Decoy receptor 3 ameliorates an autoimmune crescentic glomerulonephritis model in mice.
Autoimmune crescentic glomerulonephritis (ACGN) is a variant of crescentic glomerulonephritis. The outcome of treatment of crescentic glomerulonephritis is poor. Binding of decoy receptor 3 (DCR3) to its ligand is capable of downregulating the alloresponsiveness of T cells. DCR3 has also been shown to benefit an experimental autoimmune model of diabetes. This study tested the hypothesis that a potential immune regulator, DCR3, could prevent the evolution of ACGN. With the use of an established ACGN model in mice, mice were treated with 100 microg/10 g body wt human DCR3 by hydrodynamics-based gene delivery at 14-d intervals. The results showed that the gene therapy resulted in (1) suppression of T and B cell activation and T cell proliferation; (2) a reduction in serum levels of proinflammatory cytokines; (3) improvement of proteinuria and renal dysfunction; (4) prevention of glomerular crescent formation, renal interstitial inflammation, and glomerulosclerosis; (5) a reduction in serum levels of autoantibodies and glomerular immune deposits; (6) inhibition of apoptosis in the spleen and kidney; (7) prevention of T cell and macrophage infiltration of the kidney; and (8) suppression of fibrosis-related gene expression in the kidney compared with empty vector-treated (disease control) ACGN mice. On the basis of these findings, it is proposed that human DCR3 exerts its preventive and protective effects on ACGN through modulation of T cell activation/proliferation, B cell activation, protection against apoptosis, and suppression of mononuclear leukocyte infiltration in the kidney.
Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan, ROC.
Shuk-Man
SM
Ka
Huey-Kang
HK
Sytwu
Deh-Ming
DM
Chang
Shie-Liang
SL
Hsieh
Pei-Yi
PY
Tsai
Ann
A
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000097:blood / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D001402:B-Lymphocytes; D016207:Cytokines / Q000097:blood; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D005921:Glomerulonephritis / Q000097:blood / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D013154:Spleen / Q000503:physiopathology; D013601:T-Lymphocytes / Q000473:pathology
D016207:Cytokines; D018836:Inflammation Mediators; D053323:Receptors, Tumor Necrosis Factor, Member 6b