title: The Targeted Delivery of Interleukin 4 Inhibits Development of Endometriotic Lesions in a Mouse Model.
abstract: Endometriosis is caused by the displacement of endometrium outside the uterus contributing heavily to infertility and debilitating pelvic pain. Ectopic adhesion and growth are believed to occur under the influence of a favorable hormonal environment and immunological factors. The objective of this study is to analyze the effect of a targeted therapy with an antibody-based pharmacodelivery of interleukin 4 (F8-IL4) in a mouse model of experimentally induced endometriosis. Endometriosis-like lesions were induced in Balb/c mice. The animals were treated intravenously with F8-IL4 or with untargeted IL4 (KSF-IL4). Twelve days after disease induction, the lesions were isolated. A significant reduction in the number of total lesions/mouse and in the total volume of lesions/mouse was observed in mice treated with F8-IL4 compared to controls (P = .029 and P = .006, respectively), while no difference was found between KSF-IL4-treated mice and their controls. Gene expression was evaluated by quantitative real-time polymerase chain reaction. Expression of genes involved in cell adhesion, extracellular matrix invasion, and neovascularization was significantly downregulated in F8-IL4-treated mice compared to their controls (integrin β1: P = .02; metalloproteinase [MMP] 3: P = .02; MMP9: P = .04; vascular endothelial growth factor: P = .04). Gene expression of inflammatory cytokines (tumor necrosis factor α, IL1β, IL1α, and IL6) did not vary in the ectopic lesions isolated from F8-IL4-treated mice compared to their controls. Immunohistochemistry demonstrated a significantly reduced expression of E-cadherin and β-catenin in the lesions of mice treated with F8-IL4. Our results show that the antibody-mediated targeted delivery of IL4 inhibits the development of endometriosis in a syngeneic mouse model by likely impairing adhesion, invasion, and vascularization of the ectopic endometrium.
authors: Division of Genetics and Cell Biology, Reproductive Sciences Laboratory, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Federica
authors: F
authors: Quattrone
authors: Division of Genetics and Cell Biology, Reproductive Sciences Laboratory, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Ana Maria
authors: AM
authors: Sanchez
authors: Division of Genetics and Cell Biology, Reproductive Sciences Laboratory, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Maria
authors: M
authors: Pannese
authors: Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zürich, Switzerland.
authors: Teresa
authors: T
authors: Hemmerle
authors: Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Paola
authors: P
authors: Viganò
authors: Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Massimo
authors: M
authors: Candiani
authors: Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
authors: Felice
authors: F
authors: Petraglia
authors: Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zürich, Switzerland.
authors: Dario
authors: D
authors: Neri
authors: Division of Genetics and Cell Biology, Reproductive Sciences Laboratory, IRCCS Ospedale San Raffaele, Milan, Italy panina.paola@hsr.it.
authors: Paola
authors: P
authors: Panina-Bordignon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004717:Endometrium / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D018796:Immunoconjugates / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007135:Immunoglobulin Variable Region / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D015847:Interleukin-4 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013997:Time Factors; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D016207:Cytokines; C528643:F8 monoclonal antibody; D018796:Immunoconjugates; D007135:Immunoglobulin Variable Region; D018836:Inflammation Mediators; D011993:Recombinant Fusion Proteins; D051176:beta Catenin; D015847:Interleukin-4
keywords: IL-4; endometriosis; immunocytokine