Article

Human, viral or mutant human IL-10 expressed after local adenovirus-mediated gene transfer are equally effective in ameliorating disease pathology in a rabbit knee model of antigen-induced arthritis

Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA.
Arthritis research & therapy (Impact Factor: 3.75). 02/2006; 8(4):R91. DOI: 10.1186/ar1960
Source: PubMed

ABSTRACT

IL-10 is a Th2 cytokine important for inhibiting cell-mediated immunity while promoting humoral responses. Human IL-10 (hIL-10) has anti-inflammatory, immunosuppressive as well as immunostimulatory characteristics, whereas viral IL-10 (vIL-10), a homologue of hIL-10 encoded by Epstein Barr virus (EBV), lacks several immunostimulatory functions. The immunostimulatory characteristic of hIL-10 has been attributed to a single amino acid, isoleucine at position 87, which in vIL-10 is alanine. A mutant hIL-10 in which isoleucine has been substituted (mut.hIL-10) is biologically active with only immunosuppressive, but not immunostimulatory, functions, making it a potentially superior therapeutic for inflammatory diseases. To compare the efficacy of mut.hIL-10 with hIL-10 and vIL-10 in blocking the progression of rheumatoid arthritis, we used replication defective adenoviral vectors to deliver intra-articularly the gene encoding hIL-10, vIL-10 or mut.hIL-10 to antigen-induced arthritic (AIA) knee joints in rabbits. Intra-articular expression of hIL-10, vIL-10, and mut.hIL-10 resulted in significant improvement of the pathology in the treated joints to similar levels. These observed changes included a significant reduction in intra-articular leukocytosis and the degree of synovitis, as well as normalization of cartilage matrix metabolism. Our results suggest that hIL-10, vIL-10, and mut.hIL-10 are all equally therapeutic in the rabbit AIA model for treating disease pathology.

Download full-text

Full-text

Available from: Eric R Lechman
  • Source
    • "The present study is the first work in which WJ-hMSCs have been transduced with EBV-derived vIL-10, which has been extensively studied and is well known to have immunosuppressive properties. This cytokine-like molecule has been tested in several animal models and has proved effective at inhibiting collagen-induced arthritis, suppressing autoimmune diabetes and improving survival to sepsis[35,37,68697071. Furthermore, in several transplantation models vIL-10 consistently increased graft survival compared with hIL-10[3,30,69,72,73]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mesenchymal stromal cells (MSCs) modulate the immune response and represent a potential treatment for inflammatory and autoimmune diseases. We hypothesized that this feature could be potentiated by co-administering anti-inflammatory cytokines. In this article, we asked whether engineering of Wharton Jelly–derived human MSCs (WJ-hMSCs) to express an anti-inflammatory cytokine increases cell immunomodulatory properties without altering their native features.
    Full-text · Article · Feb 2016 · Cytotherapy
  • Source
    • "To choose the best formulation with the highest amount in arthritic knees, DFNa-loaded formulations were labeled with 99m Tc and scintigraphic imaging studies were performed in the arthritic knees of the rabbits using a gamma camera. A rabbit antigen-induced anti-inflammatory model of RA is used to assess the similarity between the human knee joint and the rabbit knee joint (Kerevala et al. 2006). We reported that DFNa-loaded lipogelosome formulations, L1J1, which were composed of DFNaloaded DMPC:DCP:CHOL (7:1:2) in C-940 gel in a ratio of 1:1 (w/w), prolonged the residence of DFNa into the arthritic knee joint of the rabbits when compared with the other formulations (Tü rker et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent research into the complex and varied components of rheumatoid arthritis (RA) is leading to the development of more effective targets for pharmaceutical approach than even before. Current treatment of RA frequently includes the use of nonsteroidal anti-inflammatory drugs, such as Diclofenac sodium (DFNa) in spite of the severe adverse effects. Local application and incorporation of the drugs in liposome based formulations may reduce those side effects and improve the efficacy of drugs by reducing the availability of them in systemic circulation and increasing accumulation and retention time in the sites of inflammation. Herein, anti-inflammatory efficacy of the DFNa containing lipogelosome formulations (L1J1) was evaluated and found that L1J1 elicits a better anti-inflammatory efficacy after a single dose i.a. administration in comparison with commercial product, VE-CP, which is used topically. Histopathological examination of the opened joints showed that joints treated with L1J1, had significantly (p < 0.05) lower scores than contra lateral control joints for inflammatory changes in the synovium. These results were also confirmed by biodistribution studies.
    Full-text · Article · Jan 2008 · Journal of Drug Targeting
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin-1 (IL-1), IL-6, IL-10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage. Modified Larsen scores of radiographic damage were determined in a cross-sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) were also assayed. The Kruskal-Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene-dose effects. An allele-dose association of IL-6 -174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti-CCP positive (P = 0.01). Patients with the IL-10 -592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti-CCP negative (P = 0.002). However, RF status and anti-CCP status were not associated with the IL-6 or IL-10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage. The reported associations of IL-6 -174G with high IL-6 production and IL-10 -592 with low IL-10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti-CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL-6 and IL-10 genotypes may be useful in predicting disease severity in autoantibody-positive and autoantibody-negative patients, respectively.
    Full-text · Article · Aug 2007 · Arthritis & Rheumatology
Show more