Cytokines autoimmunity

For the pathogenesis of multiple sklerosis, autoimmune T-lymphocy tes play a predominant role, which are directed against components of the neural myelin sheath. T-lymphocy tes by secreting cytokines such as interferon y maintain the chronic inflammation which destructs the myelin sheath. Also cytotoxic T-lymphocytes may participate directly. The cause of multiple sklerosis is unknown. Significantly increased antibody titers against several vitusses, mostly the measles virus, point to a (latent) virus infection initiating the disease. 

IFN- 3 reduces the induction by inflammatory cytokines of adhesion molecules and of MHC class I and II complex on endothelial cells, a process preceding attachment and transendothelial migration of T-cells. These anti-inflammatory effects of IFN- 3 exemplify antagonistic actions of type I and type IIIFN. There is, indeed, much clinical evidence for the involvement of IFN-y in inflammatory processes - through activation of iNOS and subsequent secretion of NO - leading to the establishment of autoimmune diseases as for instance in rheumatoid arthritis. 

TNF is a pleiotropic cytokine exerting a wide range of cellular responses, that affect biological processes such as lipid metabolism, coagulation, and insulin resistance and the function of endothelial cells. As a major proinflammatory cytokine TNF is also involved in progression of diseases like cancer, Alzheimer, Diabetes type II, cardiovascular, pulmonary or neurological disorders, and many autoimmune diseases. Blocking the action of TNF clearly reduces its inflammatory potential on various autoimmune disorders like Crohn s disease, rheumatoid arthritis (RA), and psoriasis. 

Smith SS, Bamum SR (2008) Differential expression of beta 2-integrins and cytokine production between gammadelta and alphabeta T cells in experimental autoimmune encephalomyelitis. J Leukoc Biol 83 71-79... 

The therapeutic goal in autoimmune diseases such as RA is to control disease, to establish remission, and eventually to cure. In theory, this goal can be achieved using either Ag-specific approaches, for example, elimination of self-reactive T cells (assuming that a finite number of key Ags can be identified as the target of the autoimmune process in RA), or the non-Ag-specific approaches, for example, blockade of cytokines as in the case of TNF-a neutralization. Currently, only the latter types of approaches have yielded clinical benefit, and it is in this category that approaches to block chemokines or receptors may be included. Despite their appeal in terms of effectiveness, non-Ag-specific approaches carry a higher risk of immunosuppression and opportunistic infections (48). 

It has been well documented that the anaemia of chronic disease, ACD, results in a lowering of various haematological parameters. Several mediators are involved, among them histamine, serotonin, bradykinin, prostaglandins and, as found more recently, cytokines and nitric oxide. ACD is a parameter of systemic autoimmune disorders. The severe inflammatory stimuli lead to several systemic changes, mediated by inflammation-associated cytokines, e.g. IL-6, IL-1 TNFa, TGF beta that regulate hepatic synthesis of the acute phase proteins. 

Antibodies have been used extensively as diagnostic tools in many different formats, especially for measurement of protein and cytokine abundances. Applications of antigen arrays can be found in reverse immunoassays for detection of allergens and autoimmune antibodies. 

Several pro-inflammatory cytokines, such as TNFa, IL-1, IL-6, are important in the initiation and maintenance of various autoimmune diseases, such as RA, CD, and psoriasis. Thus, targeted therapies, which have been developed to inhibit their activity, have resulted in clinical improvement of these patients. Currently, there are three TNFa inhibitors (etanercept, infliximab, and adalimumab) and one IL-1 receptor antagonist (anakinra) that have been approved for the treatment of at least one of these diseases. In addition, a number of other anti-cytokine therapies are in clinical development. The TNFa antagonists will be reviewed here. 

Priliximab (cM-T412) is an anti-CD4 chimeric monoclonal antibody that was evaluated in the clinic for the treatment of autoimmune diseases. Priliximab binds to CD4 on the surface of T cells and leads to a profound and sustained decrease in circulating CD4+ T cells decreased counts have been reported to be below normal levels at 18 and 30 months following single- and multiple-infusions.81 Similar findings were observed in preclinical studies in chimpanzees.82 The administration of priliximab was also associated with a cytokine-release syndrome that caused transient fever, myalgia, chills, headache, nausea, and/or hypotension that was accompanied by an increase in serum IL-6. Although evidence of efficacy was observed in clinical trials for CD, the... 

Khoury, S J. et al., CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Thl but spares Th2 cytokines in the central nervous system, J. Immunol., 155, 4521, 1995. 

Table 12.1 illustrates studies reporting shifts in T lymphocyte cytokine production induced by Pb. Most studies found that Pb exposure at low to moderate levels causes a significant shift in the production of Thl versus Th2 cytokines with the bias toward the latter. Production of IL-4, IL-6 and frequently IL-10 is elevated while production of IFN is decreased and production of IL-12 is below the levels needed for effective host resistance to Listeria. These results occur even at low levels of exposure and the effects are persistent. The only exceptions to Pb-induced biasing in favor of Th2 are found in the reports by Goebel and colleagues [56] and Mishra and colleagues [57], In the former case, an autoimmune prone strain of mice was employed these authors found different results upon using a normal strain of mice [58],... 

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