Anti–α8 integrin immunoliposomes in glomeruli of lupus‐susceptible mice: A novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus

Renal failure contributes significantly to the morbidity associated with Systemic Lupus Erythematosus (SLE). However, the molecular mechanisms of renal injury and progressive renal failure are complex and not completely understood. Recently, there has been increasing evidence that end organ susceptibility to disease, local milieu in the kidney and active participation by renal cells play important roles in pathogenesis of lupus glomerulonephritis (GN) (1-6). This, in turn, identifies a clear role for end organ targeted therapies in treatment of lupus GN and a new area for investigation. In SLE, systemic autoimmune responses lead to glomerular immune complexes and GN. In MRL lpr/lpr mice, glomerular immune complex deposition is associated with a rapid increase in MCP-1 and RANTES production by glomerular mesangial cells (7). This is followed by inflammatory cell infiltration into the glomeruli and progressive renal disease characterized by glomerulosclerosis, interstitial inflammation, fibrosis, and tubular atrophy. Thus, mesangial cell responses in the form of inflammatory cytokine secretion, proliferation, and extracellular matrix production have been implicated as critical elements for progressive GN (8). Our studies in NZM2328, a murine model of spontaneous SLE, also implicate an important role for a local immune response in disease progression (2). Clearly, drug delivery specifically to the mesangium and modulation of mesangial cell responses are potential avenues for therapy. However, targeting of mesangial cells using antibodies or receptor ligands has been hampered because there are no currently identified cell surface markers unique to the murine or human mesangial cells. Liposomes are a vehicle of choice for targeted drug delivery (9). Liposomes allow incorporation of hydrophobic drugs within the lipid bilayer and hydrophilic drugs in the central aqueous void volume. Significantly, liposomes can be conjugated to antibodies on their surface to form immuno-liposomes (ILs). ILs have been used for site-specific drug delivery in cancer treatments (10, 11). In this study, we have explored the use of ILs as vehicles for targeted delivery to the glomerulus, specifically to the glomerular mesangial cells. Since human and murine mesangial cells lack unique cell surface markers, our first task was to identify suitable target molecules on the mesangial cells. The integrin family of receptors is expressed on surface of mesangial cells (12). On the mesangial cells, the β1 integrin combines with α1, α3, αv, or α8 integrin chains to form the functional heterodimeric proteins. These integrins have critical functions in glomerular development and interactions with extracellular matrix proteins. Several of the integrins are present on many different cell types including the vascular endothelium (13). In comparison, α8 integrin expression is relatively restricted on glomerular mesangial cells in mice (and humans), interstitial smooth muscle cells, and alveolar myofibroblasts in lung (14, 15). α8 integrin is also expressed on hippocampal dentate hilar neurons in the brain (16). Therefore, we selected α8 integrin as a molecule on the mesangial cells for immuno-liposomal targeting. Our study is the first demonstration of targeted mesangial delivery in mice following systemic injection into the tail vein and offers a new avenue for therapeutic strategies in renal disease.