Induction of T Regulatory Cells Attenuates Idiopathic Nephrotic Syndrome

Abstract

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 ϩ CD25 ϩ FoxP3 ϩ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195-induced CD4 ϩ CD25 ϩ 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.

Rituximab in Children with Steroid-Dependent Nephrotic Syndrome

“…Most participants in the present trial remained in remission for several months after reconstitution of CD20 + lymphocytes, suggesting that the clinical effect of rituximab may continue beyond its biologic activity on CD20 and that, therefore, CD20 levels alone are not helpful in decision-making about timing of repeated infusions. Rituximab depletes the B cell population, yet this disease has been historically considered a T cell disorder 19,20 that is potentially mediated by a circulating factor. 21,22 Published investigations offer some insight as to potential explanations for this apparent paradox.…”

“…27 Second, depletion of B cells may restore the regulatory T-cell population, 29,30 which is deficient in nephrotic syndrome. 19,31 Rituximab may also deplete the IL-17-producing CD4 + T cells (Th17), which express CD20 on their surface and have been implicated in the pathogenesis of the disease. 32,33 The anti-Th17 effect of rituximab formed the theoretical basis for its use in rheumatoid arthritis [34][35][36][37] and in small vessel vasculitis.…”

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

“…However, a T helper 2-predominant T cell infiltrate accompanied by elaboration of macrophageassociated cytokines has been described in a Buffalo/Mna rat model of proteinuria with corresponding histologic FSGS lesions (23). The same group further showed amelioration of proteinuria in Buffalo/Mna rats with regression of FSGS lesions by CD4 + CD25 + T lymphocyte transfer (24), highlighting the potential therapeutic role of T regulatory cells in FSGS.…”

The Treatment of Minimal Change Disease in Adults

“…T-regulatory (T reg ) cells, which attenuate immune responses by suppression of T-effector cells, are dysfunctional in humans with MCD, 4,5 and augmentation or supplementation of T reg cell function has led to decreased proteinuria in a rat model of the idiopathic NS. 6 In addition to T reg cell dysfunction, the roles of two podocyte proteins have been explored in MCD: CD80 and angiopoietin-like protein 4 (Angptl4). CD80 (also known as B7-1) is a transmembrane protein that is present on antigen-presenting cells and acts as a costimulatory signal for T cell activation.…”