Alfons Billiau

Interferon-gamma: biology and role in pathogenesis.

Publisher Summary The chapter focuses on the salient issues and most recent advances concerning IFN-γs biological function to provide a framework for understanding its role in disease. Medical interest in IFN-γ stems from awareness that a prominent target cell of IFN-γ, the macrophage, occupies a central position in the immune system. Adequate function of the IFN-γ/macrophage system is essential for natural as well as acquired resistance to infection and cancer. Malfunctioning of the system is recognized to be instrumental in inflammatory and autoimmune disease. Of all known cytokines, IFN-γ belongs to the small group that has already been tested for therapeutical effects in patients. IFN-γ is a glycoprotein the size, amino acid sequence, and glycosylation of that are well conserved among animal species. Investigation of IFN-γ signal transduction has brought to light a new pathway—that is, the STAT molecules that are used by many different cytokines. The NK cell population has been identified as a source of IFN-γ that appears to be as important as the T cells. Identification of IFN-γ as a mediator of tissue reactions in inflammatory and autoimmune disease has generated a cogent quest for usable antagonists—for example, humanized monoclonal antibodies, soluble receptors, or antagonistic cytokines.

Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases

Freund’s adjuvants are irreplaceable components of induction protocols of many experimental animal models of autoimmune disease. Apart from the early studies done in the 1950s and 1960s, no further direct investigation on the mode of action of these adjuvants has been undertaken. It is generally assumed that incomplete (IFA) and complete Freund’s adjuvant (CFA) act by prolonging the lifetime of injected autoantigen, by stimulating its effective delivery to the immune system and by providing a complex set of signals to the innate compartment of the immune system, resulting in altered leukocyte proliferation and differentiation. Here, we review evidence collected from various types of studies that provide more insight in the specific alterations of the immune response caused by IFA and CFA. Early events include rapid uptake of adjuvant components by dendritic cells, enhanced phagocytosis, secretion of cytokines by mononuclear phagocytes, and transient activation and proliferation of CD4+ lymphocytes. The mycobacterial components within CFA signal T lymphocytes to assume a Th1 profile so that strong delayed‐type hypersensitivity against autoantigens develops. In the absence of mycobacteria, T‐lymphocyte differentiation tends to assume a Th2 profile with strong antibody production only. The mycobacterial component also accounts for a morphologic and functional remodeling of the haemopoietic system that develops over a period of several weeks and that is characterized by a drastic expansion of Mac‐1+ immature myeloid cells. These cells have been found to be associated with enhanced disease in some models but with reduced disease in others. Thus, in experimental autoimmune diseases, CFA‐mediated activation of the innate immune compartment is important not only by regulating the early induction phase but also by providing a surplus of effector and regulator cells in the late phase.

Production of Interleukin-6 by Folliculo-Stellate Cells of the Anterior Pituitary Gland in a Histiotypic Cell Aggregate Culture System

Reaggregate cell cultures of mouse or rat anterior pituitary were found to produce interleukin-6 (IL-6), a cytokine known for its multiple actions in the immune system. Studies on aggregates prepared from differentially enriched pituitary cell populations revealed the presence of folliculo-stellate (FS) cells to be essential for IL-6 production. Aggregates that contained only hormone-secreting, but no FS cells, failed to produce IL-6. Furthermore, the yield of IL-6 increased with increasing proportions of FS cells present in the aggregates. It is suggested that IL-6 participates in the local regulation of the secretory function of the hypophysis and may constitute a link between events in the immune system and those in the endocrine system.

Interferon-γ: A historical perspective

This article reviews the main lines of thinking and exploration that have led to our current conception of the role of IFN-gamma in immune defense and autoimmunity. In 1965 the first report appeared describing production of an interferon-like virus inhibitor in cultured human leukocytes following exposure to the mitogen phytohemagglutinin. In the early 1970s the active principle became recognized as being distinct from classical virus-induced interferons, leading to its designation as immune interferon or Type II interferon, and eventually IFN-gamma. Up to that point interest in the factor had come almost exclusively from virologists, in particular those among them who were believers in interferon. Evidence first coming forward in the 1980s that IFN-gamma is indistinguishable from macrophage-activating factor (MAF), then a prototype lymphokine, was the signal for immunologists at large to become interested. Today IFN-gamma ranks among the most important endogenous regulators of immune responses.

AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-gamma receptor-deficient mice.

Autoimmune collagen-induced arthritis (CIA) in IFN-γR-deficient DBA/1 mice was shown to be reduced in severity by treatment with the bicyclam derivative AMD3100, a specific antagonist of the interaction between the chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4. The beneficial effect of the CXCR4 antagonist was demonstrable when treatment was initiated between the time of immunization and appearance of the first symptoms. Treatment also reduced the delayed-type hypersensitivity response to the autoantigen, collagen type II. These observations are indicative of an action on a late event in the pathogenesis, such as chemokine-mediated attraction of leukocytes toward joint tissues. The notion of SDF-1 involvement was further supported by the observation that exogenous SDF-1 injected in periarthritic tissue elicited an inflammatory response that could be inhibited by AMD3100. The majority of leukocytes harvested from inflamed joints of mice with CIA were found to be Mac-1+ and CXCR4+, and AMD3100 was demonstrated to interfere specifically with chemotaxis and Ca2+ mobilization induced in vitro by SDF-1 on Mac-1+/CXCR4+ splenocytes. We conclude that SDF-1 plays a central role in the pathogenesis of murine CIA, by attracting Mac-1+/CXCR4+ cells to the inflamed joints.

Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock

Sepsis and its potentially lethal complication, septic shock, belong to the most frequent causes of mortality in modern clinics and, especially, in intensive care units. Moreover, the incidence of this condition is steadily increasing. Multiple circumstances underlie this increasing trend: increasing longevity in developed countries with attendant susceptibility to infections; increased use of immunosuppressive therapy, e.g. for patients with organ transplants; and increased u-e of extensive and sophisticated surgery that allows survival for patients who would otherwise die of causes such as cancer, extensive trauma, burns, extensive blood loss. etc. The pathogenesis of shock has been a matter of intensive study for many years. The vascular and tissue alterations in shock have of old been recognized to be mainly due to the pharmacological actions of plasmaand tissue-derived mediators. Amongst these mediators, the so-called cytokines have recently received increasing attention of investigators. Not only have ‘older’ members of this molecular family (e.g. the endogenous pyrogens) been fully characterized, but new members have also been discovered. Moreover, the complex of interactions amongst cytokines, the socalled cytokine network, is now being progressively disentangled. Here we wish to review current views on the role of the cytokine network in sepsis. Before doing so, it may be useful to recall that the potentially lethal complications of sepsis always comprise three elements (Fig. 1). Any one of these may act

Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-γ

Mice with a deficiency in IFN-γ or IFN-γ receptor (IFN-γR) are more susceptible to collagen-induced arthritis (CIA), an experimental autoimmune disease that relies on the use of complete Freunds adjuvant (CFA). Here we report that the heightened susceptibility of IFN-γR knock-out (KO) mice is associated with a functional impairment of CD4+CD25+ Treg cells. Treatment of wild-type mice with depleting anti-CD25 antibody after CFA-assisted immunisation with collagen type II (CII) significantly accelerated the onset of arthritis and increased the severity of CIA. This is an indication of a role of Treg cells in the effector phase of CIA. IFN-γR deficiency did not affect the number of CD4+CD25+ T cells in the central and peripheral lymphoid tissues. In addition, CD4+CD25+ T cells isolated from naive IFN-γR KO mice had a normal potential to suppress T cell proliferation in vitro. However, after immunisation with CII in CFA, the suppressive activity of CD4+CD25+ T cells became significantly more impaired in IFN-γR-deficient mice. Moreover, expression of the mRNA for Foxp3, a highly specific marker for Treg cells, was lower. We further demonstrated that the effect of endogenous IFN-γ, which accounts for more suppressive activity in wild-type mice, concerns both Treg cells and accessory cells. Our results demonstrate that the decrease in Treg cell activity in CIA is counter-regulated by endogenous IFN-γ.

How interferon-γ keeps autoimmune diseases in check

Interferon-gamma (IFN-gamma) is regarded traditionally as a proinflammatory factor and as the signature cytokine of Th1-dominated autoimmune processes. Early evidence indicative of an opposite, protective role has recently received further attention from reports revealing an increasing number of pathways by which IFN-gamma can counteract harmful inflammation in Th1-associated autoimmune diseases. Here, we review evidence for IFN-gammas anti-inflammatory effects primarily from the perspective of one experimental model, collagen-induced arthritis (CIA), and question the classic proinflammatory role of IFN-gamma and also the Th1-Th2 paradigm as a basis for explaining the regulation of autoimmune diseases. We conclude that endogenous production of IFN-gamma during inflammatory and autoimmune diseases should be considered as a process with bidirectional immunoregulatory consequences, often resulting in moderation of pathology.

Anti-interferon-γ antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia

C57BL/6N mice bearing Lewis lung tumours were treated with anti-gamma-interferon (IFN-gamma) monoclonal antibodies. Early, but not late, treatment inhibited tumour growth, suggesting that endogenous IFN-gamma promotes initial tumour cell proliferation. Tumour development was associated with failure to gain weight or with progressive weight loss. Anti-IFN-gamma given early or late counteracted this wasting syndrome, which indicates that IFN-gamma production subsists during tumour growth and is directly or indirectly responsible for tumour-associated cachexia. Studies of body composition in cachectic mice revealed fat tissue to be particularly affected. Fat loss was enhanced by IFN-gamma and antagonised by anti-IFN-gamma. Tumour-bearing mice were also hypersensitive to the lethal effect of endotoxin; anti-IFN-gamma was unable to mitigate this sensitisation, suggesting that IFN-gamma does not exert its cachexia-inducing effect through augmentation of the host response to an endogenous endotoxin source.

Specific lysis of an iliofemoral thrombus by administration of extrinsic (tissue-type) plasminogen activator

Abstract Intravenous administration of human extrinsic (tissue-type) plasminogen activator (7·5 mg over 24 h) induced complete lysis of a 6-week-old renal and iliofemoral thrombosis in a renal-allograft recipient. Thrombolysis was achieved without systemic fibrinolytic activation or haemostatic breakdown and was not associated with bleeding.