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H H FREEDMAN

Publications and source records attributed to H H FREEDMAN.

At least 19 recordsLinked to original sources
PubMed1962

Dissociation of the biological properties of bacterial endotoxin by chemical modification of the molecule.

The preparation and properties of three fractions isolated from the acetylation of endotoxin by acetic anhydride in the presence of anhydrous sodium acetate are described. One fraction is of primary interest for it allows the experimental dissociation of some of the myriad biological activities of the parent endotoxin. Pyrogenicity and acute toxicity are markedly reduced, and ability to confer tolerance to the lethality and pyrogenicity of homologous or heterologous endotoxins is equivalently diminished. In contrast, this acetylated derivative retains the ability to stimulate phagocytosis and, as shown in the following paper, to enhance non-specific host resistance to infection. Detoxification is reversible, the original toxicity and pyrogenicity being recovered following mild saponification. The implications of the findings are discussed, and it is suggested that the observed dissociation of biological properties is explained neither by deacetylation of the derivative in vivo nor by the observable alteration of physical state in the gross.

Endotoxins↗
PubMed1962

The stimulation of non-specific host resistance to infection by chemically modified endotoxin.

An acetylated derivative prepared from Salmonella typhosa O-901 endotoxin has been found to retain the ability to stimulate non-specific host resistance to a variety of bacterial infections. Relative to the parent endotoxin, the derivative has been reduced in the gross in its pyrogenicity to rabbits and lethality to mice. With the use of this chemically modified preparation under a variety of conditions, the direct dissociation of the toxic properties of endotoxin from its protective capacity appears evident. In young male mice, the endotoxin and its derivative produced a leucocytosis but no leucopenia. However, no direct correlation could be found with the level of the peripheral white blood cells and resistance to infection with Escherichia coli. Furthermore, under the conditions employed, passive transfer of early resistance to infection by serum or plasma was not detectable.

Animals↗
PubMed1960

Further studies on passive transfer of tolerance to pyrogenicity of bacterial endotoxin. The febrile and leucopenic responses.

The effect of various schedules for inducing tolerance to bacterial endotoxin in donor rabbits upon suitability for demonstration of passive transfer of tolerance to pyrogenicity in normal recipients has been investigated. Long-term treatment of donors, through 5 weeks, is no more effective than a brief series of injections, adding further evidence that tolerance is not attributable to specific antibody to the endotoxin. Qualitative differentiation of the febrile pattern of passively tolerant recipients from that seen in control animals depends upon the magnitude of the test dose of pyrogen. Passively tolerant rabbits respond to endotoxin with an acute leucopenia equivalent to that seen in controls suffering a full biphasic fever. Animals given daily injections of endotoxin continue to show the acute leucopenia, despite the early modification of the course of fever characteristic of endotoxin tolerance. The assumption that the leucopenia reflects damage to the leucocytes, with release of endogenous pyrogen, is not consistent with these findings. Rabbits rendered leucopenic by nitrogen mustard and then given endotoxin exhibit a rapidly developing fever of greater than normal intensity, the exaggeration of the febrile response being proportional to the severity of the induced leucopenia. The implications of these findings for the pathogenesis of endotoxin-induced fever are discussed. The evidence supports the hypothesis that endotoxin produces fever by direct action rather than by release of endogenous leucocytic pyrogen. It is postulated that the lesser fever, in animals having normal numbers of circulating leucocytes, reflects a limitation of available endotoxin by the known rapid sequestration in the white blood cells at the time of the acute leucopenia. It is further suggested that the biphasic febrile response of the normal rabbit results from reinoculation of the blood stream by the temporarily sequestered endotoxin, the RES of the tolerant animal clearing the released endotoxin at a rate sufficient to prevent triggering the second phase of fever.

Animals↗
PubMed1960

Passive transfer of tolerance to pyrogenicity of bacterial endotoxin.

The typical febrile response of normal rabbits given bacterial endotoxin intravenously may be modified by prior administration of plasma or, less effectively, serum of endotoxin-tolerant donors. This altered response is characterized by disappearance of the second rise in fever and by a striking reduction in fever index. It thus resembles the course of fever shown by rabbits made tolerant to endotoxin by one or more previous daily doses. This transfer of tolerance by plasma or serum depends critically upon the manner in which tolerance is induced in the donors. The plasma of donor rabbits made tolerant, then given an RES-blocking dose of carbon, still confers tolerance upon normal recipient rabbits. Such donors have lost their tolerance and are highly sensitive to endotoxin at the time their blood is taken. The implications of these findings for endotoxin tolerance and for transfer of this phenomenon are discussed. The evidence is consistent with the hypothesis that both tolerance and its transfer are based upon RES function and are independent of antibody.

Animals↗