Anti-alpha8 integrin immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus.
OBJECTIVE
Glomerular mesangial cells are active participants in the pathogenesis of lupus glomerulonephritis (GN). Thus, targeted delivery of therapeutic agents to mesangial cells would be an attractive approach to treatment. However, lack of known unique mesangial cell surface markers has hampered this process. This study was undertaken in a mouse model of lupus GN to identify mesangial markers and to develop a system for targeted drug delivery to the glomerulus.


METHODS
Based on previous observations, alpha8 integrin expressed on the surface of glomerular mesangial cells was selected as a target molecule for delivery. Two mouse strains susceptible to lupus GN, NZM2328 and (NZM2328 x NOD)F1, were studied. Glomerular expression of alpha8 integrin in normal and nephritic mice was confirmed by immunofluorescence and quantitative polymerase chain reaction analysis. Liposomes were formulated and conjugated with an anti-alpha8 integrin antibody. These immunoliposomes were loaded with DiI, a red fluorescent dye, to allow tracking in vivo, and injected into the tail vein of female mice at different ages. Specificity of targeting was studied by fluorescence microscopy and flow cytometry.


RESULTS
Expression of alpha8 integrin was observed in the glomeruli of normal and nephritic mice. Anti-alpha8 integrin immunoliposomes were detected in the glomerulus and glomerular mesangial cells after tail vein injection in normal and nephritic mice. Delivery of DiI by anti-alpha8 integrin immunoliposomes was tissue specific, being observed predominantly in the glomeruli, with some nonspecific uptake by CD11b cells.


CONCLUSIONS
These findings are the first demonstration of specific delivery of anti-alpha8 integrin immunoliposomes to the mesangium following tail vein injection in mice. Anti-alpha8 integrin immunoliposomes thus offer a novel approach for targeted drug therapy in lupus and other glomerular diseases.
Scindia
Yogesh
Y
University of Virginia, Charlottesville, VA 22908, USA.
Deshmukh
Umesh
U
Thimmalapura
Pushpa-Rekha
PR
Bagavant
Harini
H
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000918:Antibody Specificity; D005260:Female; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D007275:Injections, Intravenous; D039001:Integrin alpha Chains / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D008081:Liposomes / Q000276:immunology / Q000493:pharmacokinetics; D008181:Lupus Nephritis / Q000276:immunology* / Q000628:therapy*; D050527:Mesangial Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD
D000906:Antibodies; D039001:Integrin alpha Chains; D008081:Liposomes; C093856:integrin alpha8