LF15-0195 prevents the induction and inhibits the progression of rat anti-GBM disease

Tesch, Greg H.; Hill, Prudence A.; Mu, Wei; Dutartre, Patrick; Atkins, Robert C.

doi:10.1046/j.1523-1755.2001.00940.x

Cited by 14 publications

(15 citation statements)

References 32 publications

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“…The rejection process caused significant parenchymal (renal tubular epithelial cell) injury in both control groups as demonstrated by tubular apoptosis and proliferation (14,16). Animals given liposomal-clodronate were protected from this insult (Fig.…”

Section: Allograft Rejectionmentioning

confidence: 95%

“…A reduction in graft damage was demonstrated by several methods: First, classic histopathologic criteria of renal AR (tubulitis, glomerulitis, and interstitial infiltration) were attenuated (13); second, tubular epithelial cell injury (TUNEL ϩ or BrdU ϩ tubular epithelial cells (14,16)) was reduced; and third, graft function was preserved as shown by serum creatinine (Fig. 5).…”

Section: Immunohistology Of Allografts Demonstrates Inos (A-c) and Grmentioning

confidence: 99%

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Macrophages act as effectors of tissue damage in acute renal allograft rejection

et al. 2003

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Section: Allograft Rejectionmentioning

confidence: 95%

Section: Immunohistology Of Allografts Demonstrates Inos (A-c) and Grmentioning

confidence: 99%

Macrophages act as effectors of tissue damage in acute renal allograft rejection

et al. 2003

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“…ELISAs were used to measure urine levels of albumin (Bethyl Laboratories, Montgomery, TX) and serum levels of cystatin C (BioVendor, Karasek, Czech Republic) and immunoglobulin. 26 Levels of K + or Na + in plasma or urine were determined by indirect potentiometry using ion selective electrodes.…”

Section: Hematology and Biochemical Analysismentioning

confidence: 99%

“…Briefly, immunofluorescence staining of glomerular immunoglobulin and C3 was performed on ethanol-fixed sections and scored as previously described. 26 Immunoperoxidase staining for leukocytes (CD68, CD3, Ly6g) was performed on 2% paraformaldehydelysine-periodate-fixed kidney cryostat sections and assessed using established protocols. 28 Immunoperoxidase staining for MR, a-smooth muscle actin, activated caspase-3, and Wilms' tumor-1 was performed on formalin-fixed sections (4 mm) and analyzed according to a previous report.…”

Section: Histology and Immunostainingmentioning

confidence: 99%

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

Huang

Nikolic-Paterson

Han

et al. 2014

Journal of the American Society of Nephrology

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Clinical and experimental studies have shown that mineralocorticoid receptor (MR) antagonists substantially reduce kidney injury. However, the specific cellular targets and mechanisms by which MR antagonists protect against kidney injury must be identified. PodMRKO) to establish the role of MR in these cell types in the development of mouse GN. Accelerated anti-glomerular basement membrane GN was examined in groups of mice: MyMRKO, PodMRKO, wildtype (WT) littermates, and WT mice receiving eplerenone (100 mg/kg twice a day; EPL-treated). At day 15 of disease, WT mice had glomerular crescents (37%65%), severe proteinuria, and a 6-fold increase in serum cystatin-C. MyMRKO, PodMRKO, and EPL-treated mice with GN displayed proteinuria similar to that in these disease controls. However, MyMRKO and EPL-treated groups had a 35% reduction in serum cystatin-C levels and reduced crescent numbers compared with WT mice, whereas PodMRKO mice were not protected. The protection observed in MyMRKO mice appeared to result predominantly from reduced recruitment of macrophages and neutrophils into the inflamed kidney. Suppression of kidney leukocyte accumulation in MyMRKO mice correlated with reductions in gene expression of proinflammatory molecules (TNF-a, inducible nitric oxide synthase, chemokine (C-C motif) ligand 2, matrix metalloproteinase-12), tubular damage, and renal fibrosis and was similar in EPL-treated mice. In conclusion, MR signaling in myeloid cells, but not podocytes, contributes to the progression of renal injury in mouse GN, and myeloid deficiency of MR provides protection similar to eplerenone in this disease.

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“…LF 15-0195, the recently developed analog of DSG devoid of the abovementioned drawbacks, has improved immunosuppressive activity compared with DSG (11). LF 15-0195, which is now being investigated as a potential therapeutic drug for human inflammatory diseases, has demonstrated its efficacy in allotransplantation (12) and in Ab-mediated autoimmune diseases (13,14). However, its effect on cell-mediated autoimmunity has not yet been tested.…”

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confidence: 99%

LF 15-0195 Inhibits the Development of Rat Central Nervous System Autoimmunity by Inducing Long-Lasting Tolerance in Autoreactive CD4 T Cells

Duplan

Dutartre

Mars

et al. 2003

The Journal of Immunology

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Experimental autoimmune encephalomyelitis (EAE) is a T cell-dependent autoimmune disease induced in susceptible animals by a single immunization with myelin basic protein (MBP). LF 15-0195 is a novel immunosuppressor that has been shown to have a potent immunosuppressive effect in several pathological manifestations. The purpose of this study was to investigate the effect of this drug on the induction and progression of established rat EAE and to dissect the mechanisms involved. We show that LF 15-0195 administration at the time of MBP immunization reduces the incidence and severity of EAE in Lewis rats. This drug also inhibits ongoing and passively induced EAE, indicating that LF 15-0195 affects already differentiated pathogenic lymphocytes. Compared with lymph node cells from untreated rats, lymphocytes from MBP-immunized rats treated with LF 15-0195 proliferated equally well in response to MBP in vitro, while their ability to produce effector cytokines and to transfer EAE into syngeneic recipients was significantly reduced. This phenomenon is stable and long-lasting. Indeed, neither IL-12 nor repeated stimulation with naive APC and MBP in vitro rendered MBP-specific CD4 T cells from protected rats encephalitogenic. In conclusion, LF 15-0195 treatment suppresses EAE by interfering with both the differentiation and effector functions of autoantigen-specific CD4 T cells.

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LF15-0195 prevents the induction and inhibits the progression of rat anti-GBM disease

Cited by 14 publications

References 32 publications

Macrophages act as effectors of tissue damage in acute renal allograft rejection

Macrophages act as effectors of tissue damage in acute renal allograft rejection

Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease

LF 15-0195 Inhibits the Development of Rat Central Nervous System Autoimmunity by Inducing Long-Lasting Tolerance in Autoreactive CD4 T Cells

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