The role of cytokines in liver failure and regeneration: potential new molecular therapies

The liver is a unique organ, and first in line, the hepatocytes encounter the potential to proliferate during cell mass loss. This phenomenon is tightly controlled and resembles in some way the embryonal co-inhabitant cell lineage of the liver, the embryonic hematopoietic system. Interestingly, both the liver and hematopoietic cell proliferation and growth are controlled by various growth factors and cytokines. IL-6 and its signaling cascade inside the cells through STAT3 are both significantly important for liver regeneration as well as for hematopoietic cell proliferation. The process of liver regeneration is very complex and is dependent on the etiology and extent of liver damage and the genetic background. In this review we will initially describe the clinical relevant condition, portraying a number of available animal models with an emphasis on the relevance of each one to the human condition of fulminant hepatic failure (FHF). The discussion will then be focused on the role of cytokines in liver failure and regeneration, and suggest potential new therapeutic modalities for FHF. The recent findings on the role of IL-6 in liver regeneration and the activity of the designer IL-6/sIL-6R fusion protein, hyper-IL-6, in particular, suggest that this molecule could significantly enhance liver regeneration in humans, and as such could be a useful treatment for FHF in patients.     

The induction in vitro of immunological tolerance in T lymphocytes: an inhibitory role of macrophages.

Hapten-reactive helper T cells were generated in the spleen of C57BL/6 mice primed with sulfanilated syngeneic IgG (S-MGG). Specific immunological tolerance was induced in vitro in these helper T cells, when spleen cell suspension was passed through Sephadex G-10 column to remove adherent cells and cultured in the presence of soluble S-MGG for 21 to 24 hours. On the other hand, tolerance was not inducible in unfractionated, primed spleen cells. When G-10-passed spleen cells were added to the culture dishes containing phagocytic, adherent cells of the spleen, tolerance was no more inducible in these reconstituted cell population. From these experimental results, it was concluded that macrophages played an interfering role in tolerance induction. The experimental data were also discussed in terms of macrophage function in the recognition of antigen by T lymphocytes.     

The role of cytokines in oncology

The availability of sufficient quantities of recombinant human cytokines and promising preclinical data have led to their introduction into clinical trials. Cytokines have potential as new therapeutic agents in a variety of hematological disorders as well as in solid tumors. Only a few of the still increasing number of these glycoprotein hormones have been studied in humans so far, either as single agents or in combination with chemotherapy and other cytokines. Their clinical effects, beneficial role in supportive care, and use in the treatment of certain cancer patients are reviewed.     

The role of cytokines in cancer

The role of cytokines was intensively discussed over the course of a two and a half day meeting sponsored by the US-JAPAN Cancer Cooperative Research Program of the Office of International Affairs, National Cancer Institute and held at The National Institutes of Health, Bethesda, Maryland on 15–17 January 1996. Most of the first day was devoted to a discussion of the role of cytokines in modulating angiogenesis and the consequent effect of this on tumor growth and metastases. This was followed by sessions on the effect of various cytokines in enhancing or suppressing immunological responses to tumors. Several presentations focused on the direct inhibitory or growth promoting effects of cytokines on tumor growth. The final session consisted of a comparison of the efficacy of different approaches to tumor vaccination including gene therapy, enhanced antigen presentation, use of polymeric carriers or of DNA vectors. For background information the reader is referred to appropriate chapters on the role of cytokines in neoplastic diseases (Oppenheim JJ, Rossio JL, Gearing AJH, eds. In Clinical Application of Cytokines: Role of Pathogenesis, Diagnosis and Therapy. Oxford University Press, New York, 1993 [1]).     

The role of cytokines in toxoplasmosis

Infection withToxoplasma gondii is normally asymptomatic, but as a consequence of the AIDS epidemic the incidence of symptomatic disease and especially toxoplasmic encephalitis (TE) has grown in frequency. The high frequency of adverse reactions to conventional therapeutic regimens for toxoplasmosis highlight the need to develop new strategies for the management of this disease. The importance of cytokines in resistance againstT. gondii has been shown primarily in murine models of toxoplasmosis and a number of cytokines (e.g., IFN-, TNF-, IL-2 and IL-12) have been proposed for trials in patients with TE. One mechanism by which these cytokines produce their effects is through stimulation of macrophages and/or NK cells. However, there are problems with immunological intervention in immunocompromised patients with TE since the infection is present primarily in the central nervous system (CNS), an immunoprivileged site, and because certain cytokines may down regulate the immune response. While much valuable information has been obtained from studies conducted in immunocompetent strains of mice their relevance to an immunocompromised host is unknown. The development of genetically altered mice with immune deficiencies offers promising new models that may allow for more rational development of new treatment regimens.Abbreviations AIDS Acquired Immunodeficiency Syndrome - CNS Central Nervous System - GM-CSF Granulo cyte-macrophage colony stimulating factor - HIV Human Immunodeficiency Virus - IL Interleukin - IFN Interferon - LAK Lymphokine Activated Killer - LPS Lipopolysacharide - MIP Macrophage Inflammatory Protein - NK Natural Killer - PCR Polymerase chain reaction - SCID Severe Combined Immunodeficiency - TG Toxoplasmic encephalitis - TGF Transforming Growth Factor - TNF Tumor Necrosis Factor     

Shigella toxicity in immunological tolerance

The toxic effect of killed and live Shigella sonnei cultures on normal mice and on mice, tolerant to Shigella O-antigen and to human erythrocytes of different blood groups (in the ABO system) was under study. The toxicity of shigellae, introduced intraperitoneally, has been found to depend on their viability, on their capacity for penetration into the blood, and on the split character of immunological tolerance to Shigella antigens.     

The role of cytokines in lymphocyte homeostasis

The size of lymphocyte populations is regulated by replication and death. Cytokines produced by non-lymphoid cells provide key survival and replication signals for several lymphocyte subpopulations. The availability of these cytokines thus serves as a homeostatic regulatory mechanism by determining the upper limit of the population size. IL-7 is required for survival of naive CD4+ and CD8+ cells and memory CD8+ cells. IL-15 is required for survival of memory CD8+ cells. IL-12 and IL-4 also promote memory CD8+ survivaL BAFF is required for survival of mature B cells. Antigen receptor signals, together with these cytokine signals, are required for survival of mature B cells and naive T cells. The list of extracellular survival signals for lymphocytes remains incomplete, and the intracellular pathways leading to survival are poorly understood.     

The role of cytokines in pulp inflammation

Pulpitis is a typical inflammatory disease of dental pulp, characterized by the local accumulation of inflammatory mediators, including cytokines and chemokines. In addition to serving as intercellular messengers mediating the inflammatory response, cytokines and chemokines induce the expression and stimulate the activity of molecular and cellular agents which participate actively in destructive and reparative processes in the pulp. It is the balance between these processes which eventually determines the extent of pulp inflammation and the viability of the affected tooth. Over the last decade, a number of studies have attempted to correlate cytokine gene expression in the pulp with various stages of inflammation, with possible diagnostic applications in mind. A small survey of relevant information is presented in this paper.     

The role of cytokines in mycobacterial infection

Mycobacterial infections are a major cause of morbidity and mortality worldwide. The pathogenesis of infection and the mechanisms for the development of protective immunity are poorly known, but cytokines appear to play an important role in the modulation of the immune response. Evidence exists for the role of tumor necrosis factor (TNF-), granulocyte macrophage colony stimulating factor (GM-CSF) and interferon-gamma (IFN-) in the host defense against mycobacteria. In this article we discuss recent findings about the role of cytokines in leprosy, tuberculosis andMycobacterium avium infection, usingin vitro andin vivo human and murine data.Abbreviations M.TB Mycobacterium tuberculois - IFN- interferon gamma - TNF- tumor necrosis factor-alpha - LAM Lipoarabinomannam - IL-8 Interleukin-8 - IL-6 Interleukin-6 - IL-2 Interleukin-2 - CMI cell-mediated immunity - PPD purified protein derivative of tuberculin - MAC Mycobacterium avium complex - AIDS Acquired Immunodeficiency Syndrome - GM-CSF granulocyte macrophage colony stimulating factor - IL-10 Interleukin-10 - TGF transforming growth factor ₁     

The potential role of preventing atherosclerosis by induction of neonatal tolerance to VLDL

Induction of immune tolerance to ox-LDL could reduce atherosclerosis by modulation immune response. We suppose that very low density lipoprotein (VLDL) may have a similar role to ox-LDL in autoimmune response of atherosclerosis. In this study, neonatal rats were injected with ox-LDL, VLDL, or equal-volume saline, respectively. Vaccination with ox-LDL reduced the level of specific antibody, T cells proliferation response, and the level of endothelins. The method also had a tendency of reducing blood lipids. Vaccination with VLDL obviously reduced the level of specific antibody and T cells proliferation. Though there was also a tendency of reducing blood lipids and endothelins, the effect was less prominent than that with ox-LDL. We conclude that, although the effect was less obvious, vaccination with VLDL to induce neonatal tolerance had an effect on modulating immune response, protecting endothelial cells, and reducing blood lipids.     

Historical overview of immunological tolerance

A fundamental property of the immune system is its ability to mediate self-defense with a minimal amount of collateral damage to the host. The system uses several different mechanisms to achieve this goal, which is collectively referred to as the "process of immunological tolerance." This article provides an introductory historical overview to these various mechanisms, which are discussed in greater detail throughout this collection, and then briefly describes what happens when this process fails, a state referred to as "autoimmunity."     

Antigen presentation in acquired immunological tolerance

In acquired tolerance, previous exposure to antigen under certain conditions induces specific unresponsiveness instead of specific immunological memory. It has been studied as an approach to the mechanisms of self-tolerance that operate on immunocompetent T and B lymphocytes once they leave their sites of origin in the thymus and the bone marrow. Possible mechanisms involve induction of specific suppressor cells or inactivation of antigen-specific lymphocytes (clonal anergy) as a consequence of abortive antigen presentation, in which the antigen receptor is effectively engaged but certain poorly defined accessory signals the T lymphocytes require are lacking. We propose that small, resting B lymphocytes, which lack these accessory signals, are the inactivating antigen-presenting cells in acquired tolerance to proteins and to the class II transplantation antigens. B lymphocytes, which can use their antigen receptors to gather and process antigens that are present at very low concentrations, may play a role in self-tolerance. In addition, B lymphocytes and T lymphocytes rendered anergic by encounter with self antigens could persist as self-specific suppressor cells to block an autoimmune response of autoreactive clones that had escaped deletion or anergy.     

Mitochondria and fungal pathogenesis: drug tolerance, virulence, and potential for antifungal therapy

Recently, mitochondria have been identified as important contributors to the virulence and drug tolerance of human fungal pathogens. In different scenarios, either hypo- or hypervirulence can result from changes in mitochondrial function. Similarly, specific mitochondrial mutations lead to either sensitivity or resistance to antifungal drugs. Here, we provide a synthesis of this emerging field, proposing that mitochondrial function in membrane lipid homeostasis is the common denominator underlying the observed effects of mitochondria in drug tolerance (both sensitivity and resistance). We discuss how the contrasting effects of mitochondrial dysfunction on fungal drug tolerance and virulence could be explained and the potential for targeting mitochondrial factors for future antifungal drug development.