Systemic delivery of an adenovirus expressing EBV-derived vIL-10 in mice infected with Schistosoma mansoni or Leishmania amazonensis: controversial effects on the development of pathological parameters.
Within the context of microorganism/host interactions, those which last over weeks are expected to be sensitive to more or less sustained and targeted immuno-intervention, such as delivery of cytokines known to operate as down-regulators of acute inflammatory processes. IL-10 has received growing attention as a potential tool in immunotherapy, due to its anti-inflammatory and immunosuppressive properties. Therefore, using two experimental models of long-term interactions between parasites and laboratory mice, we monitored some effects of the systemic delivery of an adenovirus (Ad) expressing EBV-derived IL-10 (vIL-10) designated Ad-vIL-10. We first monitored the vIL-10 serum level following intranasal, intraperitoneal, intramuscular and intravenous administration. The i. p. and i.v. delivery of Ad-vIL-10 allowed a high serum level of vIL-10 (= 100 ng/ml), the i.v. route leading to a more sustained expression (up to 3 weeks). As a first model of parasite/mouse interaction, Schistosoma mansoni/C57Bl/6 mouse was selected. Ad-vIL-10 delivery was performed 4 weeks after S. mansoni infection i.e. at the time of egg-laying, and several parameters were monitored: (i) number of adult worms in the mesenteric vein, (ii) number of eggs trapped in the liver and intestine, (iii) liver fibrosis, (iv) serum levels of egg-reactive antibody subclasses, (v) serum content of cytokines, and (vi) cytokine production in the supernatant of antigen-stimulated mesenteric lymph node cells. No apparent effect was observed, either on the different parasitological parameters or on fibrosis development at day 70 of infection. Surprisingly, a marked increase in both Th1 and Th2 type cytokines was observed in the sera of the Ad-vIL-10 injected animals, as well as in the supernatants of their Ag-stimulated mesenteric lymph node cells. Nevertheless, polarization of the humoral response towards a Th2 profile was demonstrated by an increase in the IgE level in the Ad-vIL-10-injected animals. As far as the second model is concerned, namely the Leishmania amazonensis /C57Bl6 mouse interactions, Ad-vIL-10 was delivered intravenously one day before subcutaneous injection of stationary promastigotes and footpad swelling was monitored over 110 days. Under these conditions, vIL-10 exhibited a biphasic effect, decreasing the lesion size at the early stages of infection, but leading to a more pronounced lesion size during the chronic phase. This observation suggests a deactivation of the macrophage host cells under the influence of vIL-10. The results are discussed in the context of immunotherapy and the paradoxical effects observed in immunointervention with vIL-10.
URA CNRS 1854, Institut Pasteur de Lille, 1, rue du Pr-Calmette, PO Box 447, 59021 Lille, France. Claudie.Verwaerde@pasteur-lille.fr
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Verwaerde
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Thiam
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Delanoye
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Fernandez-Gomez
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D'Halluin
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Auriault
D000260:Adenoviruses, Human / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000909:Antibodies, Helminth / Q000096:biosynthesis / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology; D004333:Drug Administration Routes; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000235:genetics*; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D007891:Leishmania / Q000302:isolation & purification; D007896:Leishmaniasis / Q000276:immunology / Q000469:parasitology / Q000628:therapy*; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology / Q000628:therapy*; D008222:Lymphokines / Q000097:blood / Q000378:metabolism; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D012550:Schistosoma mansoni / Q000302:isolation & purification; D012555:Schistosomiasis mansoni / Q000276:immunology / Q000469:parasitology / Q000628:therapy*; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000909:Antibodies, Helminth; D000947:Antigens, Helminth; D007074:Immunoglobulin G; D008222:Lymphokines; D016753:Interleukin-10; D007073:Immunoglobulin E; D007371:Interferon-gamma