Prophylaxis of antibody-induced acute glomerulonephritis with genetically modified bone marrow-derived vehicle cells.

Glomerulonephritis is an inflammatory disease of the renal glomerulus, which often progresses either slowly or rapidly, ending in renal death despite the availability of various antiinflammatory drugs. Gene therapy may be a promising method of suppressing the progression of glomerulonephritis through the blockage of key inflammatory molecule(s). However, the difficulty of local gene delivery into the glomerulus has made the clinical use of gene therapy difficult. As a solution to this issue, we applied a novel ex vivo technique that may allow site-specific gene delivery into the inflamed site and thus suppress local inflammation in the glomerulus, and examined the feasibility of this system as a prophylaxis of glomerulonephritis. The gene encoding the antiinflammatory cytokine interleukin 1 receptor antagonist (IL-1ra) was delivered into animal models of inflamed glomeruli evoked by anti-glomerular basement membrane antibody; this animal model is an analog of the human Goodpasture syndrome. Vehicle cells did indeed accumulate in the glomeruli on the induction of nephritis and were confirmed to secrete recombinant IL-1ra. Renal functions as well as morphology were preserved by this intervention for up to 14 days after IL-1ra introduction. These data demonstrate the possible application of gene therapy for acute glomerulonephritis. A gene encoding an antiinflammatory molecule, IL-1 receptor antagonist, was delivered into inflamed glomeruli, using a technique that may allow site-specific gene delivery into inflamed tissues. The progression of experimental acute glomerulonephritis was effectively suppressed by this intervention for at least 14 days after gene introduction. This success may strengthen the rationale for gene therapy in the treatment of inflammatory diseases such as glomerulonephritis.