New immunosuppresor strategies in the treatment of murine lupus nephritis

Abstract

Renal involvement in systemic lupus erythematosus is a common complication that significantly worsens morbidity and mortality. Although treatment with corticosteroids and cytotoxic drugs may be useful in many cases, morbidity associated with these drugs and the relapsing nature of the disease make it necessary to develop new treatment strategies. Five-month old female NZB/W F1 mice were divided into the following groups: CYP group (n = 10), cyclophosphamide (CYP) 50 mg/kg intraperitoneally every 10 days; RAPA 1 group (n = 10) oral daily sirolimus (SRL), 1 mg/kg; RAPA 12 group (n = 13), oral daily SRL, 12mg/kg; FTY group (n = 10), oral fingolimod (FTY720), 2 mg/kg three times per week. An additional group of 13 non-treated mice were used as a control (control group). Follow-up was performed over four months. Animal survival, body weight, anti-DNA antibodies and proteinuria were determined. Kidneys were processed for conventional histology and immunofluorescence for IgG and complement. Total histological score (HS) was the sum of mesangial expansion, endocapillary proliferation glomerular deposits, extracapillary proliferation, interstitial infiltrates, tubular atrophy and interstitial fibrosis. All treated groups had lower proteinuria at the end of the follow-up with respect to the control group (P < 0.0001). Serum anti-DNA antibodies were appropriately controlled in RAPA 1 and CYP groups, but not in FTY or RAPA 12 groups. SRL and CYP arrested, and perhaps reversed almost all histological lesions. FTY720 ameliorated histological lesions but did not control mesangial expansion or interstitial infiltrates. SRL produces great improvement in murine lupus nephritis, while FTY720 seems a promising alternative if used in appropriate doses.

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

“…Although glomerular injury is always accompanied by interstitial inflammation in lupus nephritis, the pathogenesis of these entities and their responses to some treatments seem to be different. For example, treatment with oral fingolimod (FTY720) and with the targeted murine C3 complement inhibitor CR2-Crry was found to be more effective in ameliorating glomerular injury than in controlling interstitial infiltrates and lesions (37,38). Otherwise, blockade of CCR1 could selectively halt interstitial leukocyte recruitment and fibrosis but not glomerular injury in MRL/lpr mice (39).…”

Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

“…Rapamycin was described on the one hand to limit autoimmune disease 7 but on the other hand to have the potential to Figure 1. Rapamycin started on the day of immunization significantly reduces albuminuria and PAS-positive deposits in glomeruli.…”

“…4,5 In addition, rapamycin has been shown to inhibit the proliferation of B cells and has very recently been described to be a potential ther-apeutic option in systemic lupus erythematosus. 6,7 Both studies evaluated the effect of rapamycin or its derivative everolimus on lupus-prone mice, namely NZB/W F1 or B6.Sle1 z .Sle3 z mice. 6,7 They provided evidence that rapamycin treatment significantly decreased autoantibody production, thereby reducing glomerulonephritis (GN) 6,7 ; however, further evidence suggested that rapamycin can lead to an increase in proteinuria followed by a decline in renal function.…”

“…6,7 Both studies evaluated the effect of rapamycin or its derivative everolimus on lupus-prone mice, namely NZB/W F1 or B6.Sle1 z .Sle3 z mice. 6,7 They provided evidence that rapamycin treatment significantly decreased autoantibody production, thereby reducing glomerulonephritis (GN) 6,7 ; however, further evidence suggested that rapamycin can lead to an increase in proteinuria followed by a decline in renal function. 8 -10 Oberbauer et al 11 reported a significant increase in the rate of proteinuria in patients who had been switched from a calcineurin inhibitor-based immunosuppressive regimen to rapamycin.…”

“…Divergent findings on the influence of rapamycin in experimental models of kidney disease have been published. Whereas some of the studies found rapamycin to be beneficial for the outcome of kidney disease, 7,[13][14][15] others observed that rapamycin treatment led to exacerbation of disease. 16 Mechanistically, both outcomes were traced back to the widely known inhibitory effect of rapamycin on vascular endothelial growth factor-A (VEGF-A).…”