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Many clinical studies or case reports have focused on the clinical consequences of immunoenhancement or immune dysregulation mediated by therapeutic cytokines. Flu-like reactions, and the facilitation or exacerbation of inflammatory diseases, are the main consequences of immunoenhancement. Flu-like symptoms commonly are observed in patients treated with interferons, interleukin (IL)-l, IL-2, IL-3, or tumor necrosis factora. They typically consist of fever and chills, malaise, tachycardia, arthralgias, and myalgias that develop within a few hours after administration. The mechanism is not clearly understood but probably involves the acute release of fever-promoting factors in the hypothalamus. Because various cytokines are directly or indirectly involved in the pathogenesis of immune-mediated inflammatory disorders and autoimmune diseases, it is not surprising that such disorders develop after the administration of pharmacological doses of these cytokines. Another adverse consequence is the development of cytokine-specific antibodies in the sera of treated patients. [ABSTRACT FROM AUTHOR]

The goal of cancer immunotherapy is to induce effective immune responses to malignant tumors. Immunostimulatory cytokines can promote antitumor immunity by augmenting immune responses to cancer cells and by reversing anergy and/or tolerance of immune effector cells. The clinical development of cytokines for cancer therapy has been hampered by difficulty in determining the optimal dose and schedule of these molecules. The successful development of cytokine-based therapy requires assays that can measure appropriate surrogate endpoints for the induction of effective antitumor immunity in vivo. Several in vitro assays that have been useful for monitoring the immunological effects of cytokine therapy in humans will be discussed in this chapter. Each technique has advantages and limitations and no single assay has been found to reliably predict antitumor efficacy during clinical immunotherapy. [ABSTRACT FROM AUTHOR]

The expression of cytochrome P450 and P-glycoprotein is altered during the operation of host defense mechanisms. The basis for this interaction is predominantly through cytokine-mediated pathways. Most of the major cytokines, including interleukin (IL)-lα, IL-lβ, IL-2β, IL-6, tumor necrosis factor-α, inteferon-α, inteferon-γ, and transforming growth factor-β, are known to downregulate the major forms of cytochrome P450 and P-glycoprotein. In most cases individual cytochrome P450 forms are downregulated at the level of gene transcription, with a resulting decrease in the corresponding messenger ribonucleic acid, protein, and enzyme activity. The cytokine-mediated loss in drug metabolism is channeled predominantly through the modification of specific transcription factors. Similar pathways appear to alter the expression of P-glycoprotein. In clinical medicine, there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component and the production of cytokines. The direct administration of cytokines to humans depresses the levels of several cytochrome P450-mediated pathways. The production of cytokines in humans often results in altered drug responses and increased toxicities, which has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs is severely compromised. Changes in drug-handling capacity during inflammation/infection will continue to be one of the many factors that complicate therapeutics. [ABSTRACT FROM AUTHOR]

A key component for the success of any therapeutic cytokine is the degree of immunogenicity mediated by the cytokine. There are many factors that can contribute to a cytokine being immunogenic, such as aggregation. The understanding of cytokine immunogenicity requires a thorough knowledge of the antibody testing that was performed. Some of the methods used to test for antibodies against cytokines are the enzyme-linked immunosorbent assay, radioimmune precipitation assay, electrochemiluminescence, and surface plasmon resonance platforms. To understand whether an anticytokine antibody can neutralize the biological effect of a cytokine, it is necessary to perform a bioassay. The significance of cytokine immunogenicity can only be understood in the context of antibody testing data coupled with clinical data related to effects on the patient. [ABSTRACT FROM AUTHOR]

The vascular leak syndrome (VLS) is a major dose-limiting toxicity of cytokine therapy. VLS is characterized by an increase in vascular permeability resulting in tissue edema and, ultimately, multiple organ failure. The most frequent clinical manifestations of cytokine-induced VLS include weight gain, edema, oliguria, hypotension, and dyspnea. Respiratory insufficiency requiring mechanical ventilation and hypotension requiring pressor support have been described as the most severe manifestations of VLS. The pathogenesis of vascular damage is complex and can involve activation of endothelial cells and leukocytes, release of cytokine and inflammatory mediators, and alterations in cell—cell and cell—matrix adhesion with disturbance of vascular integrity. A better understanding of these mechanisms may lead to the development of interventions that will improve the therapeutic efficacy of cytokines. This chapter discusses the clinical manifestation, possible mechanisms, and therapeutic modalities for VLS induced by cytokine therapy. [ABSTRACT FROM AUTHOR]

The identification of the role of cytokines in inflammatory and autoimmune diseases has led to significant progress in treatment. The best example is probably the beneficial effect of blocking TNFα in an increasing number of inflammatory diseases, starting with rheumatoid arthritis. However since not all patients respond and since the treatment is suspensive, other cytokine inhibitors are now ready to be tested. The negative consequences of blocking cytokines have demonstrated their role in immunity as observed by the reactivation of tuberculosis following TNFa inhibition. Similarly, adminsitration of other cytokines such as Interferona has been associated with the induction of autoimmune manifestations, often in a predisposed context. [ABSTRACT FROM AUTHOR]

Flu-like reactions have been described, long before the introduction of therapeutic cytokines, in the clinical setting to treat a variety of pathological conditions. Indeed, flu-like reactions are commonly associated with vaccination as well as a number of infectious diseases unrelated to the influenza virus. Flu-like symptoms have also been described after the early use of supposedly immunostimulating drugs. When the first interferon formulations began to be used to treat cancerous patients, flu-like symptoms with some variation according to the type of interferon, route of administration, schedule, and dose, were observed in most patients. Since then, the flu-like syndrome emerged as a common-if-not universal complication of therapeutic cytokines. [ABSTRACT FROM AUTHOR]

In response to the need to treat disorders such as Crohn's disease, rheumatoid arthritis, allergies, and diabetes, the pharmaceutical industry has pursued the development of cytokines as therapeutic agents. Cytokines possess unique characteristics that are distinctly different than small molecule drugs. These hormone-like proteins possess complex structural features, demonstrate unique binding specificities and, in many cases, share overlapping physiological functions. These characteristics make development of cytokine therapeutics a challenge to drug-development scientists. Preclinical development of these molecules is complicated by the challenge of differentiating between toxicity and exaggerated immunopharmacology and understanding and analyzing the impact of antidrug antibody on the pharmacodynamics and pharmacokinetics of the parent compound. Regulatory agencies have recognized these issues and established guidance documents to address the nonclinical development of biological products. Several examples, including the nonclinical development of interleukin (IL)-, IL-5 antagonists, IL-6, IL-10, and IL-18 are reviewed in the context of these issues. [ABSTRACT FROM AUTHOR]

In the United States, the association between drugs of abuse and increased risk of infection has been suspected since colonial times. More recent studies have confirmed this relationship for most commonly abused drugs. Studies in animal models and in human subjects indicate that this increased susceptibility to infection is associated with decreased effectiveness of important innate and acquired immune defense mechanisms. All of the major drugs of abuse have been reported to affect cytokine and chemokine responses, which are critical in resistance to most infections. In general, proinflammatory, proimmune cytokine responses are decreased and anti-inflammatory, immunosuppressive cytokine responses are increased. The mechanisms by which this occurs have not been fully delineated, but receptor mediated effects, which probably act by interfering with immune stimulus-mediated signaling and indirect effects mediated by stress hormones, clearly are involved in the action of most drugs of abuse. [ABSTRACT FROM AUTHOR]

Cytokines are polypeptide mediators produced by a variety of cell types that play crucial roles in immune and inflammatory responses. Genes that code for cytokines are highly polymorphic, and some of these polymorphisms directly or indirectly influence cytokine expression. The most frequent types of mutations are characterized by a change in a single nucleotide base pair and are called single nucleotide polymorphisms (SNPs). Many SNPs that affect cytokine expression represent disease modifiers and influence the severity or progression of immune-mediated and chronic inflammatory diseases. SNPs in cytokine genes have been associated with common diseases, including cardiovascular diseases, cancer, neurodegenerative diseases, allergy, and asthma, and data are now accumulating on their role in occupational/environmental diseases. All these diseases are multigenic and multifactorial in nature and involve interactions between genetic, physiological, and environmental factors. Currently, there exist inconsistencies in association studies examining relationships between cytokine SNPs and disease because of known limitations in population-based studies. Recent advances in geno typing platforms for largescale genetic studies, more robust study designs, and haplotype analysis should help reduce the amount of spurious and inconsistent associations in the literature and allow for incorporating genetic information into the risk assessment process although challenges still remain. [ABSTRACT FROM AUTHOR]

Exposure to airborne particles and gases including silica, asbestos, diesel exhaust, and ozone is associated with significant risk of pulmonary and cardiovascular morbidity and mortality. Increasing evidence suggests that macrophages and inflammatory mediators released, including cytokines, play a role in the pathogenic process. In response to lung injury, alveolar macrophages become activated and release increased quantities of cytokines such as TNF-α, IL-1, IL-6, and IL-10, as well as chemokines and growth factors such as TGF-γ and PDGF. Although these mediators are released to protect the host and initiate wound repair, when generated in excessive amounts or at inappropriate times or places, they can damage host tissue and exacerbate or perpetuate injury. In this chapter, the role of inflammatory cytokines and growth factors released by macrophages in xenobiotic-induced pulmonary toxicity is reviewed. Potential mechanisms mediating expression of cytokine genes and the implications to human health are also discussed. [ABSTRACT FROM AUTHOR]

Many chemicals cause skin sensitization, resulting in allergic contact dermatitis, a delayed type hypersensitivity reaction. Chemical respiratory allergy is also an important occupational health problem, but there are currently available no validated methods for hazard identification, partly because of the fact that the relevant cellular and molecular mechanisms of sensitization of the respiratory tract have been unclear, with particular controversy regarding an obligatory role for IgE. Increasing evidence now exists that respiratory sensitization is associated with the preferential activation of type 2 T-lymphocytes and the expression of type 2 cytokines interleukin (IL)-, IL-5, IL-10, and IL-13. Type 2 cell products favor immediate type hypersensitivity reactions, serving as growth and differentiation factors for mast cells and eosinophils, the cellular effectors of the clinical manifestations of the allergic responses, and promoting IgE antibody production. In contrast, chemical contact allergens induce type 1 cytokine expression profiles. There has been considerable interest in the application of cytokine profiling for the characterization of chemical allergens, with cytokine phenotypes analyzed in freshly isolated tissue, or after culture in the presence or absence of mitogen at the level of protein secretion or messenger ribonucleic acid expression. The most common configuration of cytokine profiling, measurement of induced cytokine secretion patterns in the absence of restimulation, shows considerable promise as an approach for the identification and characterization of chemical respiratory allergens. [ABSTRACT FROM AUTHOR]

The chemokine network, comprising cell surface G protein-coupled receptors and soluble small molecular-weight protein ligands, constitutes a highly evolved system that facilitates leukocyte recruitment in both innate and adaptive immunity. As such, it has attracted attention from the research community as a means of modulating the immune system, a hypothesis that it appears has already been tested rigorously by microbes during coevolution. Several examples exist to support the notion that viruses, protozoa, and helminths have derived strategies of either exploitation or subversion, for example, using the chemokine network to gain cellular entry or to evade host immune surveillance. It is anticipated that, in the coming years, close examination of the mechanisms underlying these processes should provide opportunities for the generation of novel therapeutics. These may be of use to both thwart the microbial defense strategies and also to treat a variety of inflammatory diseases in which the inappropriate or excessive production of chemokines is pathologically implicated. [ABSTRACT FROM AUTHOR]

Early events in an immune response stimulate the production of cytokines that direct the subsequent development of T-cells. The innate immune system initiates T-cell activation by inducing naïve T-cells to differentiate into functional effector or memory T-cells. Effector T-cells produce cytokines and chemokines, which in turn affect the function (differentiation, proliferation, migration, etc.) of innate and adaptive immune cells. The effect of chronic immunization, infection, or disease results in the differentiation of naïve T-cells into polarized subsets of effector T-cells that can be differentiated from each other by the cytokines each T-cell subset produces. The Th 1/Th2 paradigm is the best characterized example of T-cell polarization. In simplest terms, T-helper cell type 1 (Thl) and T-helper cell type 2 (Th2) cells are defined as differentiated CD4+ αβ T-cells that produce predominantly interferon (IFN) γorinterleukin(IL)-, respectively (1). Thl and Th2 cells can be differentiated phenotypically and functionally by parameters other than IFN-γ and IL-4 production, but these two cytokines quintessentially define the Thl/Th2 paradigm. The function of Thl and Th2 cells is to help or instruct the innate and adaptive immune systems to respond in a specific manner to pathogens and cancer cells. In general, Thl cells help the immune system respond to intracellular pathogens, and Th2 cells help the immune system respond to extracellular pathogens. Polarized Thl and Th2 immunity should be considered endpoints of T-cell differentiation in response to chronic immunization or disease. Similar to CD4+ T-cells, CD8+ T-cells can develop into IFN-γ-or IL-4-producing cells, also called T cytotoxic-type 1 (Tc1) and T cytotoxic-type 2 (Tc2) cells, respectively. The nomenclature can be simplified to include both Thl and Tel cells asTl cells. Similarly, Th2 and Tc2 cells are grouped together as T2 cells. Finally, uncontrolled T-cell responses can lead to pathologies, such as Tl-mediated organ autoimmunity or T2-mediated asthma and allergy. This chapter will provide an overview of T1/T2 responses to xenobiotics, with a focus on nonclinical evidence of the involvement of the T1/T2 paradigm in hypersensitivity reactions and on the clinical evidence of various T-cell populations involved in drug hypersensitivities. This chapter will then focus on the regulation of Tl and T2 responses, both in humans and in the mouse. Finally, it will provide an overview of methods available to measure T1 and T2 immunity. [ABSTRACT FROM AUTHOR]

Since the early 1990s, the measurement of cytokines has become an important tool to understand mechanisms of immunotoxicity as well as to identify and classify xenobiotics. During the past decade, several major scientific and technical developments have greatly increased the efficiency of measurement. Most of the current attention is focused on methods that allow the simultaneous measurement of many cytokines, be at the messenger ribonucleic acid level (microarrays) or at the protein level (Luminex-based assays). Next, during the last decade quantitative polymerase chain reaction methods have gained widespread use. Finally, intracellular cytokine staining has provided detailed and invaluable information on the immune responses. This chapter describes the most widespread techniques for measuring cytokines. In addition, it tries to suggest which technique may be the optimal choice for specific purposes. [ABSTRACT FROM AUTHOR]

Cytokines play a key role inmodulation of immune responses. Cytokine networks regulate lymphocyte turnover, differentiation, and activation. Many different cell types, in addition to immune cells, produce cytokines and express receptors for cytokines. Cell-to-cell communication (cellular "crosstalk") is maintained via cytokine networks. In disease, these networks undergo imbalance. By measuring amplification or downregulation of cytokine signaling cascades in response to pathological insults or therapeutic interventions, it might be possible to evaluate disease progression or regression. Multiplex formats for cytokine profiling are now available and appear to be especially useful in monitoring cytokine profile alterations in a variety of human diseases. [ABSTRACT FROM AUTHOR]

The article presents information on regulatory guidance in immunotoxicology. The development of the earliest codified immunotoxicology test guidelines aims to augment toxicological analysis of chemicals that have the potential for large-scale human exposure. The guidelines include the ruling concerning the safety testing of small molecule pharmaceuticals.