No abstract

Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-␤/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-␤ signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 ؋ DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-B activation (P < 0.01), thereby inhibiting ␣-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1␤ and IL-6), adhesion molecule/ chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4 ؉ cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.

Lupus nephritis (LN) is divided into 6 classes based on the severity of the renal histopathologic lesions (1), and histologic transformation between the classes occurs frequently (2,3). Although the exact mechanisms for the histologic transformation of mild mesangial LN into severe renal conditions remain unclear, acute induction of cellular and humoral autoimmunity, including the production of anti-double-stranded DNA (antidsDNA) antibodies (4,5), overexpression of cytokines and chemokines (6,7), differential activation of B cells (8,9), abnormal T cell activation (6,10), and Dnase1 deficiency (11,12), has been implicated. In addition, abundant production of interleukin-12 (IL-12) and IL-18 is seen in the glomeruli of patients and in mouse models of LN, and Th1 cytokines are highly implicated in the development and progression of .IL-18 has also been reported to promote the migration of circulating dendritic cells to the kidney in active LN (15,16). We recently demonstrated that expression of IL-18, induced with lipopolysaccharide

The EAL regimen can achieve an efficacy similar to that of the standard EBTM therapy. It may be very useful in countries where bismuth salts are not available. Compliance, CYP2C19 genotype and resistances to antibiotics may influence the outcome of levofloxacin-based rescue therapy. It seems advisable to reserve levofloxacin for rescue treatment to avoid an increase in the resistance phenomenon.

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 g/10 g body wt human DCR3 by hydrodynamicsbased 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.