The immunobiology of toll-like receptor 4 agonists

From endotoxin tolerance to immunoadjuvants

Julia K. Bohannon, Antonio Hernandez, Perenlei Enkhbaatar, William L. Adams, Edward R. Sherwood

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Lipopolysaccharide (LPS, endotoxin) is a structural component of the gram-negative outer membrane. The lipid A moiety of LPS binds to the LPS receptor complex expressed by leukocytes, endothelial cells, and parenchymal cells and is the primary component of gram-negative bacteria that is recognized by the immune system. Activation of the LPS receptor complex by native lipid A induces robust cytokine production, leukocyte activation, and inflammation, which is beneficial for clearing bacterial infections at the local level but can cause severe systemic inflammation and shock at higher challenge doses. Interestingly, prior exposure to LPS renders the host resistant to shock caused by subsequent LPS challenge, a phenomenon known as endotoxin tolerance. Treatment with lipid A has also been shown to augment the host response to infection and to serve as a potent vaccine adjuvant. However, the adverse effects associated with the pronounced inflammatory response limit the use of native lipid A as a clinical immunomodulator. More recently, analogs of lipid A have been developed that possess attenuated proinflammatory activity but retain attractive immunomodulatory properties. The lipid A analog monophosphoryl lipid A exhibits approximately 1/1,000th of the toxicity of native lipid A but retains potent immunoadjuvant activity. As such, monophosphoryl lipid A is currently used as an adjuvant in several human vaccine preparations. Because of the potency of lipid A analogs as immunoadjuvants, numerous laboratories are actively working to identify and develop new lipid A mimetics and to optimize their efficacy and safety. Based on those characteristics, lipid A analogs represent an attractive family of immunomodulators.

Original languageEnglish (US)
Pages (from-to)451-462
Number of pages12
JournalShock
Volume40
Issue number6
DOIs
StatePublished - Dec 2013

Fingerprint

Immunologic Adjuvants
Lipid A
Toll-Like Receptor 4
Endotoxins
CD14 Antigens
Immunologic Factors
Shock
Leukocytes
Vaccines
Inflammation
Gram-Negative Bacteria
Bacterial Infections
Lipopolysaccharides
Immune System
Endothelial Cells
Cytokines
Safety

Keywords

  • adjuvant
  • Endotoxin
  • innate immunity
  • lipid A
  • MyD88
  • TLR4
  • TRIF

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

Cite this

The immunobiology of toll-like receptor 4 agonists : From endotoxin tolerance to immunoadjuvants. / Bohannon, Julia K.; Hernandez, Antonio; Enkhbaatar, Perenlei; Adams, William L.; Sherwood, Edward R.

In: Shock, Vol. 40, No. 6, 12.2013, p. 451-462.

Research output: Contribution to journalArticle

Bohannon, Julia K. ; Hernandez, Antonio ; Enkhbaatar, Perenlei ; Adams, William L. ; Sherwood, Edward R. / The immunobiology of toll-like receptor 4 agonists : From endotoxin tolerance to immunoadjuvants. In: Shock. 2013 ; Vol. 40, No. 6. pp. 451-462.
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