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The occurrence of tolerance or host unresponsiveness in animals and humans administered multiple doses of microbe or microbial products has long been recognized by scientists and physicians with published reports appearing in professional journals dating back to the 19 th century. Following the identification and purification of lipopolysaccharide LPS in the 20 th century, it was determined that the microbial product, LPS itself, can be highly tolerogenic.
From these observations, it has been postulated that tolerance serves to protect the host from the detrimental consequences of the robust and extensive inflammatory responses that follow exposure to LPS. Tolerance cannot, however, be characterized as a global downregulation of responsiveness as some LPS-responsive characteristics remain unchanged or in some cases can actually be upregulated in experimental models of tolerance.
In studies carried out by numerous investigators over the years to clarify the concept of tolerance, a variety of terms have been used to designate the observed alteration in immune responses that occur upon repeated administration of LPS. All are arguably accurate to some extent, although many of these should not be used interchangeably, as some of these terms refer to tolerance that can be established only under specific conditions.
Numerous studies have been dedicated to the elucidation of LPS structures from various microbes in order to account at the molecular level for LPS tolerance. From these studies, it has been established that the lipid A moiety of LPS is responsible for almost all of the described activities of LPS. In this regard, both early and late tolerance have been described.
Early tolerance is usually observed within hours of LPS administration and may last up to a week or more. During early tolerance, suppression of cytokine production, fever, and endotoxin lethality occur independently of antibody production. In contrast to early tolerance, late tolerance is induced many days after LPS treatment when early tolerance has generally ceased or markedly waned.
Late tolerance is characterized by the production of antibodies directed against LPS, which confers the specificity and lack of cross-tolerance observed in this phase.
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