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Introduction: A cytokine storm is an overreaction of the body's immune system leading to overproduction of inflammatory mediators. Cytokine storm appears to be a common condition induced by a variety of diseases including several strains of influenza.
What are cytokines? : Cytokines are the chemical mediators that result in inflammation. Their release is a triggered by a variety of molecular events that result from response to invasion by a pathogen. Cytokines have diverse roles in modulating immune and inflammatory responses and as such have a complicated classification system.
Molecular Basis of Hypercytokinaemia: The molecular events in immune response are described. Hypercytokinaemia is an overreaction of the normal immune response. A cytokine storm results from the over expression of cytokine molecules which trigger expression of other inflammatory molecules and increased cytokine released. A cytokine storm is therefore a positive feedback molecular mechanism. It results in the over-production of cytotoxic T-cells which attack the body's own tissues.
Pharmacological Intervention: An introduction to the groups of drugs used in the treatment of a cytokine storm: NSAIDS, glucocorticoids, Anti-TNF-alpha drugs and the new compound Ox40IG.
Glucocorticoids: Glucocorticoids are powerful anti-inflammatory compounds. As a result of corticosteroid action, inflammation is decreased due to decreased numbers of TH cells and cytokines.
Ox40IG: Ox40IG is a new compound that has emerged as a pioneering treatment for cytokine storm in influenza victims. Ox40IG binds to the receptors of T cell and blocks Ox40 binding, thus reducing the T-cell immune response and cytokine production.
TNF-ALPHA Inhibitors: The Anti-TNF-alpha drugs are recombinant engineered antibodies. These pharmaceuticals bind to TNF and inhibit its effects.
Infection of the body by a range of pathogens is dealt with by the immune system which provides the body with mechanisms for combating this infection. The immune system can be divided into two responses: innate and adaptive which work together with a variety of mediators to give rise to inflammation (Campell and Farrell 2007). This well-evolved system is present for our protection, but occasionally goes awry. In certain cases, invasion of a pathogen or even taking a pharmaceutical can induce an overproduction of the chemical mediators (cytokines) produced by the system leading to numerous health complications. This is termed hypercytokinaemia or a cytokine storm (Matsuda and Hattori 2006). The term is believed to be first recorded in medical literature by Ferrara in 1993 to describe the mechanism of Graft Versus Host disease (Ferrara 1993). It is believed that cytokine storms were responsible for the many deaths that occurred during the 1918 influenza pandemic (de Jong et al. 2006). The condition appears to be particularly relevant at the moment with the reports of high mortality among healthy young adults in recent the swine flu outbreak. Some reports have suggested that in these disease cases, an active immune system may be a liability, rather than an advantage (de Jong et al. 2006). The condition is still poorly understood as immunology and inflammation is a particularly complex area of study in biology. Nonetheless, pharmacological treatment for a cytokine storm does exist. These drugs intervene in the molecular mechanism that results in hypercytokinamia. This essay will discuss the molecular basis of the immune response and why a cytokine storm might occur. It will also look in detail at the potentially life-saving compounds that have been developed to deal with a cytokine storm episode.
Fig 1: Proposed Mechanism for the potential cytokine storm now associated with different influenza viruses.
The possible molecular mechanism of the condition will be described in more detail later on. (NEJM 2005)
What are cytokines?
Before the molecular basis of the cytokine storm can be discussed, it is important to have knowledge of cytokines. A pathogen only causes disease if it has bypassed the body's front-line defense. This is referred to as innate immunity. If this occurs, the adaptive or acquired immune system is activated and cellular warrior molecules arise and carry out their functions. Dendritic cells engulf invaders by endocytosis. These cells are referred to as antigen-presenting cells (APCs) and are the starting point of many of the responses traditionally associated with immune system action. The dendritic cells present their antigens to T cells which release chemicals called cytokines (Campell and Farrell 2008). Cytokines are chemicals which stimulate and mediate other cellular members of the immune system. Cytokines are small proteins produced by a variety of the body's cells and include interferons (IFNs), interleukins (ILs) and tumour necrosis factors (TNFs). Cytokine molecules bind to specific receptors on the surface of a responsive cell and generate a signal that alters cell activity, usually by phosphorylation. The cell responds to the cytokine by preparing to divide, undergoing differentiation or secreting its own cytokines. One family of cytokines act primarily as chemoattractants that stimulate the migration of lymphocytes to inflamed tissues. These are known as chemokines. Some of the different types of cytokines are discussed in table 1 (Karp 2007).
Induces inflammation, stimulates TH cell proliferation
Stimulates T-cell and B-cell Proliferation
Suppresses inflammatory cytokine action
Stimulates B-cell differentiation
T cells, macrophages
Pro-inflammatory AND anti-inflammatory action
T cells, macrophages
Inhibits macrophage function, suppresses inflammatory cytokine action
TH cells, CTLs
Induces MHC expression in APCS, activates NK cells
Stimulates growth and proliferation of granulocytes and macrophages
Table 1: Classification and functions of some cytokines (adapted from Karp 2007).
Molecular Basis of Hypercytokinaemia
Hypercytokinaemia or a cytokine storm results from an uncontrolled positive feedback loop between cytokine production and an inflammatory or immune response. The homeostatic mechanisms of the immune system are disrupted and dysregulation in cytokine production is witnessed. With reference to influenza episodes, a variety of studies have indicated a marked increase of cytokines and chemokines in the lungs of humans and animals during H5N1A influenza infection (Droebner et al. 2008). Some individuals appear to be more susceptible than others to a cytokine storm and it is therefore believed the disorder has a strong genetic component (Matsuda and Hattori 2006). The molecular basis of Hypercytokinaemia is still poorly understood. It is believed that the helper T cells (TH cells) are stimulated to overproduce cytokines. A pathogen in the body is detected by the activation of Toll-like receptors (TLRs) on macrophages on APCs. APCs are presented to the TH cells. TH cells can be subdivided into two classes: CD4 and CD8 receptors. When these cells are activated, the main pro-inflammatory cytokines are released: IL-1 and TNF-a. These molecules act on the vascular endothelium in the body, causing vasodilatation. An increase in exudate fluid is also seen, which contains enzyme cascade molecules. The TH cells acquire IL-2 receptors and generate IL-2. IL-2 has autocrine activity and causes the cells to proliferate. This results in more cytokine molecules being produced (Rang and Dale 2007). Cd8-bearing T-cells are stimulated by cytokines to develop into cytotoxic T cells which cause death of the pathogen cells by induced apoptosis. The excess cytokines go on to stimulate other members of the immune system including more cytokines and killer T cells or cytotoxic T cells (CTLs). More cytokines are produced and a positive feedback look exists where overproduction of cytokines leads to stimulation of more cytokine molecules and the production of more cytotoxic T cells. The excess cytotoxic T-cells can go on to cause damage to the host's tissues leading to a range of unpleasant symptoms including pneumonia and multiple organ failure (Ball and Egeler 2008).
Fig 3: Cell-mediated Immune Response
Simplified drawing of the cell-mediated immune response described above. T helper cells are stimulated to produce cytokines (triangles) which go on to stimulate more cellular events.
Healey 2009 but adapted from Ball et al. 2008.
Numerous anti-inflammatory and immunosuppressant compounds exist. Some of these are employed as treatment for cytokine storm but all pharmaceuticals vary in their effectiveness. Many drugs carry the risk of adverse drug reactions and therefore the therapeutic index of the drug must be considered before it is administrated.
Glucocorticoids are powerful anti-inflammatory compounds that are used in the treatment of a cytokine storm. Immunosupression by glucocorticoids employs both the effects of the class of drug on the immune response and their anti-inflammatory function. Glucocorticoid mechanism of action involves intracellular receptors that are expressed in almost every cell-type in the body. Glucocorticoid drugs bind to these receptors and regulate transcription of specific genes (see figure 3) (Janeway et al. 2001). Glucocorticoids chiefly inhibit the proliferation of T H cells by decreasing the transcription of the gene for Il-2. However, glucocorticoids also control expression of many other genes, including those for TNF-a, IFN-y, and Il-1. Key examples of glucocorticoids include hydrocortisone, prednisalone and dexamethasone. As a result of corticosteroid action, inflammation and innate immune response is decreased due to decreased numbers of TH cells and cytokines (Rang and Dale 2007).
Fig 3: Mechanism of Glucocorticoid action.
Drug binds to steroid receptor complex, releasing Hsp90. Drug can then cross the nuclear membrane and bind to specific gene regulatory sequences and activate or deactivate transcription of specific genes (Janeway et al. 2001).
A new compound has emerged as a pioneering treatment for cytokine storm in influenza victims. Ox40Ig is an immunoglobulin peptide which selectively targets the T cells that have recently been activated by an antigen. OX40 or (CD134) is a membrane-bound member of the tumour-necrosis-factor-receptor superfamily which is expressed on activated CD4+ T cells(Weinberg 2002). Ox40 or CD134 is an ideal target for therapy because it is absent on naïve T cells but up-regulated one or two days after antigen encounter. OX40 sends a survival signal to the T cell, preventing activation-induced cell death by up-regulating an anti-apoptosis gene and increasing cytokine production leading to the immune response. Ox40IG binds to the receptors of T cell and blocks Ox40 binding, thus reducing the T-cell immune response and cytokine production. It is hoped that if clinical trials of this drug are successful, an influenza-induced cytokine storm episode may be preventable (Humphreys et al. 2003).
Fig 5: Ox40 pathway
Enhancing OX40 signalling through agonists increases Tâ€‘cell development (above) while blocking OX40 signalling induces T-cell apoptosis.
Adapted from Croft and Weinberg 2009.
TNF- α inhibitors
Anti-cytokine drugs are an example of one of the greatest pharmaceutical breakthroughs in treatment of chronic inflammation or cytokine storm for many years. Anti-cytokine drugs are employed for treatment of Rheumatoid Arthritis, Crohn's Disease and even breast cancer. The drugs are recombinant engineered antibodies. As such, they are difficult and expensive to produce and therefore, their use is limited. Infliximab and adalimumab are chimeric mouse/human monoclonal antibodies against TNF-alpha. Entanercept is a TNF receptor fused to the Fc domain of a human immunoglobulin molecule and acts as an IL-1 antagonist (Rang and Dale). This class of drugs binds TNF and inhibit its effects. Unfortunately, these drugs are associated with adverse drug reactions such as the encouragement of opportunist infections and even tuberculosis in some patients (Raychaudhuri et al. 2009).
Fig 5: Tumour necrosis factor- blockers Mechanism of Action.
Soluble receptors such as etanercept or monoclonal antibodies such as infliximab prevent TNF-alpha binding to the p55 or p75 receptors. TNF- signalling and the TNF-mediated inflammatory response are prevented (Mease 2003).
A cytokine storm is potentially fatal condition now associated with a range of diseases. There is even evidence to suggest that cytokine storm may have been responsible for some of the deaths that occurred this year with the H1N1/09 virus. A cytokine storm is an overstimulation of immune function resulting from an error in the homeostasis of the system causing an uncontrolled positive feedback loop between cytokine production and the immune cells. An elevated level of cytokines is observed in the patient's bloodstream. Overproduction of cytokines leads to over-expression of cytotoxic T cells which trigger apoptosis in antigen cells, but in Hypercytokinaemia attack the host's cells causing acute tissue damage and even leading to multiple organ failure. A major hurdle in the clinical management of hypercyotkinaemia is the lack of effective treatment. Many pharmaceutical compounds exist for treatment of a cytokine storm; however all vary in their effectiveness. Recombinant cytokine expression in suitable cloning vectors and expression systems have allowed for high diverse and sustainable means of drug development. Compounds which target specific cytokines or T-cells have been developed which can intervene in the molecular mechanism of inflammation. However, many of these compounds may have adverse effects in patients. It is important to stress that pharmacology of the immune system is very difficult because if an immune response is suppressed, the patient may be susceptible to further infection.
As our understanding of molecular mechanisms behind a cytokine storm advances, it is likely more targets can be addressed for pharmaceutical intervention. A pharmaceutical must be discovered that maintains the balance of the immune system or restores its homeostatic mechanisms.
Glossary- Commonly used Abbreviations and Acronyms
APC: antigen presenting Cell
CD4 and CD8: Co receptors in T Lymphocytes.
CTL: Cytotoxic T lymphocyte
mAb: Monoclonal Antibody
MHC: major histocompatibility complex
NK: Natural Killer Lymphocyte
Th: T-helped Lymphocyte
TLR: Toll receptor
TNF- α: Tumour Necrosis factor alpha
IFN-É£- Interferon gamma