title: Single application of low-dose mycophenolate mofetil-OX7-immunoliposomes ameliorates experimental mesangial proliferative glomerulonephritis.
abstract: IgA nephropathy, one of the most frequent forms of glomerulonephritis, characterized by mesangial hypercellularity and glomerular extracellular matrix (ECM) expansion, often leads to end-stage renal disease over a prolonged period. We investigated whether antiproliferative treatment in a single low dose specifically targeted to the glomerular mesangium by immunoliposomes (ILs) results in an amelioration of mesangial proliferative glomerulonephritis in rats (anti-Thy1.1 nephritis). Mycophenolate mofetil (MMF) containing ILs was generated that targets the Thy1.1 antigen (OX-7) in rat mesangial cells. Treatment benefit of a single intravenous dose of these ILs given 2 days after disease induction was investigated by stereology, immunohistochemistry, and functional analyses (creatinine, albuminuria) until day +9 and was compared among untreated and free MMF-treated rats using six male Wistar rats per group. MMF-loaded OX7-IL prevented creatinine increase and albuminuria. Stereological analyses of MMF OX7-IL-treated animals yielded 30% reduction of mesangial cells on day +9 and a 40% reduction of glomerular ECM volume on day +5, compared with all of the other nephritic animals. Furthermore, at days +5 and +9 we observed decreased ECM content and decreased glomerular volume (day +5) in the MMF-OX7-IL-treated group compared with the nephritic group treated with free MMF. In conclusion, MMF-OX7-IL-based directed drug delivery represents a novel approach for treating mesangial cell-mediated forms of glomerulonephritis.
authors.affiliation: Department of Nephrology and Hypertension, University of Bern Inselspital, Freiburgstrasse 15, CH-3010 Bern, Switzerland.
authors.forename: A J
authors.initials: AJ
authors.lastname: Suana
authors.forename: G
authors.initials: G
authors.lastname: Tuffin
authors.forename: B M
authors.initials: BM
authors.lastname: Frey
authors.forename: L
authors.initials: L
authors.lastname: Knudsen
authors.forename: C
authors.initials: C
authors.lastname: Mühlfeld
authors.forename: S
authors.initials: S
authors.lastname: Rödder
authors.forename: H-P
authors.initials: HP
authors.lastname: Marti
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019921:Biotinylation; D004396:Coloring Agents; D004337:Drug Carriers; D005109:Extracellular Matrix / Q000187:drug effects / Q000648:ultrastructure; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D008081:Liposomes / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008689:Methacrylates; D008854:Microscopy, Electron; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016612:Paraffin Embedding; D011092:Polyethylene Glycols; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018800:Thy-1 Antigens; D016610:Tissue Embedding; D014048:Tolonium Chloride
chemical_list: D000199:Actins; D004396:Coloring Agents; D004337:Drug Carriers; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D008081:Liposomes; D008689:Methacrylates; D018809:Proliferating Cell Nuclear Antigen; D018800:Thy-1 Antigens; D014048:Tolonium Chloride; D011092:Polyethylene Glycols; D009173:Mycophenolic Acid