Certain characteristics of tolerance which develops to the pyrogenic effects of old tuberculin (OT) in BCG-vaccinated rabbits have been described. Rabbits made tolerant by several injections of OT lost their ability to produce detectable amounts of endogenous pyrogen (EP) in response to the specific agent (OT) but mobilized normal amounts of EP when given a small unrelated stimulus. On the other hand, when this stimulus followed shortly after an initial tuberculin fever of sufficient magnitude, release of additional EP was suppressed, presumably due to an inhibitory effect of the EP previously mobilized by tuberculin. Similarly, a single large dose of endotoxin almost completely suppressed the response of sensitized rabbits to OT given several hours later. Since several spaced injections of the same dosage were ineffective, this phenomenon does not appear to be attributable to the known mechanisms by which endotoxins promote non-specific resistance to toxicity and infection. Tolerance to tuberculin could not be definitely shown following an injection of Newcastle disease virus which also produces a circulating EP, and it has been inferred that endotoxin blocks the pyrogenic action of antigen on host tissues directly rather than through mobilizing EP. On the basis of these observations, the relationship of specific to non-specific tolerance to tuberculin fever has been compared in terms of the ability of such tolerant animals to mobilize EP to heterologous stimuli and it is concluded that the two forms of tolerance are different. Furthermore, the fact that a number of unrelated agents produce tolerance non-specifically supports the concept that there may be a common source of EP released by a number of stimuli, including endotoxins and myxoviruses, as well as antigen in specifically sensitized hosts.

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Activated Hageman factor, when injected into the rabbit ear chamber, produces a delayed and prolonged inflammatory response characterized by prominent sticking and emigration of leucocytes. In contrast, preformed bradykinin evokes an immediate and more transient response in which leucocytic emigration occurs less frequently. It is concluded that either Hageman factor produces its inflammatory effects by mechanisms other than kinin release, or bradykinin released endogenously has effects quite different from those resulting from a single injection of the exogenous material.

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Material obtained from the in vitro incubation of granulocytes from saline-induced peritoneal exudates of rabbits has been shown to produce inflammation and fever in rabbits. The supernatant material from cells incubated in saline has been termed granulocytic substance (GS) and is heat-labile. Its production is temperature dependent, occurring at 37°C but not at 4°C, requires viable cells, and is inhibited by potassium ions. A similar material is liberated when cells are incubated in a more physiologic medium. Freezing and thawing of granulocytes does not release GS and the active principle cannot be obtained from the incubation of lymphocytes. GS produces a delayed inflammatory response as measured by leucocyte sticking and emigration in the rabbit ear chamber and the leakage of protein-conjugated dye at the site of intradermal injection. The former response can be accurately quantitated by calculation of the inflammatory index from reactions observed in the ear chamber. The inflammatory reaction and the properties of GS distinguish it from a variety of previously described mediators of inflammation, but GS appears to be identical with leucocytic pyrogen. The possible role of GS in delayed and protracted inflammation and its relationship to the pathogenesis of fever are discussed.