Inhibition of murine nephritogenic effector T cells by a clone-specific suppressor factor.

Abstract

We have used a murine model of organ-specific autoimmunity to characterize therapeutic modalities capable of downregulating the cellular limb of the autoimmune response. Murine interstitial nephritis is an autoimmune disease mediated by tubular antigen-specific CD8+ nephritogenic effector T cells which are delayed-type hypersensitivity (DTH)

A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens

“…Although effector suppressor cells are antigen specific, once activated they produce factors that nonspecifically suppress immune responses to other antigens in the vicinity (22). This suggests that the final molecule that suppresses immune responses is probably an antigennonspecific regulatory molecule (probably a suppressive cytokine).…”

TGF-β and Regulation ofInterstitial Nephritis

“…The presentation of this tubular antigen in tolerogenic forms (such as with IFA [24], or coupled to the surface of syngeneic spleen cells [25,26]) results in the maturation of effector T cells which suppress both disease activity and the actions of nephritogenic effector T cells [17,27]. In the course of investigating the requirements for such suppression, we found that inhibition of murine nephritogenic effector T cells by antigenspecific suppressive mechanisms required the expression of TGF-ß1 [28]. We showed that the induction of TGF-ß1 expression in a nephritogenic effector T-cell clone (which was cytotoxic to tubular epithelial cells) was required both for inhibition of T-cell-mediated cytotoxicity and inhibition of nephritogenic function following adoptive transfer.…”

“…We showed that the induction of TGF-ß1 expression in a nephritogenic effector T-cell clone (which was cytotoxic to tubular epithelial cells) was required both for inhibition of T-cell-mediated cytotoxicity and inhibition of nephritogenic function following adoptive transfer. Nephritogenic function refers to the ability of the T cells to infiltrate the kidney and elicit inflammatory lesions following adoptive transfer [18,28]. Induced TGF-ß expression in the nephritogenic T-cell clone was a stable change in cytokine expression and constituted an autocrine mechanism of inhibition of T-cell function [28].…”

“…Nephritogenic function refers to the ability of the T cells to infiltrate the kidney and elicit inflammatory lesions following adoptive transfer [18,28]. Induced TGF-ß expression in the nephritogenic T-cell clone was a stable change in cytokine expression and constituted an autocrine mechanism of inhibition of T-cell function [28]. It is interesting that cyclosporine A also induces the expression of TGF-ß in lymphocytes [29], as well as other cell types, including renal parenchymal cells [30].…”

Regulation of Inducible Class II MHC, Costimulatory Molecules, and Cytokine Expression in TGF-β1 Knockout Renal Epithelial Cells: Effect of Exogenous TGF-β1

“…In these models, systemic administration of TGF-β1 delays the onset or reduces the severity of disease, while the administration of anti-TGF-β1 antibodies increases their severity [2, 3, 4]. Moreover, other investigations indicate that blocking TGF-β1 expression augments inflammatory responses in the kidney [5, 6, 7]. Such observations are noteworthy in view of the widely held notion that TGF-β plays a prominent pathologic role in extracellular matrix accumulation in immune system mediated renal diseases [8, 9, 10, 11].…”