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Intravascular injection of guinea pigs with the fourth complement component (C4) inactivator from shark serum resulted in severe serum C4 depletion that lasted for several hours. Active and direct passive Arthus reactions did not develop or were extremely mild in such C4 inactivator-treated animals as judged by gross and histological observation. In consideration of the specificity of the C4 inactivator, its independence of cofactors, and its failure to generate biologically active materials in the process of C4 inactivation, it is concluded that complement-dependent immune injury can be suppressed or avoided by interruption of the complement cascade at a single early step. The depression of the Arthus reaction beyond the time of C4 recovery prompted quantitative speculations concerning (i) the in vivo rate of C5a generation under conditions of limited C4 supply and (ii) the “saturation” of immune complexes. This view is supported by in vitro demonstration of functional inactivation or “saturation” of immune precipitates by repeated incubation with fresh guinea pig complement. It seems therefore conceivable that even temporary complement inactivation may have a profound beneficial effect on complement-dependent immune injuries.

Specific Inactivation of the Fourth Complement Component I. In Vivo Studies