Biomedical subjects

F Apparailly

Publications and source records attributed to F Apparailly.

5 recordsLinked to original sources

PubMed1999

Systemic viral interleukin-10 gene delivery prevents cartilage invasion by human rheumatoid synovial tissue engrafted in SCID mice.

OBJECTIVE: To assess the effects of viral interleukin-10 (vIL-10) gene delivery on human rheumatoid synovial tissue. METHODS: SCID mice were engrafted subcutaneously with human rheumatoid synovial tissue and homologous cartilage before systemic injection of 10(9) plaque-forming units of type 5 E1a Elb-deficient non-replicative adenovirus vector containing the vIL-10 gene under control of the cytomegalovirus promoter (AdvIL-10; n = 10) or a control gene (AdvIL-10mut; n = 7). Three weeks later, the graft was removed for histologic analysis of cartilage invasion by synovial tissue. The number of CD3-positive mononuclear cells was assessed in the synovial tissue by immunohistology. Messenger RNA (mRNA) expression of matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and proinflammatory cytokines was determined by polymerase chain reaction. RESULTS: Systemic vIL-10 gene transfer resulted in high sustained production of vIL-10 protein in SCID mouse sera (mean +/- SD 25 +/- 5 ng/ml on day 40 post vector injection). Moreover, vIL-10 mRNA expression was detected in the synovial tissue 3 weeks after intravenous injection of AdvIL-10, reflecting the gene transfer in the human graft. In animals treated with AdvIL-10, cartilage invasion by rheumatoid synovial tissue was significantly inhibited compared with the control vector (mean +/- SD histologic score 2.5 +/- 0.52 versus 0.75 +/-0.8; P < 0.0001). The number of T cells infiltrating the synovium and perichondral resorption in the animals treated with AdvIL-10 gene were not significantly modified relative to the control vector. In animals treated with AdvIL-10, the MMP-3-TIMP-1 balance was partially restored, independent of the effect on mRNA expression of tumor necrosis factor a, IL-1, IL-6, or IL-8. CONCLUSION: Systemic vIL-10 gene transfer prevented cartilage invasion by synovial tissue engrafted in SCID mice. This model offers the opportunity to study the biologic effects of gene transfer in vivo in rheumatoid synovium.

Adenoviridae↗

PubMed1998

Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis.

IL-10 is a potent anti-inflammatory cytokine that has received growing attention for its therapeutic potential. We examined the efficiency of adenoviral-mediated gene transfer of IL-10 on the incidence and severity of murine collagen-induced arthritis (CIA). Male DBA1 mice immunized with collagen II were treated by systemic administration of 10(9) plaque-forming units of replication-defective adenoviral vector expressing viral IL-10 (vIL-10) on day 30, when clinical symptoms of arthritis start. The transgene was shown to inhibit the onset of CIA, to decrease severity, and profoundly suppress the overall joint histopathology of the experimental arthritis. Significant IL-10 concentrations were obtained in the serum of injected animals for 7 days. Inhibition of arthritis was enhanced by administration of increasing doses of adenovirus-vIL-10. In addition, the local immunosuppressive effect of gene-delivered vIL-10 could be neutralized by a monoclonal anti-vIL-10 Ab. The CIA symptoms in the group treated with the same construct expressing inactive vIL-10 (vIL-10 mut) were similar to those in untreated animals. Our data indicate that a single systemic administration of an adenoviral vector encoding vIL-10 may be a good candidate to suppress arthritis.

Adenoviridae↗

PubMed1998

Interleukin-4 and interleukin-10 are chondroprotective and decrease mononuclear cell recruitment in human rheumatoid synovium in vivo.

We used the severe combined immunodeficient (SCID) mouse model to assess the effect of interleukin-4 (IL-4) or IL-10 injection on cartilage degradation and mononuclear cell (MNC) recruitment to human rheumatoid synovium in vivo. Human rheumatoid synovium and cartilage from five rheumatoid arthritis patients, obtained after joint replacement surgery, were engrafted subcutaneously to 6-8-week-old SCID CB17 mice. Synovial tissues were injected with recombinant human IL-4 (rhIL-4, 100 ng; rhIL-10, 100 ng), both cytokines, or tumour necrosis factor-alpha (TNF-alpha) (1000 U), or phosphate-buffered saline twice a week for 4 weeks. The graft was removed and immunochemical analysis was carried out to assess intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin expression. Moreover, cartilage degradation was assessed through the quantification of the erosion surface on a computerized image of the engrafted cartilage at high power view. MNC recruitment in the synovial tissue was determined by labelling blood MNC with indium-111 before their intraperitoneal injection. The activity obtained in the region of the graft were determined with a gamma camera 72 hr postinjection. The results are expressed as a percentage of initial injected activity. After 4 weeks we observed a decrease of cartilage area in controls (77 +/- 8%), inhibited after injection of IL-4, IL-10, or both cytokines (90 +/- 3%, 89.1 +/- 4%, 89.2 +/- 5% respectively), and 57 +/- 17% after TNF-alpha injection. The % MNC activity in the graft decreased to 77 +/- 81% (NS), 9 +/- 4% (P < 0.003) and 19 +/- 6% (P < 0.007) compared with untreated synovial tissue after treatment with IL-4, IL-10, or both cytokines, respectively. Moreover, IL-10 but not IL-4 decreased the expression of ICAM-1 but not VCAM-1 or E-selectin by synovial cells. These results suggest that IL-10 and IL-4 could have chondroprotective properties, and that IL-10 but not IL-4 inhibits MNC traffic towards the synovial tissue efficiently.

Animals↗

PubMed1994

Role of sialic acid residues in the in vitro superactivity of human choriogonadotropin (hCG) in rat Leydig cells.

The binding activity (B) of porcine Luteinizing Hormone (pLH) to rat LH receptor as well as its stimulating activity (S) of testosterone secretion by rat Leydig cells in vitro are similar to those of the homologous hormone rat LH (S/B = 1). By contrast, the human Chorionic Gonadotropin (CG) and hLH exhibit stimulating activities relative to rat LH that are considerably higher than their relative binding activities (S/B > 100) indicating that they have an abnormally high transducing efficiency (superactivity) after receptor binding. The heterologous hybrid alpha pLH x beta hCG is as superactive as native hCG and recombined alpha hCG x beta hCG whereas alpha hCG x beta pLH exhibits no superactivity, like native pLH and alpha pLH x beta pLH demonstrating that hCG superactivity is due to its beta-subunit. The removal of sialic acid residues with neuraminidase dramatically diminished hCG stimulating activity without impairing its receptor binding activity but the S/B ratio for asialo-hCG never reached values lower than 1. Similar treatments had no effect on the S/B ratios of non-superactive gonadotropins, pLH and equine CG. Sialic acid residues in the Asn beta 30 carbohydrate chains of hLH and hCG appear to be responsible for their superactivity in the in vitro stimulation of testosterone secretion by rat Leydig cells.

Animals↗

PubMed1994

Structure-function relationships and mechanism of action of pituitary and placental gonadotrophins.

Data from the author's laboratory on relationships between structure and function of equine luteinizing hormone, follicle-stimulating hormone and choriogonadotrophin as well as their mechanisms of action are reviewed and compared with their human counterparts. Polymorphism of these hormones and problems associated with their purification are discussed as well as the association and dissociation of their alpha- and beta-subunits. The affinity of receptor binding, the superactivity of membrane transduction and homologous desensitization of target cells by non-stimulatory doses of the gonadotrophins are also reviewed.

Chorionic Gonadotropin↗