveling the pathogenic basis of enthesitis will have important implications for understanding and defining therapies in SpA.     

Animal models of ankylosing spondylitis

The pathology of ankylosing spondylitis (AS) and related spondyloarthropathies (SpA) characteristically involve a sacroiliitis and inflammation of the intervertebral discs (IVD) in the lumbar spine, and an enthesitis at sites of ligamentous insertions into bone. The proteoglycans aggrecan and versican are large molecules that aggregate with hyaluronic via a globular 1 domain. These domains share significant homology at the level of B and T cell epitope recognition. Both proteoglycans are present in the intervertebral disc and hyaline cartilages of the sacroiliac joint, as well as in entheses. Whereas aggrecan is most concentrated in the nucleus of the IVD and in articular cartilages and endplates, versican is generally absent from these tissues except in the sacroiliac joint, but is concentrated in ligaments and the annulus. Immunity to these molecules in BALB/c mice results in an AS-like pathology, including sacroiliitis, enthesitis, and discitis. The pathology of AS is closely associated with the expression of the class I molecule human leukocyte antigen-B27. Rats bearing this transgene develop an AS-like pathology, as well as other various signs of autoimmunity. Ankylosing spondylitis is characterized by an ankylosing pathology whereby bone formation in the annulus leads to intervertebral fusion. Mice bearing the ank/ank defect gene develop a bony ankylosis of the spine like that seen in advanced AS and related SpA. These three animal models provide insight into the pathogenesis of SpA, and opportunities to investigate their pathology in relationship to human disease where investigation of the pathobiology is very difficult, because of restricted access to involved tissues.     

IFNγ/TNFα synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis

Aims/hypothesis: Interferon-γ (IFNγ) and TNFα synergistically induce pancreatic beta-cell apoptosis. Apart from their direct effect, we studied the possible indirect immunological role of IFNγ/TNFα synergism on pancreatic beta-cell death by investigating MHC class II induction by cytokines. The effect of nicotinamide on the cytokine-induced MHC class II expression and pancreatic beta-cell death was also studied. Methods: Immunocytochemistry, flow cytometry and RNase protection assay were used to study MHC class II expression. Immunoblotting was done to study downstream signals of IFNγ. The effects of nicotinamide on islet-cell apoptosis and diabetes mellitus were examined using MTT assay and adoptive transfer model. Results: IFNγ alone induced MHC class II expression on a small number of insulinoma cells. TNFα alone did not induce MHC class II expression, but enhanced IFNγ-induced MHC class II expression. MHC class II expression by cytokine(s) was due to the induction of class II transactivator (CIITA). Nicotinamide reduced MHC class II expression by cytokine(s) but did not protect insulinoma-cell apoptosis by IFNγ and TNFα in combination or protect against the development of diabetes mellitus after adoptive transfer of diabetogenic lymphocytes. Conclusion/interpretation: IFNγ and TNFα synergistically induced MHC class II expression on insulinoma cells through the induction of CIITA; nicotinamide reduced the expression of cytokine-induced MHC class II expression on insulinoma cells through its effect on CIITA expression; and the preventive effect of nicotimamide on Type I (insulin-dependent) diabetes mellitus is probably due to its effect of MHC class II expression rather than that on islet cell apoptosis. [Diabetologia (2002) 45: 385–393] Received: 13 August 2001 and in revised form: 22 October 2001     

Berberine inhibits the expression of TNFα, MCP-1, and IL-6 in AcLDL-stimulated macrophages through PPARγ pathway

Macrophages are the main source of cytokines in atherosclerotic plaques. Modified low-density lipoproteins may stimulate macrophages to produce large quantities of proinflammatory cytokines that promote atherosclerosis. Berberine is the main component of the traditional Chinese medicine umbellatine, which has a widespread effect and was used to treat many diseases clinically. Our previous study found that berberine could increase adipophilin expression in macrophages, which is a target gene of PPARγ. PPARγ agonist could decrease proinflammatory cytokines in macrophage. In this study, we investigated the effects and the mechanism of action of berberine on the expression and secretion of TNFα, MCP-1, and IL-6 in vitro to identify new pharmacological actions of berberine. The results of RT-PCR and ELISA shows that berberine may inhibit the expression and secretion of the tumor necrosis factor α (TNFα), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6) in macrophages stimulated by acetylated low-density lipoprotein (AcLDL), whereas the peroxisome proliferator-activated receptor γ (PPARγ) inhibitor GW9662 could attenuate this effect of berberine. This study demonstrates that berberine may inhibit the expression and production of TNF-α, MCP-1, and IL-6 in AcLDL-stimulated macrophages. This effect might be partially mediated through PPARγ activity.     

Seronegative spondyloarthropathy-associated inflammatory bowel disease

Seronegative spondyloarthropathy (SpA) usually starts in the third decade of life with negative rheumatoid factor, human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis, dactylitis, enthesitis and extra-articular manifestations (EAMs). Cases can be classified as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, or juvenile-onset spondyloarthritis. Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease (IBD), with shared genetic and immunopathogenic mechanisms. IBD is a common EAM in SpA patients, while extraintestinal manifestations in IBD patients mostly affect the joints. Although individual protocols are available for the management of each disease, the standard therapeutic guidelines of SpA-associated IBD patients remain to be established. Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA, whereas their use is controversial in IBD due to associated disease flares. Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy. Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD, and a drug of choice for treating SpA-associated IBD. Janus kinase inhibitors, approved for treating SpA and ulcerative colitis, are promising therapeutics in SpA coexistent with ulcerative colitis. A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.     

Patient demographics and disease variables correlate with distinct cytokine patterns in mitogen-stimulated peripheral blood mononuclear cells from rheumatoid arthritis patients

There is paucity of literature on the association of peripheral blood cytokine patterns with patient demographics and disease variables in rheumatoid arthritis (RA). We test the hypothesis that there may be differences in peripheral blood levels of inflammatory cytokines in RA subjects according to various disease variables. In this case, we could identify peripheral blood cytokine markers that correlate with different disease variables. Forty-two seropositive RA patients were characterized according to the age at onset, gender, disease duration, severity, activity and ACR functional class. The production levels in mitogen-stimulated PBMCs of five pro-inflammatory cytokines (IFNγ, TNFα, TNFβ, IL-8, IL-18) and three anti-inflammatory cytokines (IL-4, IL-10, IL-13) were evaluated in these patients and in healthy controls. Several new findings emerge: (1) higher levels of IL-4 correlate with female gender, milder disease, non-erosive disease, and earlier age at onset; (2) higher levels of IL-10 correlate with the requirement of ≤2 DMARDs; (3) higher levels of IL-18 correlate with non-erosive disease and younger age at onset; (4) higher TNFβ levels correlate with older present age of patients; and (5) higher IL-8 levels correlate with established/late disease. There are several interesting differences in cytokine patterns with respect to age at onset, current age, disease severity, and the number of DMARDs the patients require.     

Biology of TNFα and IL-10, and their imbalance in heart failure

Our understanding of the multiple in vivo functions of the proinflammatory cytokine, tumor necrosis factor (TNFα), is advancing at a rapid pace. In addition to its antitumor effects, overproduction of TNFα provokes tissue injury and organ failure. TNFα has also been shown to be cardiodepressent and responsible for various cardiovascular complications. It appears that still much needs to be learned for a full comprehension of the role of TNFα in heart biology. Another cytokine, interleukin-10 (IL-10), has been shown to have anti-inflammatory properties. It is suggested to counterbalance many adverse effects of TNFα. IL-10 suppresses the production of TNFα and many other proinflammatory cytokines. TNFα-induced oxidative stress is also known to be mitigated by IL-10. Moreover, improvement in cardiac function after treatment with various drugs is also shown to be associated with an increase in IL-10 content. Based on the data reviewed in here, it is suggested that an optimal balance between IL-10 and TNFα may be a new therapeutic strategy for a healthier heart.     

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

Aims/hypothesis The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1β and IFNγ, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFκB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of pro-apoptotic genes. NFκB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. Materials and methods The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1β and IFNγ. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFκB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. Results HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1β induced a bi-phasic phosphorylation of inhibitor protein kappa Bα (IκBα) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IκBα degradation and NFκB DNA binding. Conclusions/interpretation HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFκB transactivating activity.     

Current issues in pediatric inflammatory bowel diseaseassociated arthropathies

Joint involvement is the most common extraintestinal manifestation in children with inflammatory bowel disease(IBD)and may involve 16%-33%of patients at diagnosis or during follow-up.It is possible to distinguish asymmetrical,transitory and migrating arthritis(pauciarticular and polyarticular)and spondyloarthropathy(SpA).Clinical manifestations can be variable,and peripheral arthritis often occurs before gastrointestinal symptoms develop.The inflammatory intestinal pattern is variable,ranging from sub-clinical inflammation conditions,classified as indeterminate colitis and nodular lymphoid hyperplasia of the ileum,to Crohn’s disease or ulcerative colitis.Unlike the axial form,there is an association between gut inflammation and evolution of recurrent peripheral articular disease that coincides with a flare-up of intestinal disease.This finding seems to confirm a key role of intestinal inflammation in the pathogenesis of SpA.An association between genetic background and human leukocyte antigen-B27 status is less common in pediatric than n adult populations.Seronegative sacroiliitis and SpA are the most frequent forms of arthropathy in children with IBD.In pediatric patients,a correct therapeutic approach relies on the use of nonsteroidal antiinflammatory drugs,local steroid injections,physiotherapy and anti-tumor necrosis factor therapy(infliximab).Early diagnosis of these manifestations reduces the risk of progression and complications,and as well as increasing the efficacy of the therapy.     

Gut inflammation and microbiome in spondyloarthritis

Spondyloarthritis (SpA) is chronic inflammatory disease involving joints and the spine. Bowel inflammation is common in SpA, which may be classified as acute or chronic. Chronic gut inflammation is most common in SpA patients with axial involvement as compared to those presenting with peripheral involvement alone. The pathogenesis of gut inflammation in SpA could be explained by two factors—over-activation of immunological cells and altered gut microbiome. This is exemplified by SpA animal models, namely HLA-B27-expressing transgenic animals and SKG mice models. Immunological mechanisms include homing of activated T cells from gut into synovium, excess pro-inflammatory cytokines secretion by immune cells such as IL-23 and genetic variations in immunological genes. The evidence for role of gut microbiome in SpA is gradually emerging. Recently, metagenomic study of gut microbiome by sequencing of microbial nucleic acids has enabled identification of new microbial taxa and their functions in gut of patients with SpA. In SpA, the gut microbiome could emerge as diagnostic and prognostic marker of disease. Modulation of gut microbiome is slated to have therapeutic potential as well.     

The activation of intracellular tyrosine kinases by interferon-alpha (IFNα) correlates with its antiproliferative activity in B-lymphoid cell lines, but not in B-cell chronic lymphocytic leukemia patients

 The response to interferon-alpha (IFNα) treatment in leukemias of the B-cell lineage shows a marked heterogeneity. A distinct subset of patients with B-CLL responds to treatment with IFNα, while the drug has no therapeutic effect in the majority of patients. The mechanism of this phenomenon is poorly understood. The cellular events induced by this cytokine mediated by a number of specific signaling events. Therefore, we studied the effect of recombinant IFNα on tyrosine phosphorylation and proliferation of cytosolic proteins in human cell lines and in freshly isolated B-CLL cells in order to test the potential value of these events as a pretreatment test for IFNα in CLL. In human lymphoid cell lines, IFNα induced tyrosine phosphorylation of multiple cytosolic proteins in a time- and concentration-dependent manner. This effect correlated with its growth-inhibitory effect in almost all cell lines. In marked contrast, in freshly isolated B-CLL cells IFNα seemed to have both stimulatory and inhibitory effects on proliferation, but it consistently stimulated tyrosine phosphorylation. Moreover, the clinical response of B-CLL to IFNα did not correlate with the activation of tyrosine kinases nor with the inhibition of cell growth in vitro. Therefore, the assessment of IFNα-induced tyrosine phosphorylation of cytosolic phosphoproteins does not allow to predict the treatment response to IFNα in CLL patients. Received: March 24, 1999 / Accepted: July 19, 1999     

Chemokines in synovial inflammation in rheumatoid arthritis: basic and clinical aspects

 Rheumatoid arthritis (RA) is a chronic, multisystem autoimmune disease characterized by persistent synovitis. Since chemotactic cytokines (chemokines) may play critical roles in the recruitment of leukocytes in RA, analyses of chemokines and their receptors should provide insight into events in synovial inflammation in RA. The production of chemokines is regulated by cytokines such as tumor necrosis factor (TNF)-α produced in the inflamed joint, suggesting that the efficacy of anti-TNF-α therapy is mediated at least partly by the reduction of chemokine production. Chemokines have a role in joint inflammation not only by inducing leukocyte chemotaxis, but also by activating immune cells and angiogenesis. The pathogenesis of RA has been shown to be mediated by Th1-type T cells, because Th1-related chemokine receptors are preferentially expressed on cells in synovial fluid and synovial tissue. Accordingly, antichemokine therapy may be important as a possible new approach to therapeutic intervention in RA.     

Clonal expansions in selected TCR BV families of rheumatoid arthritis patients are reduced by treatment with the TNF�� inhibitors etanercept and infliximab

Clonal expansions of autoreactive CD4+ T cells are frequently present in patients with rheumatoid arthritis (RA) and are stable over long periods of time. This study was undertaken to investigate the influence of anti-TNFα treatment on such clonal expansions in the peripheral CD4+ T-cell compartment. TNFα inhibiting therapies significantly reduced the total number of expanded clonotypes. This effect was mainly observed in clonal expansions in the BV6 family, while in clonal expansions of the BV14 family no such effect was seen. No change in the percentage of CD4+ CD28 null T cells was observed. Serum concentrations of the pro-homeostatic cytokine IL-7 were found to increase in patients responding TNFα-inhibiting therapy. These data argue for a normalization of adaptive immune mechanisms under TNFα inhibiting therapies, which may be secondary to the control of inflammation but contribute to the efficacy of cytokine blockade therapy.