Rheumatoid Arthritis: Jorgensen C

Jorgensen C, Maillefert JF. · No affiliation provided · Joint Bone Spine. · Pubmed #10773963 No free full text.

This publication has no abstract.

Jorgensen C, Djouad F, Bouffi C, Mrugala D, Noël D. · Inserm U844, CHU Saint Eloi, Bâtiment INM, 80 avenue Augustin Fliche, Montpellier F-34091, France. <> · Best Pract Res Clin Rheumatol. · Pubmed #18455684 No free full text.

Abstract: Although cartilage defects are common features of osteoarthritis and rheumatoid arthritis, current treatments can rarely restore the full function of native cartilage. Recent studies have provided new perspectives for cartilage engineering using multipotent mesenchymal stromal cells (MSC). Moreover, MSC have been used as immunosuppressant agents in autoimmune diseases and have tested successfully in animal models of arthritis. However, the sequential events occurring during chondrogenesis must be fully understood before we can reproduce the complex molecular events that lead to MSC differentiation and long-term maintenance of cartilage characteristics in the context of chronic joint inflammation. This chapter focuses on the potential of MSC to repair cartilage, with an emphasis on the factors that are known to be required in inducing chondrogenesis and on their immunosuppressive potential.

Khoury M, Jorgensen C, Apparailly F. · Inserm U 844, INM Hôpital Saint Eloi, BP 74103, 80 rue Augustin Fliche, 34091 Montpellier cedex 5, France. · Curr Opin Mol Ther. · Pubmed #17932812 No free full text.

Abstract: Rheumatoid arthritis is a chronic autoimmune disease of unknown etiology that is characterized by chronic systemic inflammation, mainly affecting the joints, leading to subsequent destruction of the cartilage and bone. RNA interference (RNAi) has been used as a remarkable new research tool to control gene expression and is ultimately envisioned to be useful in clinical treatments. The potential application of RNAi-based therapy in rheumatoid disorders is evaluated. The first successful attempts at TNFalpha silencing by local and systemic delivery of small interfering RNA in experimental arthritic models are discussed. In addition, RNAi and current biotherapies used in the clinic are compared and contrasted.

Tyndall A, Walker UA, Cope A, Dazzi F, De Bari C, Fibbe W, Guiducci S, Jones S, Jorgensen C, Le Blanc K, Luyten F, McGonagle D, Martin I, Bocelli-Tyndall C, Pennesi G, Pistoia V, Pitzalis C, Uccelli A, Wulffraat N, Feldmann M. · Rheumatology, University Hospital Basel, Felix Platter Spital, Burgfelderstrasse 101, Basel, CH-4012, Switzerland. · Arthritis Res Ther. · Pubmed #17284303 links to  free full text

Abstract: Multipotent mesenchymal stromal cells isolated from bone marrow and other sites are currently being studied to determine their potential role in the pathogenesis and/or management of autoimmune diseases. In vitro studies have shown that they exhibit a dose-dependent antiproliferative effect on T and B lymphocytes, dendritic cells, natural killer cells and various B cell tumour lines--an effect that is both cell contact and soluble factor dependent. Animal models of autoimmune disease treated with multipotent mesenchymal stromal cells have mostly exhibited a positive clinical response, as have a limited number of patients suffering from acute graft versus host disease. This review summarizes the findings of a 1-day meeting devoted to the subject with the aim of coordinating efforts.

Wendling D, Jorgensen C. · Service de rhumatologie, centre hospitalier universitaire Jean-Minjoz, 25030 Besançon cedex, France. · Rev Med Interne. · Pubmed #12504237 No free full text.

Abstract: PURPOSE: Interleukin -1 receptor antagonist ( IL-1Ra ) is a new option among biotherapies against rheumatoid arthritis ( RA ). THE AIM: of this review is to recall the rationale of use of IL-1Ra and to analyse the results available in the current literature. CURRENT KNOWLEDGE AND KEY POINTS: Pathophysiological data of RA give a specific position for IL-1 as a potential target for immunotherapy in this disease, confirmed in animal models. Phase II and III studies with IL-1Ra (Anakinra) demonstrated clinical efficacy versus placebo (42% responders in ACR 20 in Anakinra + methotrexate, and 23% in the placebo + methotrexate group at 24 weeks) and a structural effect (slowing of radiological progression at six months). Anakinra has obtained an European license and is indicated in RA not controlled by methotrexate, in daily subcutaneous administration (100 mg/day), in combination with methotrexate. Tolerance is fair; the most frequent side effect is represented by injection site reactions. FUTURE PROSPECTS AND PROJECTS: This ambulatory biotherapy offers new perspectives in combination with other slow acting drugs as well as biologic agents such as anti-TNF, currently under evaluation.

Bessis N, Doucet C, Cottard V, Douar AM, Firat H, Jorgensen C, Mezzina M, Boissier MC. · UPRES EA-3408 (Université Paris 13) and Service de Rhumatologie (CHU Avicenne, AP-HP), Bobigny, France. · J Gene Med. · Pubmed #12439850 No free full text.

Abstract: Rheumatoid arthritis (RA) is a severe autoimmune systemic disease. Chronic synovial inflammation results in destruction of the joints. No conventional treatment is efficient in RA. Gene therapy of RA targets mainly the players of inflammation or articular destruction: TNF-alpha or IL-1 blocking agents (such as anti-TNF-alpha monoclonal antibodies, soluble TNF-alpha receptor, type II soluble receptor of IL-1, IL-1 receptor antagonist), antiinflammatory cytokines (such as IL-4, IL-10, IL-1), and growth factors. In this polyarticular disease, the vector expressing the therapeutic protein can be administered as a local (intra-articular injection) or a systemic treatment (extra-articular injection). All the main vectors have been used in experimental models, including the more recent lentivirus and adeno-associated virus. Ex vivo gene transfer was performed with synovial cells, fibroblasts, T cells, dendritic cells, and different cells from xenogeneic origin. In vivo gene therapy is simpler, although a less controlled method. Clinical trials in human RA have started with ex vivo retrovirus-expressing IL-1 receptor antagonists and have demonstrated the feasibility of the strategy of gene therapy. The best target remains to be determined and extensive research has to be conducted in preclinical studies.

Jorgensen C, Noel D, Gross G. · Immuno-rheumatology Department, INSERM U475, 34295 Montpellier, France. · Ann Rheum Dis. · Pubmed #11779749 links to  free full text

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Jorgensen C, Noel D, Apparailly F, Sany J. · Service d'Immuno-Rhumatologie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France. · Ann Rheum Dis. · Pubmed #11247853 links to  free full text

This publication has no abstract.

Jorgensen C. · Service d'immunorhumatologie, hôpital Lapeyronie, 34295 Montpellier, France. · Rev Med Interne. · Pubmed #11234674 No free full text.

Abstract: INTRODUCTION: Tumor necrosis factor (TNF) blocking agents have changed the therapeutic approach in rheumatoid arthritis, but a true clinical remission remains rare. Gene therapy opens new perspectives in immunotherapy in rheumatoid arthritis. This review focuses on the research, data and clinical development in rheumatoid arthritis using this strategy. CURRENT KNOWLEDGE AND KEY POINTS: New therapeutical targets have been described besides the cytokine inhibitors: apoptosis inducers, angiogenesis inhibitors and metalloprotease inhibitors, cell activation and signalization have been used in experimental models to inhibit arthritis. Gene therapy makes it possible to better understand the physiopathology of rheumatoid arthritis and offers the opportunity to induce true remissions of experimental arthritis. FUTURE PROSPECTS AND PROJECTS: Biotechnology allows the development of new safer vectors which permit long-term expression. However, the difficulties to produce high titers and safe vectors limit the use of this strategy. The previous clinical data on gene therapy in rheumatoid arthritis are limited to feasibility studies. We believe that the efficiency of gene therapy will be obtained by combining two or more complementary targets.

Jorgensen C. · Immunorheumatology Department, Lapeyronie Teaching Hospital, Montpellier, France. · Joint Bone Spine. · Pubmed #10963074 No free full text.

Abstract: Gene therapy has the significant advantage of providing targeted and continuous administration of a therapeutic agent within the joint. A number of targets of choice are discussed, including cytokines, metalloproteinase inhibitors and angiogenesis costimulators. Gene transfer can also be used to inhibit intracellular biological cascades (apoptosis, signal transduction, cell differentiation). Preliminary Phase I ex vivo studies have confirmed the feasibility of gene therapy in rheumatoid arthritis. Vectors will have to be improved before in vivo studies are performed.

Jorgensen C, Apparailly F, Sany J. · Immuno-rheumatology Department, CHU Lapeyronie, Montpellier, France. · Ann Rheum Dis. · Pubmed #10364909 links to  free full text

This publication has no abstract.

Kaiser MJ, Bozonnat MC, Jorgensen C, Daurès JP, Sany J. · Hôpital Lapeyronie, Montpellier, France. · Arthritis Rheum. · Pubmed #11840464 No free full text.

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Mason U, Aldrich J, Breedveld F, Davis CB, Elliott M, Jackson M, Jorgensen C, Keystone E, Levy R, Tesser J, Totoritis M, Truneh A, Weisman M, Wiesenhutter C, Yocum D, Zhu J. · GlaxoSmithKline Pharmaceuticals, Greenford, Middlesex, UK. · J Rheumatol. · Pubmed #11838838 No free full text.

Abstract: OBJECTIVE: Double blind studies were conducted with the anti-CD4 monoclonal antibody (Mab) keliximab in patients with active, stable rheumatoid arthritis (RA), to confirm preliminary evidence of efficacy and safety from open. uncontrolled studies. METHODS: We enrolled 136 and 186 patients into 2 consecutive, randomized, double blind trials, with similar populations [apart from inclusion of disease modifying antirheumatic drug (DMARD)-naïve patients in Study 2]. Patients received 4 weeks intravenous placebo or keliximab [40, 80, 120, or 140 mg twice weekly (bw), or 240 mg once weekly (ow)].The primary endpoint was the American College of Rheumatology (ACR) 20 response criteria, one week after the end of treatment. RESULTS: ACR 20 response rates in Study I were 19%, 42%, 51%*, and 69%* (*p < 0.05 compared to placebo), with placebo, 40, 80, or 140 mg keliximab bw, respectively. The response rates in Study 2 were 30%, 39%, 46% and 47% with placebo, 80 or 120 mg bw, or 240 mg keliximab ow, respectively. In the 2 studies, there was a dose dependent increase in peripheral blood CD4+ T cell coating with keliximab, but a different pattern of CD4 depletion was seen. While only 12% of keliximab treated patients in Study I had CD4 counts below 250 cells/mm3 at the end of the treatment period, 47% fell below this level in Study 2. Clinical response was not correlated with CD4 depletion, but was correlated with CD4+ T cell coating with keliximab. CONCLUSION: Coating of peripheral blood CD4+ T cells with keliximab, but not CD4 depletion, is a determinant of clinical response.

Maravic M, Bologna C, Daures JP, Jorgensen C, Combe B, Sany J. · Service d'Immuno-Rhumatologie, CHU Montpellier, Unité INSERM U475, France. · J Rheumatol. · Pubmed #9972956 No free full text.

Abstract: OBJECTIVE: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug. METHODS: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used. RESULTS: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method. CONCLUSION: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.

Djouad F, Bouffi C, Ghannam S, Noël D, Jorgensen C. · Inserm, U844, Montpellier, France. · Nat Rev Rheumatol. · Pubmed #19568253 No free full text.

Abstract: Mesenchymal stem cells (MSCs), or multipotent mesenchymal stromal cells as they are also known, have been identified in bone marrow as well as in other tissues of the joint, including adipose, synovium, periosteum, perichondrium, and cartilage. These cells are characterized by their phenotype and their ability to differentiate into three lineages: chondrocytes, osteoblasts and adipocytes. Importantly, MSCs also potently modulate immune responses, exhibit healing capacities, improve angiogenesis and prevent fibrosis. These properties might be explained at least in part by the trophic effects of MSCs through the secretion of a number of cytokines and growth factors. However, the mechanisms involved in the differentiation potential of MSCs, and their immunomodulatory and paracrine properties, are currently being extensively studied. These unique properties of MSCs confer on them the potential to be used for therapeutic applications in rheumatic diseases, including rheumatoid arthritis, osteoarthritis, genetic bone and cartilage disorders as well as bone metastasis.

Courties G, Presumey J, Duroux-Richard I, Jorgensen C, Apparailly F. · Inserm, U844, Université Montpellier 1, CHU Lapeyronie, Montpellier, France. · Expert Opin Biol Ther. · Pubmed #19392574 No free full text.

Abstract: BACKGROUND: RNA interference (RNAi) is a powerful endogenous process initiated by short double-stranded RNAs, which results in sequence-specific posttranscriptional gene silencing. The possibility of blocking the expression of any protein carries huge expectations for potential therapeutic applications in a wide range of diseases. For clinical development, however, the use of RNAi-based therapeutics has to overcome major obstacles, mainly targeted delivery and safety issues. OBJECTIVE/METHODS: In this short review, we provide an overview of specifications for RNAi-based gene therapy in rheumatoid arthritis (RA) and discuss recent progresses in the development of efficient silencing, focusing on expression of short hairpin RNAs. RESULTS/CONCLUSIONS: Combining advances in RNAi methodology with gene therapy technology opens avenues for rapid applications to RA.

Fabre S, Guisset C, Tatem L, Dossat N, Dupuy AM, Cohen JD, Cristol JP, Daures JP, Jorgensen C. · Immuno-rheumatology, Lapeyronie University Hospital, Montpellier, France. · Clin Exp Immunol. · Pubmed #19220830 No free full text.

Abstract: In rheumatoid arthritis (RA) there are currently no good indicators to predict a clinical response to rituximab. The purpose of this study was to monitor and determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to rituximab in RA. Blood samples were collected at baseline and at 3 months from 46 RA patients who were treated with rituximab. Responders are defined by the presence of three of four American College of Rheumatology criteria: >or=20% decrease in C-reactive protein, visual analogical score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28) (four values) by >or=1.2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array, including interleukin-6 (IL-6), tumour necrosis factor-alpha, IL-1a, IL-1b, IL-2, IL-8, interferon-gamma, IL-4, IL-10, monocyte chemoattractant protein-1, epidermal growth factor and vascular growth factor. We showed that C-reactive protein and IL-6 levels decrease significantly at 3 months in the responder group compared with baseline. At day 90 we identified a cytokine profile which differentiates responders and non-responders. High serum levels of two proinflammatory cytokines, monocyte chemoattractant protein-1 and epidermal growth factor, were significantly higher in the responder group at day 90 compared with non-responders. However, we were not able to identify a baseline cytokine profile predictive of a good response at 3 months. These findings suggest that cytokine profiling by proteomic analysis may be a promising tool for monitoring rituximab and may help in the future to identify responder RA patients.

Khoury M, Escriou V, Courties G, Galy A, Yao R, Largeau C, Scherman D, Jorgensen C, Apparailly F. · INSERM, U 844, INM, Hôpital St Eloi, and Université Montpellier 1, UFR de Médecine, Montpellier, France. · Arthritis Rheum. · Pubmed #18668557 links to  free full text

Abstract: OBJECTIVE: Blocking tumor necrosis factor (TNF) effectively inhibits inflammation and joint damage in rheumatoid arthritis (RA), but 40% of RA patients respond only transiently or not at all to the current anti-TNF biotherapies. The purpose of this study was to develop an alternative targeted therapy for this subgroup of RA patients. As proof of concept, we tested the efficiency of an RNA interference (RNAi)-based intervention that targets proinflammatory cytokines in suppressing murine collagen-induced arthritis (CIA). METHODS: Two synthetic short interfering RNA (siRNA) sequences were designed for each of the proinflammatory cytokines interleukin-1 (IL-1), IL-6, and IL-18. Their silencing specificity was assessed according to lipopolysaccharide-induced messenger RNA expression in J774.1 mouse macrophages as compared with control siRNA. For in vivo administration, siRNA were formulated as lipoplexes with the RPR209120/DOPE liposome and a carrier DNA and were injected intravenously (0.5 mg/kg) into DBA/1 mice with CIA. RESULTS: Weekly injections of anti-IL-1, anti-IL-6, or anti-IL-18 siRNA-based lipoplexes significantly reduced the incidence and severity of arthritis, abrogating joint swelling and destruction of cartilage and bone, both in the preventative and the curative settings. The most striking therapeutic effect was observed when the 3 siRNA were delivered in combination. The siRNA lipoplex cocktail reduced all pathologic features of RA, including inflammation, joint destruction, and the Th1 response, and overall parameters of RA were improved as compared with anti-TNF siRNA lipoplex-based treatment. CONCLUSION: Our results present a novel option for in vivo RNAi-based antiinflammatory immunotherapy. Our findings indicate that intravenous administration of a lipoplex cocktail containing several anticytokine siRNA is a promising novel antiinflammatory therapy for RA, as well as a useful and simple tool for understanding the pathophysiology of RA and for evaluating new therapeutic candidates.

Fabre S, Dupuy AM, Dossat N, Guisset C, Cohen JD, Cristol JP, Daures JP, Jorgensen C. · Department of Immuno-Rheumatology, Lapeyronie University Hospital, Montpellier, France. · Clin Exp Immunol. · Pubmed #18549443 links to  free full text

Abstract: In rheumatoid arthritis (RA) there are currently no useful indicators to predict a clinical response to tumour necrosis factor-alpha (TNF-alpha) blockade. The purpose of this study was to determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to etanercept in RA. Peripheral blood samples were collected at baseline and at 3 months from 33 patients with active disease who were treated twice weekly by etanercept therapy. Responders are defined by the presence of three of four American College of Rheumatology criteria: > or =20% decrease in C-reactive protein (CRP), visual analogue score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28; four values) by > or =1.2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array (protein biochip array, Investigator Evidence, Randox France), including interleukin (IL)-6, TNF-alpha, IL-1a, IL-1b, IL-2, IL-8, interferon-gamma, IL-4, IL-10, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF) and vascular endothelium growth factor. Our results showed that high serum levels of MCP-1 and EGF were associated with a response to etanercept. In addition, the increase of two combined parameters CRP and EGF was predictive of a response to etanercept treatment at 3 months (sensitivity: 87.5% and specificity: 75%, accuracy: 84.4%). These findings suggest that cytokine profiling by proteomic analysis before treatment initiation may help to identify a responder patient to TNF-alpha blocking agents in RA.

Kastrinaki MC, Sidiropoulos P, Roche S, Ringe J, Lehmann S, Kritikos H, Vlahava VM, Delorme B, Eliopoulos GD, Jorgensen C, Charbord P, Häupl T, Boumpas DT, Papadaki HA. · Department of Haematology, University of Crete School of Medicine, Heraklion, Crete, Greece. · Ann Rheum Dis. · Pubmed #17921184 No free full text.

Abstract: OBJECTIVE: Bone marrow (BM) mesenchymal stem cells (MSCs) are being considered as potential therapeutic agents in various inflammatory autoimmune diseases for their tissue-repair and anti-inflammatory tissue-protective properties. This study investigates the reserves and function, the molecular and proteomic profile and the differentiation potential of BM MSCs in patients with active rheumatoid arthritis (RA). METHODS: We evaluated the frequency of MSCs in the BM mononuclear cell fraction using a limiting dilution assay, the proliferative/clonogenic potential and the capacity of cells to differentiate towards the osteogenic/chondrogenic/adipogenic lineages using appropriate culture conditions. We also assessed the molecular and proteomic characteristics in terms of inflammatory cytokine gene and protein expression, the relative telomere length and the survival characteristics of BM MSCs. RESULTS: MSCs from patients with RA (n = 26) and age- and sex-matched healthy individuals (n = 21) were similar in frequency, differentiation potential, survival, immunophenotypic characteristics, and protein profile. Patient MSCs, however, had impaired clonogenic and proliferative potential in association with premature telomere length loss. Transcriptome analysis revealed differential expression of genes related to cell adhesion processes and cell cycle progression beyond the G1 phase. Previous treatment with methotrexate, corticosteroids, anti-cytokine and biological agents or other disease-modifying anti-inflammatory drugs did not correlate with the clonogenic and proliferative impairment of BM MSCs. CONCLUSION: In spite of some restrictions related to the impaired clonogenic and proliferative potential, our findings support the use of autologous BM MSCs in RA and may have important implications for the ongoing efforts to repair tissue injury commonly seen in the course of the disease.

Khoury M, Adriaansen J, Vervoordeldonk MJ, Gould D, Chernajovsky Y, Bigey P, Bloquel C, Scherman D, Tak PP, Jorgensen C, Apparailly F. · Inserm, U 844, F-34091 Montpellier, France. · J Gene Med. · Pubmed #17514770 No free full text.

Abstract: BACKGROUND: The tumor necrosis factor (TNF)-alpha plays a central role in rheumatoid arthritis (RA) and current biotherapies targeting TNF-alpha have a major impact on RA treatment. The long-term safety concerns associated with the repetitive TNF blockade prompt optimization of therapeutic anti-TNF approaches. Since we recently demonstrated that intra-articular gene transfer using a recombinant adeno-associated virus serotype 5 (rAAV5) efficiently transduces arthritic joints, we evaluate its effect on collagen-induced arthritis (CIA) when encoding TNF antagonists. METHODS: Recombinant AAV5 vectors encoding the human TNFRp55 extracellular domain fused to the Fc region of mice IgG1 (TR1) or a small molecular weight dimeric human TNFRp75 extracellular domain (TR2), under two different promoters, the CMV or a chimeric NF-kappaB-based promoter inducible by inflammation, were injected into mouse CIA joints. RESULTS: Best protection against arthritis was obtained with the rAAV5 encoding the TR1, as reflected by delayed disease onset, decreased incidence and severity of joint damage. This effect was associated with a transient expression of the anti-TNF agent when expressed under a NF-kappaB-responsive promoter, only detectable during disease flare, while the antagonist expression was rapidly increased and stable when expressed from a CMV promoter. Importantly, using the intra-articular administration of the rAAV5-NF-kappaB-TR1 vector, we observed a striking correlation between local TR1 expression and inflammation. CONCLUSIONS: These findings strongly support the feasibility of improving the safety of anti-TNF approaches for the treatment of arthritis by local rAAV5-mediated gene expression under an inflammation-responsive promoter, able to provide a limited, transient and therapeutically relevant expression of anti-TNF compounds.

Adriaansen J, Khoury M, de Cortie CJ, Fallaux FJ, Bigey P, Scherman D, Gould DJ, Chernajovsky Y, Apparailly F, Jorgensen C, Vervoordeldonk MJ, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Ann Rheum Dis. · Pubmed #17363402 links to  free full text

Abstract: BACKGROUND: In the context of preclinical development, we studied the potential of intra-articular gene delivery using a recombinant adeno-associated virus 5 (rAAV5) encoding a chimeric human tumour necrosis factoralpha (TNFalpha) soluble receptor I linked to a mouse immunoglobulin heavy chain Fc portion (TNF receptor I; TNFRI-Ig). METHODS: Expression was under control of a nuclear factor kappa B (NFkappaB)-responsive promoter and compared with a cytomegalovirus (CMV) promoter (rAAV5.NFkappaB-TNFRI-Ig and rAAV5.CMV-TNFRI-Ig, respectively). RESULTS: Fibroblast-like synoviocytes transduced in vitro with rAAV5.NFkappaB-TNFRI-Ig were able to produce TNFRI-Ig protein in response to several stimuli, and this was inhibited upon treatment with a specific NFkappaB blocking agent. A bioassay revealed that the synthesised TNFRI-Ig was bioactive, showing a higher affinity for human than for rat TNFalpha. Transcription of the transgene and protein production were detectable in joints injected with both constructs. No dissemination of the vector was observed outside the joints. A significant reduction in paw swelling was seen in rats treated with rAAV5.NFkappaB-TNFRI-Ig. This clinical effect was accompanied by a decrease in pro-inflammatory cytokine levels and an increase in IL10 expression in the synovium. CONCLUSION: These results provide evidence that intra-articular gene therapy using rAAV5 encoding TNFRI-Ig may be a safe and feasible approach for the treatment of rheumatoid arthritis. The higher affinity for human TNFalpha suggests that in patients with rheumatoid arthritis the therapeutic effect might be even more pronounced than in rat adjuvant arthritis.

Desmetz C, Lin YL, Mettling C, Portalès P, Noël D, Clot J, Jorgensen C, Corbeau P. · Institut de Génétique Humaine du CNRS UPR1142, Montpellier, F-34000, France. · Clin Immunol. · Pubmed #17363330 No free full text.

Abstract: As we have recently shown that the number of CCR5 molecules at the cell surface determines the efficiency of its function as a chemokine receptor, we tested the hypothesis that cell surface CCR5 density could influence the intensity of T lymphocyte recruitment into the rheumatoid joint. For this purpose, we established two Jurkat cell line-derived clones that differed only by their cell surface CCR5 densities. We studied their chemotaxis towards TNF-alpha-transduced rheumatoid synoviocytes supernatant. The Jurkat cell subline that expressed the higher cell surface CCR5 density migrated more intensively towards the supernatant of TNF-alpha-transduced synoviocytes than the Jurkat cell subline that expressed a lower surface CCR5 density. Moreover, this migration was blocked by an anti-CCR5 mAb. The CCR5 density on T cell surface, which is constant over time for a given individual, but varies drastically from one individual to another, might thus be a factor determining the intensity of joint inflammation in the course of RA.

Khoury M, Louis-Plence P, Escriou V, Noel D, Largeau C, Cantos C, Scherman D, Jorgensen C, Apparailly F. · INSERM U475 and University of Montpellier I, Montpellier, France. · Arthritis Rheum. · Pubmed #16729293 links to  free full text

Abstract: OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) is among the most prominent cytokines in rheumatoid arthritis (RA) and is secreted mainly by macrophages. A direct method for restoring the immunologic balance in RA is use of small interfering RNA (siRNA) for silencing the TNFalpha transcript. The aim of this study was to determine the therapeutic effect of systemic administration of TNFalpha siRNA in an experimental model of RA, optimizing its delivery using new liposome formulations. METHODS: Murine macrophages were transfected with siRNA targeting TNFalpha, and expression was measured. The therapeutic effect in collagen-induced arthritis (CIA) was assessed after intravenous delivery of TNFalpha siRNA. Delivery was optimized using a carrier DNA for complexation with the cationic liposome RPR209120/DOPE. Levels of TNFalpha and other cytokines were measured in sera and joint tissue-conditioned media. Biodistribution was determined using a fluorescent siRNA. RESULTS: In vitro, TNFalpha siRNA efficiently and specifically modulated the expression of TNFalpha at both the messenger RNA and protein levels. In vivo, complete cure of CIA was observed when TNFalpha siRNA was administered weekly, complexed with the liposome and combined with carrier DNA. Inhibition (50-70%) of articular and systemic TNFalpha secretion was detected in the siRNA-injected groups, which correlated with a decrease in the levels of interleukin-6 and monocyte chemotactic protein 1. The main organs targeted by siRNA were the liver and spleen; the addition of liposome RPR209120 and carrier DNA significantly increased organ uptake. CONCLUSION: We demonstrated the efficiency of systemic delivery of siRNA designed to silence TNFalpha in CIA, using a liposome carrier system as a way to address the methodologic limitations in vivo.

Fabre S, Gibert C, Lechiche C, Dereure J, Jorgensen C, Sany J. · Department of Immuno-Rheumatology, CHU Lapeyronie, 371 av Doyen Gaston Giraud, 34090 Montpellier, France. · Clin Exp Rheumatol. · Pubmed #16396712 No free full text.

Abstract: Anti-TNFalpha strategies can result in significant clinical benefits in rheumatoid arthritis (RA), but with an increased rate of opportunistic infections. Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised hosts, principally in HIV patients. VL in RA patients treated with TNFalpha antagonists is an extremely rare event, and only one case has been described. Here we report a case of VL, occurring after 9 infusions of infliximab in association with azathioprine, in a patient who developed blood cytopenia, fluctuant fever, and splenomegaly.