Mucosal adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and IL-4.

Abstract

Despite pathophysiologic effects including diarrhea, cholera toxin (CT) is a potent mucosal immunogen and adjuvant. We investigated the influence of CT on T helper (Th)-type 1 (Th1) and Th2 cell-regulated Ag-specific B cell isotype and IgG subclass Ab responses elicited when the toxin was co-administered orally with different protein Ags. When mice were orally immunized with tetanus toxoid (TT) and CT as adjuvant, this regimen induced TT-specific secretory IgA responses in the gastrointestinal tract as well as serum IgG, including IgG1 and IgG2b subclasses, and IgA responses. This oral regimen also induced TT- and CT-B-specific IgE responses. In addition, CT also elicited adjuvant effects for Ag-specific IgG1, IgE, and IgA responses when two other protein Ags, OVA and hen egg white lysozyme, were given by the oral route. Quantitative reverse transcriptase-PCR was performed to assess levels of mRNA for Th1 (IFN-gamma) and Th2 (IL-4) cytokine expression in TT-stimulated CD4+ T cell cultures. Both Peyer's patches and splenic CD4+ T cells expressed markedly increased levels of IL-4-specific message, but did not result in changes in IFN-gamma mRNA expression. To determine whether the route of immunization influenced IgE responses, mice were immunized s.c. with TT and CT as adjuvant. Significant increases in total and TT-specific IgE Abs were induced when CT was co-administered. Taken together, these results show that CT acts as a mucosal adjuvant to enhance Th2-type responses and in particular, the IL-4 produced results in a characteristic Ab isotype pattern associated with this cytokine.

Goat Milk is Less Immunogenic than Cow Milk in a Murine Model of Atopy

“…To bypass the tendency of mice to develop oral tolerance, we used CT, which has been reported to stimulate a Th2 response and the production of IgG1 antibodies (35,36). Furthermore, Balb/C mice were used because this strain of mice is prone to develop Th2 responses easier than other strains (37).…”

Mucosal adjuvanticity of immunostimulatory DNA sequences

“…The adjuvants ISS-ODN and CT have previously been considered to promote antigen-specific Th 1-and The-biased cytokine profiles, respectively [9,15,20,23,31,35]. To confirm that i.n.…”

“…In contrast, Th2-biased immune responses are associated with the synthesis of IgG1 and IgE [25,35]. ISS-ODN is considered to be a Th t adjuvant when delivered systemically, while CT is considered to be a Th 2 adjuvant when delivered mucosally [9,15,20,23,31,35]. The serum antibody profile after i.n.…”

“…CT is an extremely potent mucosal adjuvant, but is inherently toxic and induces a Thz-biased antibody response which can include the development of IgE and consequent allergic sensitization toward the target antigen [20,35]. At present, such toxicity and other technical problems have kept many adjuvants, including CT, from becoming available for use in humans [13].…”

“…Unfortunately, like many adjuvants it has unacceptable toxicity for use in humans [37]. In addition, CT biases systemic immune responses toward a Th 2 phenotype, potentially leading to IgE production and allergic hypersensitivity toward the antigen [20,35].…”