Abstract
Native type I heat-labile toxins (LTs) produced by enterotoxigenic Escherichia coli (ETEC) strains exert strong adjuvant effects on both antibody and T cell responses to soluble and particulate antigens following co-administration via mucosal routes. However, inherent enterotoxicity and neurotoxicity (following intra-nasal delivery) had reduced the interest in the use of these toxins as mucosal adjuvants. LTs can also behave as powerful and safe adjuvants following delivery via parenteral routes, particularly for activation of cytotoxic lymphocytes. In the present study, we evaluated the adjuvant effects of a new natural LT polymorphic form (LT2), after delivery via intradermal (i.d.) and subcutaneous (s.c.) routes, with regard to both antibody and T cell responses. A recombinant HIV-1 p24 protein was employed as a model antigen for determination of antigen-specific immune responses while the reference LT (LT1), produced by the ETEC H10407 strain, and a non-toxigenic LT form (LTK63) were employed as previously characterized LT types. LT-treated mice submitted to a four dose-base immunization regimen elicited similar p24-specific serum IgG responses and CD4+ T cell activation. Nonetheless, mice immunized with LT1 or LT2 induced higher numbers of antigen-specific CD8+ T cells and in vivo cytotoxic responses compared to mice immunized with the non-toxic LT derivative. These effects were correlated with stronger activation of local dendritic cell populations. In addition, mice immunized with LT1 and LT2, but not with LTK63, via s.c. or i.d. routes developed local inflammatory reactions. Altogether, the present results confirmed that the two most prevalent natural polymorphic LT variants (LT1 or LT2) display similar and strong adjuvant effects for subunit vaccines administered via i.d. or s.c. routes.
Highlights
Type I heat-labile toxins (LTs) produced by some enterotoxigenic Escherichia coli (ETEC) strains belong to a family of structurally and immunologically related enterotoxins associated with traveler’s diarrhea [1]
We further investigated the immunological features of LT2 in comparison with other known LT forms, including LT1 and LTK63, with regard to the adjuvant effects for both humoral and cellular (T cell) responses elicited in mice immunized via parenteral routes with co-administered recombinant HIV-1 p24 protein as a model antigen
In the present study, we investigated the adjuvant effects of a natural LT form (LT2) after administration of a soluble antigen administered via i.d. and s.c. routes to mice
Summary
Type I heat-labile toxins (LTs) produced by some enterotoxigenic Escherichia coli (ETEC) strains belong to a family of structurally and immunologically related enterotoxins associated with traveler’s diarrhea [1]. The enhanced 3 ,5 -cyclic monophosphate (cAMP) levels promote massive ion and water losses from the enterocytes to the intestinal lumen, leading to diarrhea [1]. In addition to their pivotal role in the etiology of ETECassociated secretory diarrhea, LTs have attracted considerable interest due to their strong adjuvant effects observed after coadministration of the toxin with soluble or particulate antigens via mucosal [2,3,4,5,6,7,8,9] or transcutaneous routes [9,10,11]. Clinical trial results were disappointing due either to the induction of unacceptable side effects (transient facial paralysis) after intra-nasal administration of LTK63 or to reduced adjuvant effects in subjects immunized with LT-adjuvanted adhesive vaccine patches [10, 11, 15]
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