Elsevier

Cytokine & Growth Factor Reviews

Volume 13, Issues 4–5, August–October 2002, Pages 315-321
Cytokine & Growth Factor Reviews

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Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments

https://doi.org/10.1016/S1359-6101(02)00019-9Get rights and content

Abstract

Deregulated TNF production, be it low or high, characterizes many autoimmune diseases. Recent evidence supports a dualistic, pro-inflammatory and immune- or disease-suppressive role for TNF in these conditions. Blocking TNF in autoimmune-prone chronic inflammatory diseases may, therefore, lead to unpredictable outcomes, depending on timing and duration of treatment. Indeed, blockade of TNF in human rheumatoid arthritis or inflammatory bowel disease patients, although so far impressively beneficial for the majority of patients, it has also led to a significant incidence of drug induced anti-dsDNA production or even in manifestations of lupus and neuro-inflammatory disease. Notably, anti-TNF treatment of multiple sclerosis patients has led almost exclusively to immune activation and disease exacerbation. We discuss here recent evidence in murine disease models, indicating an heterogeneity of TNF receptor usage in autoimmune suppression versus inflammatory tissue damage, and put forward a rationale for a predictably beneficial effect of ‘anti-TNFR’ instead of ‘anti-TNF’ treatment in human chronic inflammatory and autoimmune conditions.

Introduction

It is widely accepted today that TNF serves very important functions in pathophysiology, being a factor that interferes strongly with the growth, differentiation and death of both immune and non-immune cell types. By directing its two transmembrane receptors to deliver signals of cellular proliferation, differentiation or apoptosis, TNF appears not only to orchestrate acute responses to infection and immunological injury but also to act as a balancing factor required for the re-establishment of physiological homeostasis and immune regulation. The level, timing and duration of TNF activity are of pivotal regulatory significance in immune physiology. Aberrations in any of these factors result in perturbed phenotypes that depend in a multitude of TNF receptor-mediated activities, be it pro-inflammatory, immune activating, or even immunosuppresive. Within such pleiotropism of functions, blockade of TNF in recent clinical trials of rheumatoid arthritis or inflammatory bowel disease, although so far impressively beneficial for the majority of patients, has also led in some cases to a significant incidence of drug induced anti-dsDNA production and lupus, and in manifestations of neuroinflammatory disease [1], [2], [3]. Moreover, TNF blockade in multiple sclerosis patients has led almost exclusively to immune activation and disease exacerbation [4], [5]. We discuss here recent advances in our understanding of the independent roles played by the two TNF receptors in models of chronic organ-specific or systemic autoimmune disease, and put forward a rationale for a predictably beneficial effect of anti-TNF receptor treatments in these pathologies. Presented data have important implications for potential flaws with current anti-TNF therapies in human immunopathologies, and strongly suggest that alternative anti-TNFR strategies may be advantageous.

Section snippets

Contrasting activities of TNF in inflammation and autoimmunity

There is now clear evidence that aberrations in TNF production in vivo may be either pathogenic or protective. The temporal and spatial deregulation of TNF production in transgenic, non-autoimmune-prone mice, promotes p55TNF-R-dependent pathologies, such as multi-organ inflammation [6], [7], [8], rheumatoid arthritis [9], multiple sclerosis [10], [11], [12] and inflammatory bowel disease [13]. However, in contrast to a predictable enhancing effect of chronic inflammation on autoimmune

The role of TNF and receptors in anti-myelin autoimmunity: TNF exerts strong tolerogenic activities even in the absence of TNFRI

Primed T cells differentiate into effectors and exert their function, which in the case of CD4+ T cells, is mainly the elimination of intracellular pathogens and viruses, as well as help for other lymphocytes. Once the pathogen is eliminated, the majority of the responding cells subside, but also immunological memory to the pathogen is established. In contrast to memory of foreign antigens, which is well established, recent studies have challenged the development of T cell ‘memory’ for

Role of TNF and receptors on systemic autoimmunity and associated tissue damage

Systemic lupus erethymatosus (SLE) is a prototype systemic autoimmune disease of a complex multigenic character. Common features of SLE, present both in the human condition and its animal models include the (a) appearance of auto-antibodies against a variety of nuclear antigens indicating a breaking of tolerance to those widespread antigens and (b) the development of glomerulonephritis from the deposition of the immune complexes onto the glomerulus basement membrane in the kidney. Although, the

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