While there is only limited evidence for the physiological significance of effects of SRs observed in vitro, there is extensive documentation that, by injecting sufficient amounts of SRs, it is possible to reproduce artificially in vivo at least one of the effects that SRs can mediate in vitro, namely, blocking of signaling. Use of chimeric soluble receptor-Fc regions ('im-munoadhesins'), or of SRs coupled to polyethylene glycol, whose clearance rate is lower than that of the natural SRs, allows prolonged maintenance of these molecules in the body and, in the case of the soluble receptors for TNF, more effective binding to the ligand (by virtue of the ability of the dimeric SRs to bind simultaneously to two protomers of the trimeric TNF molecules). Ongoing clinical trials demonstrate effective therapeutic effects of SRs in humans. Blocking of TNF function by its SRs, for example, has been found to be highly beneficial in rheumatoid arthritis and in chronic inflammatory bowel diseases.
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