3rtq

Publication Abstract from PubMed

Activation of type I NKT (iNKT) cells by CD1d-presented agonists is a potent immunotherapeutic tool. alpha-Galactosylceramide (alpha-GalCer) is the prototypic agonist, but its excessive potency with simultaneous production of both pro- and anti-inflammatory cytokines hampers its potential therapeutic use. In search for novel agonists, we have analyzed the structure and function of HS44, a synthetic aminocyclitolic ceramide analog designed to avoid unrestrained iNKT cell activation. HS44 is a weaker agonist compared with alpha-GalCer in vitro, although in vivo it induces robust IFN-gamma production, and highly reduced but still functional Th2 response. The characteristic cytokine storm produced upon alpha-GalCer activation was not induced. Consequently, HS44 induced a very efficient iNKT cell-dependent antitumoral response in B16 animal model. In addition, intranasal administration showed the capacity to induce lung inflammation and airway hyperreactivity, a cardinal asthma feature. Thus, HS44 is able to elicit functional Th1 or Th2 responses. Structural studies show that HS44 binds to CD1d with the same conformation as alpha-GalCer. The TCR binds to HS44 similarly as alpha-GalCer, but forms less contacts, thus explaining its weaker TCR affinity and, consequently, its weaker recognition by iNKT cells. The ability of this compound to activate an efficient, but not massive, tailored functional immune response makes it an attractive reagent for immune manipulation.

Structural and functional characterization of a novel nonglycosidic type I NKT agonist with immunomodulatory properties.,Kerzerho J, Yu ED, Barra CM, Alari-Pahisa E, Girardi E, Harrak Y, Lauzurica P, Llebaria A, Zajonc DM, Akbari O, Castano AR J Immunol. 2012 Mar 1;188(5):2254-65. Epub 2012 Feb 1. PMID:22301545^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.