The typical biphasic febrile response of the normal rabbit given endotoxin intravenously is modified by continued daily administration of the bacterial lipopolysaccharide. This development of tolerance (1) to endotoxin p~ogenicity is characterized by disappearance of the second, major, phase of fever and by gradual diminution of the initial phase (2). Attempts at passive transfer of tolerance to pyrogenicity have yielded negative results (1, 3). Therefore it is generally considered that tolerance cannot be so conferred upon a normal animal (2, 4). In a previous paper (5), we have shown that passive transfer of another aspect of endotoxin tolerance, substantial resistance to lethality of homologous and heterologous endotoxin, could be achieved with serum of rabbits given a brief series of injections of bacterial lipopolysaccharide.The present report describes the decrease in magnitude and duration, with disappearance of the second phase, of the biphasic fever pattern of the noruaal rabbit given endotoxin subsequent to the administration of plasma or serum of tolerant donor rabbits. Studies on reticuloendothelial system function in recipient animals, tolerant by passive transfer, will be reported separately (6). Materials and MethodsThe endotoxln used throughout was the Hpopolysaecharide of S. typhosa O 901 (Difco).Temperatures were taken with clinical mercury thermometers prior to and at 30, then 60, minute intervals after giving endotoxin. A "fever index" for each rabbit was determined by plotting its fever curve on standard graph paper, cutting out the area under the curve, and weighing the cut-out. The weight is directly proportional to the area, and the latter summate~ magnitude and duration of fever. The area was enclosed by dropping a vertical from the last measured temperature to the time axis. Donor blood was collected aseptically either by heart puncture or by bleeding from the carotid with precautions to avoid pyrogen contamination. In control experiments it was noted that hundredths of a microgram of the endotoxin given shortly before the 2.5/~g. test dose resulted in substantial increase in the febrile response, making mandatory avoidance of contamination of the donor blood. All glassware, syringes, and needles were kept at 175°C. for 2 to 3 hours before use. Pyrogen-free distilled water was used for preparing solutions and these, as well as representative samples of donor serum or plasma, were proven non-pyrogenic in normal rabbits. Plasma was obtained by using one volume of 3.8 per cent sodium citrate for five volumes of whole blood and centrifuging the same day. For serum, blood was allowed to clot and was kept at room temperature for 4 to 453 on

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In a previous report (1) we have described the passive transfer of tolerance to pyrogenicity of bacterial endotoxin. Such transfer was shown to depend upon the manner in which tolerance was induced in the donor animal, and this parameter has been further investigated. Both prolonged administration of the bacterial lipopolysaccharide, through 5 weeks, and daily injections of a large constant dose of endotoxin for a few days, permit demonstration of passive transfer, depending upon the magnitude of the test dose of the pyrogen in the recipient.Intravenously injected doses of endotoxin which cause a fever also elicit an almost immediate peripheral granulocytopenia. It has been thought that development of tolerance to the fever-producing effect of the toxin, which is accompanied by refractoriness to various other responses, extends to the acute leucopenia (2-5). If tolerance to leucopenia regularly paralleled tolerance to pyrogenicity the hypothesis suggesting endogenous leucocytic pyrogen as the mediator of endotoxin-induced fever (4) would be strengthened. Not finding refractoriness to the drop in peripheral white cell count in our rabbits passively tolerant to the pyrogenicity of endotoxin, we have studied the changes in numbers of circulating leucocytes in endotoxin-treated animals. We have not found tolerance to the leucopenia under conditions yielding substantial tolerance to pyrogenicity. A search of the literature largely supports this finding that tolerance to the pyrogenic effect becomes manifest without change in the acute leucopenic response (6)(7)(8)(9)(10)(11)(12).Following the demonstration by Grant and Whalen (13) of an endogenous pyrogen in the blood of rabbits injected with typhoid vaccine, an impressive series of experiments by Wood and coworkers (14-17) has led to the hypothesis that endotoxininduced fever is a consequence of the action of the exogenous pyrogen upon the leucocytes, or other cells, causing release of endogenous pyrogen which then acts upon the thermoregulatory centers of the brain (4). From an equally impressive series of researches, Bennett and associates (9,(18)(19)(20)(21)(22)(23)(24)(25) have shown that the fever seen after administration of endotoxin requires neither significant numbers of circulating leucocytes nor the presence of endogenous serum pyrogen, and have postulated a dual mechanism, involving a direct action of endotoxin, possibly accounting for the biphasic nature of the febrile response (3). 619on May 7, 2018 jem.rupress.org Downloaded from

PROTEIN COMPONENT OF ENDOTOXINblood glucose must be maintained for a certain period before its reduction to stimulate HGH secretion.Oufr observation is difficult to interpret, but raises some questions on the regulatory manner of HGH secretion mlediated by glucose metabolism. If the stimulation of HGH secretion CUTS by intracellular glucose deprivation( 1-3) in the hypothalamus( 2,7) as proposed, glucose infused for a short period in most cases is unable to induce enough metabolic shift in the hypothalamic cells to stimulate HGH secretion, in spite of other definite responses such as plasna NEFA change. An alternative explanation may be that the direct stimulant of HGH secretion is not the extracellular or intracellular glucose itself, but the metabolites or other substances related to glucose metabolism, which are different quanrtitatively or qualitatively in the conditions of Short and long continuous glucose infusion. Since plasma NEFA change was similar in all cases, it is apparent that there is no conrelation between the rise of plasma HGH and the value of plasma NEFA. In these respects, our results may support the observation of Quabbe et aZ (8), who showed the absence of correlation between plasma HGH rise and blood glucose or plasma NEFA level during a 24-hour fast in normal subjects.Summary. Serial plasma HGH concentrations were measured, in 18 normal subjects, following continuous intravenous glucose in-fusion performed for periods of 3, 10, 20 and 30 minutes. In 5 of 8 cases infused for 3 minutes, no rise of plasma HGH was olbserved in spite of the rapid fall of blood glucose with (4 cases) or without (1 case) its reduction below the fasting level. The 3 other cases infused for 3 minutes and all 10 cases of 10, 20 and 30 minutes' infusion showed definite rise of plasma HGH at 90-180 minutes following the infusion. From the results obtained, it appears that the falling blood glucose per se is not a direct stimulus, and the reduction of blood glucose !below the fasting level is not necessarily a stimulus to HGH secretion.

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