Pretreatment of lipopolysaccharide (LPS)-responder C57BVlOScSn mice with killed Propionibacterium acnes enhanced tumor necrosis factor alpha (TNF-a) production and lethality in response to a subsequent challenge with LPS. Sensitization to LPS increased with time of pretreatment and reached its maximum after 7 days. Sensitization was paralleled by gamma interferon (IFN-y) production that was detectable from day 3 onward. In contrast, a similar P. acnes pretreatment of LPS-nonresponder C57BL/lOScCr mice had no apparent effect on their high resistance to LPS. Challenge with LPS at any time during the 7-day period after P. acnes treatment led to no detectable TNF-ax formation and caused no lethal effects. The absence of sensitization in C57BL/lOScCr mice was paralleled by an absence of IFN-y production. Administration of monoclonal IFN-y antibodies in C57BLIlOScSn mice up to day 3 ofP. acnes treatment completely inhibited the overproduction of TNF-a by LPS. Anti-IFN-y administered later than day 3 had only a partial, although significant, inhibitory effect. Injection of appropriate amounts of anti-IFN-y also abolished the development of hypersensitivity to the lethal action of LPS. The effect of exogenously administered IFN-y on LPS sensitivity (e.g., TNF-ct production, lethal effects) was studied in LPS-responder and nonresponder mice. Administration of murine recombinant IFN-y increased the sensitivity of C57BLJlOScSn mice to LPS and established LPS responsiveness in LPS-nonresponder C57BL/lOScCr and C3H/HeJ mice. The data provide evidence that IFN-y mediates the sensitization towards LPS induced by P. acnes. Bacterial lipopolysaccharides (LPS, endotoxins) are causative agents of a number of pathophysiological reactions seen during infection with gram-negative pathogens. Many of these reactions are elicited by purified LPS in experimental animals (for a review, see reference 30). The interaction of LPS with macrophages and the subsequent formation of endogenous mediators represent essential early steps in the development of LPS lethal toxicity (16, 18, 31, 44). Tumor necrosis factor alpha (TNF-a), a macrophage-derived cytokine inducible by LPS (5, 45), has been recognized as a principal mediator of endotoxin shock. Injection of mice with exogenous TNF-a leads to pathophysiological reactions similar to those seen after LPS administration (36, 38, 60). Antibodies against TNF-a were shown in different experimental models to protect mice from LPS lethality (2, 17, 20, 61). Susceptibility to LPS of different mouse strains is genetically determined. LPS responsiveness is controlled by a gene locus identified on mouse chromosome 4. It occurs in two allelic forms, lps' for normal and lpsd for defective responsiveness (51). To date, three lpsd mouse strains, C3H/HeJ, C57BL10/ScCr (Cr), and C57BL/1OScSN (Sn), are known (10, 51, 56, 62). Mice belonging to these strains are highly resistant to all known LPS effects, including its

While breast feeding should be promoted for children at risk for atopy, mothers can be encouraged to stay on normal diet during pregnancy and the breast feeding period.

The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.

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