This finding suggests that the properties of these cells were modified by the LF15-0195 treatment and indicates the acquisition of a specificity for a pathologic element

This finding suggests that the properties of these cells were modified by the LF15-0195 treatment and indicates the acquisition of a specificity for a pathologic element. recurrence. The frequency of splenic and peripheral CD4+CD25+FoxP3+ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195Cinduced CD4+CD25+ T cells to irradiated Buff/Mna rats significantly reduced their proteinuria compared with the transfer of untreated control cells, suggesting that LF15-0195 induces regulatory T cells that are able to induce regression of rat nephropathy. These data suggest that idiopathic nephrotic syndrome/FSGS disease can be regulated by cellular transfer, but how this regulation leads to the reorganization of the podocyte cytoskeleton remains to be determined. Idiopathic nephrotic syndrome (INS) with primary FSGS lesions is a disease of unknown cause that is defined by selective proteinuria, hypoalbuminemia, and nonspecific lesions with a glomerular sclerosis. Although treatments such as corticosteroids, cyclosporin A (CsA), and cyclophosphamide remain useful, at least 20% of affected patients ultimately require hemodialysis and/or kidney transplantation for end-stage renal failure. Moreover, despite treatment, the initial disease immediately relapses in 30 to 50% of transplant patients1 and leads to the loss of the graft. This immediate (and iterative) recurrence, together with the beneficial effect of plasmatic exchanges2 or immunoadsorptions,3,4 strongly supports the presence of a circulating factor. The majority of animal models of FSGS present secondary forms5C7 and do not supply a causal model with a permeability factor.8 The Buffalo/Mna rat strain develops a spontaneous glomerulonephritis (with albuminuria, edema, and lipidic disorders) at 3 mo of age, and FSGS lesions appear at 4 to 6 6 mo of age.9,10 In addition to a genetic background predisposing to Rabbit Polyclonal to Cytochrome P450 26C1 proteinuria11 (a growing concept also noted in humans), we recently highlighted the involvement of an extrarenal circulating factor. We demonstrated both the recurrence of the initial disease after transplantation of normal rat kidneys into Buff/Mna recipients and remission when nephrotic Buff/Mna kidneys were transplanted into normal rats.12 We also highlighted the involvement of activated macrophages and Th2 lymphocytes in this disease,13 as reported in the human disease. All Refametinib of these findings suggest that this rat model may be relevant for studying the challenge of INS recurrence after transplantation in the clinic. In this study, we used the Buff/Mna strain to test the antiproteinuric effect of various immunoregulatory compounds. Only Refametinib a deoxyspergualin (DSG) derivative, LF15-0195,14 specifically induced a rapid and complete Refametinib remission of the initial kidney disease as well as its posttransplantation recurrence. This effect was manifested as a resolution of both proteinuria and histologic lesions. These findings may provide novel insights into the development of innovative, clinically applicable therapeutics for the treatment of INS. RESULTS Effect of Drugs Frequently Used in the Clinic for the Treatment of Patients with INS/FSGS and AntiCT Cell Receptor MAb Corticosteroid treatment significantly reduced urinary protein excretion (lowest proteinuria at day 10 51% reduction), but treatment did not lower levels to those within the normal range of proteinuria for healthy rats ( 0.2 g/mmol). In the same way, CsA treatment and the combination of corticosteroids and CsA resulted in a significant decrease in proteinuria (lowest at day 30 64% reduction; lowest at day 63 68% reduction, respectively) but again did not normalize it (see Supplemental Figures a through c). The administration of R7.3 antibodies for 9 d rapidly decreased proteinuria (50% reduction), but this decrease was transient and did not reach normalization. The combination of R7.3 and CsA significantly decreased proteinuria Refametinib (65%) but did not normalize levels (Supplemental Figure d). LF15-0195 Consistently Induces a Complete Remission of the Buff/Mna Native Disease as Well as Its Recurrence after Kidney Transplantation Effect of LF15-0195 on the Initial Nephrotic Syndrome. First, we showed that Refametinib LF15-0195 treatment prevented the development of nephrotic-range proteinuria in 2-mo-old Buff/Mna rats when administered at the onset of proteinuria (0.2 g/mmol; Figure 1A). The prevention of proteinuria occurrence in these animals was still efficient 1 mo after treatment withdrawal, at which point proteinuria reverted progressively to reach the values observed in vehicle-treated, aged-matched Buff/Mna.