Based on the aforementioned concept, a more rational approach to interfering with acute and chronic human diseases has been developed that has led to numerous clinical trials which may culminate in clinical use. The general principle is that the absolute level of a cytokine has to be analyzed in terms of balance with regard to that of its natural inhibitor(s). Thus, IL-IRa, sIL-lR and sTNFR may guard against the proinflammatory cytokines. IL-4 and IL-10 are at present being assessed in clinical trials. An attempt to increase local expression of cytokine inhibitors has also been made through gene therapy. At present, the overexpression of IL-IRa is being tested in animal models of arthritis.
Recombinant forms of natural inhibitory cytokines such as recombinant IL-IRa, recombinant soluble TNF-R p55 or recombinant soluble TNF-R p75 with human Fc constructs (rTNFRTc p60 or rTNFR-Fc80 fusion protein), short motifs of such peptides, or polyethyleneglycol (PEG-rsTNF-RI) or TNF-binding protein (TNF-bp-PEG) arc now available in large amounts and their pharmacokinetics and safety profiles are being tested. Approaches using gene therapy to reach the local site of the inflammatory destructive lesion are under investigation. A complete assessment of the efficacy of these new agents will comprise their evaluation for long-term treatment, not only in patients with refractory and longstanding disease, but also in those in the early stages of disease. Thus, potentially better therapies are provided along with a better understanding of the pathogenetic mechanisms of immune inflammatory diseases.
See also: Antibodies, specificity; Cytokine genes, regulation of; Cytokine receptors, soluble; Cytokines; Cytokine receptors; Interferon y; Interleukin 1 and its receptors; Interleukin 2; Interleukin 2 receptor; Interleukin 3; Interleukin 4 receptor; Interleukin 6; Interleukin 6 receptor; Interleukin 12 and its receptor; Poxvirus, infection and immunity; Tumor necrosis factor a; Lymphotoxin; TNF receptors.
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