Regulatory T cells and minimal change nephropathy: in the midst of a complex network

Abstract

Minimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (Tregs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct Treg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating Tregs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of Tregs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigen-presenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years.

Keywords: IL-2; LPS nephropathy; minimal change nephropathy; regulatory T cells.

Figure 1

An overview of cells involved in an inflammatory event. Monocytes and polymorphonuclear cells produce oxidants (O2^–) in response to an external inflammatory trigger (bacteria, virus, etc.) as a first defence. Adenosine‐5′‐triphosphate (ATP) deriving from necrosis of these cells activates professional antigen‐presenting cells that interact with both CD4⁺ effectors and CD4⁺CD25⁺forkhead box protein 3 (FoxP3) regulatory cells. Both cell lineages (i.e. CD4⁺ effector and regulatory cells) derive from activation of CD4⁺ thymocytes upon T cell receptor interaction with major histocompatibility complex (MHC) class II that process proteins deriving from the inflammatory trigger to produce specific cells counterbalancing pathogen effects. The balance between CD4⁺ and CD4⁺CD25⁺FoxP3 regulatory cells drive evolution of the inflammatory event. If regulatory T cells (T_regs) prevail over CD4⁺ effectors, then ATP is transformed in adenosine that exerts an anti‐inflammatory effect. Interleukin 10 (IL‐10) also plays an anti‐inflammatory role. If CD4⁺ effectors prevail over T_regs, other inflammatory cells and cytokines expand the inflammatory process. Mechanisms driving the equilibrium between CD4⁺ and CD4⁺CD25⁺FoxP3 regulatory cells are shown in Fig. 2.

Figure 2

Mechanisms regulating CD4⁺ and CD4⁺CD25⁺forkhead box protein 3 (FoxP3) balance. An antigen‐presenting cell (APC) cell interacts with both CD4⁺ and CD4⁺CD25⁺FoxP3 by means of the same ligands, i.e. the T cell receptor (TCR)/CD4/CD3 that interacts with the major histocompatibility complex (MHC) II complex and CD80/86 and CD40. The former molecules, i.e. TCR/CD4/CD3, are present on both CD4⁺ and CD4⁺CD25⁺FoxP3 and does not represent a regulatory mechanism; this route activates the Signal 1 pathway. At variance, CD80/86 interact with CD4⁺CD25⁺FoxP3 cells: in the former case, i.e. CD4⁺, CD80/86 interacts with CD28 and constitutes a positive stimulus for CD4⁺ expansion (in black), whereas it interacts preferentially with cytotoxic T lymphocyte antigen 4 (CTLA‐4) in CD4⁺CD25⁺FoxP3 and represents an inhibitory mechanism (in purple). Actually, regulatory CD4⁺CD25⁺FoxP3 cells contain both CD28 and CTLA‐4 in a ratio of 1 : 2 that implies that negative regulatory mechanisms prevail in these cells and block the Signal 2 pathway that is necessary for activating CD4⁺ effector cells. CD40–CD40L has the same expression in both cell lineages and does not represent a regulatory mechanism.

Figure 3

Podocytes may be directly involved in the early immunity response. Oxidants produced by circulating cells in the early immune response may be toxic for podocytes. regulatory T cells (T_regs) reduce the oxidative impact by metabolizing adenosine‐5′‐triphosphate (ATP) to adenosine. Under inflammatory stimuli, podocytes express both Toll‐like receptor (TLR)‐4 and CD80 and become a part of the initial immune response. Podocytes also express CD40 constitutively, whose stimulation by soluble (s)CD40L induces the redistribution and loss of nephrin and increases albumin permeability in isolated rat glomeruli.