Induction of T Regulatory Cells Attenuates Idiopathic Nephrotic Syndrome

Buffalo/Mna rats spontaneously develop FSGS and nephrotic syndrome as a result of an immune disorder. Similar to some humans with FSGS, the disease recurs after renal transplantation, suggesting the involvement of a circulating factor. Here, we tested the effect of several immunosuppressive treatments on these rats. Although corticosteroids, cyclosporin A, and anti–T cell receptor treatment reduced proteinuria, only the deoxyspergualin derivative LF15-0195 led to a rapid and complete normalization of proteinuria. Furthermore, this compound led to the regression of renal lesions during both the initial disease and posttransplantation recurrence. The frequency of splenic and peripheral CD4⁺CD25⁺FoxP3⁺ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195–induced 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 forms^5–7 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 mo of age.^9,10 In addition to a genetic background predisposing to 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 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 a deoxyspergualin (DSG) derivative, LF15-0195,¹⁴ specifically induced a rapid and complete 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.