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Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses.

Marinaro M, Boyaka PN, Finkelman FD, Kiyono H, Jackson RJ, Jirillo E, McGhee JR - J. Exp. Med. (1997)

Bottom Line: Intraperitoneal administration of rmIL-12 shifted TT-specific responses toward Th1-type and resulted in CD4+ T cells producing IFN-gamma and IL-2 with markedly reduced levels of Th2-type cytokines.Interestingly, oral rmIL-12 did not result in significant levels of serum IL-12 nor altered S-IgA Ab responses and resulted in higher levels of some Th2-type cytokines both in vitro and in vivo when compared with parenteral IL-12.Our results show that the shifts in systemic immune responses with intact S-IgA Abs which occur after oral delivery of IL-12-liposomes are due to cytokine effects in the Peyer's patches and suggest new strategies for the targeted manipulation of Th1- and Th2-type responses to mucosal vaccines.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Alabama at Birmingham 35294-2170, USA.

ABSTRACT
Our past studies have shown that the mucosal adjuvant cholera toxin (CT) induces T helper type 2 (Th2) responses with systemic IgG1, IgE and mucosal secretory IgA (S-IgA) antibodies (Abs). In this study, recombinant murine IL-12 (rmIL-12) was given either parenterally or orally to mice orally immunized with tetanus toxoid (TT) and CT to determine whether this cytokine could redirect the CT-induced Th2-type responses and what effect this shift would have on S-IgA Ab responses. Intraperitoneal administration of rmIL-12 shifted TT-specific responses toward Th1-type and resulted in CD4+ T cells producing IFN-gamma and IL-2 with markedly reduced levels of Th2-type cytokines. This cytokine profile was accompanied by increased delayed-type hypersensitivity (DTH) and shifts in serum IgG1 to IgG2a and IgG3 anti-TT Ab responses. Further, serum IgE and S-IgA Ab responses were markedly reduced by parenteral IL-12. When IL-12 complexed to liposomes was given orally both shifts to IgG2a and IgG3 and low IgE Abs again occurred concomitant with enhanced serum IFN-gamma and DTH responses. Interestingly, oral rmIL-12 did not result in significant levels of serum IL-12 nor altered S-IgA Ab responses and resulted in higher levels of some Th2-type cytokines both in vitro and in vivo when compared with parenteral IL-12. Our results show that the shifts in systemic immune responses with intact S-IgA Abs which occur after oral delivery of IL-12-liposomes are due to cytokine effects in the Peyer's patches and suggest new strategies for the targeted manipulation of Th1- and Th2-type responses to mucosal vaccines.

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The induction of Th1-type (IFN-γ) and Th2-type (IL-5 and IL-10) cytokines in sera of mice receiving rmIL-12 and orally immunized with  TT and CT as adjuvant. Mice received the combined oral vaccine (unshaded) together with rmIL-12 by the i.p. route (striped, 15 times, 100 ng/dose) or  by the oral route (shaded six times, 1,000 ng/dose). Levels of IFN-γ, IL-5, and IL-10 in the serum were determined on day 21 by ELISA. The results are  expressed as the mean ± one SD and are representative of three different experiments.
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Figure 6: The induction of Th1-type (IFN-γ) and Th2-type (IL-5 and IL-10) cytokines in sera of mice receiving rmIL-12 and orally immunized with TT and CT as adjuvant. Mice received the combined oral vaccine (unshaded) together with rmIL-12 by the i.p. route (striped, 15 times, 100 ng/dose) or by the oral route (shaded six times, 1,000 ng/dose). Levels of IFN-γ, IL-5, and IL-10 in the serum were determined on day 21 by ELISA. The results are expressed as the mean ± one SD and are representative of three different experiments.

Mentions: To directly compare the in vivo effects of oral or i.p. delivery of rmIL-12, we measured serum cytokine levels (IL-2, IFN-γ, IL-4, IL-5, IL-6, and IL-10) in mice that received the oral vaccine and oral or parenteral rmIL-12. While serum IL-2 and IFN-γ were undetectable in mice receiving the oral vaccine alone, i.p. delivery of 100 ng/ dose of rmIL-12 induced high levels of serum IFN-γ (Fig. 6 A). Interestingly, oral administration of rmIL-12–liposomes (6 doses; 1,000 ng/dose) also resulted in significant serum IFN-γ levels in mice orally immunized with TT plus CT as adjuvant; however, systemic rmIL-12 induced the highest levels of serum IFN-γ (Fig. 6 A). When serum IL-4, IL-5, IL-6 and IL-10 levels were assessed in the three different mouse groups, oral TT and CT as adjuvant induced high levels of IL-5 and IL-10 (Fig. 6, B and C), while both IL-4 and IL-6 were undetectable in all groups tested (data not shown). Serum IL-5 and IL-10 levels were significantly decreased in mice receiving parenteral IL-12 (Fig. 6 B), while mice fed oral IL-12–liposomes exhibited higher levels of both IL-5 and IL-10. These findings again show that the route of rmIL-12 delivery affects the pattern of cytokines secreted in vitro and in vivo.


Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses.

Marinaro M, Boyaka PN, Finkelman FD, Kiyono H, Jackson RJ, Jirillo E, McGhee JR - J. Exp. Med. (1997)

The induction of Th1-type (IFN-γ) and Th2-type (IL-5 and IL-10) cytokines in sera of mice receiving rmIL-12 and orally immunized with  TT and CT as adjuvant. Mice received the combined oral vaccine (unshaded) together with rmIL-12 by the i.p. route (striped, 15 times, 100 ng/dose) or  by the oral route (shaded six times, 1,000 ng/dose). Levels of IFN-γ, IL-5, and IL-10 in the serum were determined on day 21 by ELISA. The results are  expressed as the mean ± one SD and are representative of three different experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196042&req=5

Figure 6: The induction of Th1-type (IFN-γ) and Th2-type (IL-5 and IL-10) cytokines in sera of mice receiving rmIL-12 and orally immunized with TT and CT as adjuvant. Mice received the combined oral vaccine (unshaded) together with rmIL-12 by the i.p. route (striped, 15 times, 100 ng/dose) or by the oral route (shaded six times, 1,000 ng/dose). Levels of IFN-γ, IL-5, and IL-10 in the serum were determined on day 21 by ELISA. The results are expressed as the mean ± one SD and are representative of three different experiments.
Mentions: To directly compare the in vivo effects of oral or i.p. delivery of rmIL-12, we measured serum cytokine levels (IL-2, IFN-γ, IL-4, IL-5, IL-6, and IL-10) in mice that received the oral vaccine and oral or parenteral rmIL-12. While serum IL-2 and IFN-γ were undetectable in mice receiving the oral vaccine alone, i.p. delivery of 100 ng/ dose of rmIL-12 induced high levels of serum IFN-γ (Fig. 6 A). Interestingly, oral administration of rmIL-12–liposomes (6 doses; 1,000 ng/dose) also resulted in significant serum IFN-γ levels in mice orally immunized with TT plus CT as adjuvant; however, systemic rmIL-12 induced the highest levels of serum IFN-γ (Fig. 6 A). When serum IL-4, IL-5, IL-6 and IL-10 levels were assessed in the three different mouse groups, oral TT and CT as adjuvant induced high levels of IL-5 and IL-10 (Fig. 6, B and C), while both IL-4 and IL-6 were undetectable in all groups tested (data not shown). Serum IL-5 and IL-10 levels were significantly decreased in mice receiving parenteral IL-12 (Fig. 6 B), while mice fed oral IL-12–liposomes exhibited higher levels of both IL-5 and IL-10. These findings again show that the route of rmIL-12 delivery affects the pattern of cytokines secreted in vitro and in vivo.

Bottom Line: Intraperitoneal administration of rmIL-12 shifted TT-specific responses toward Th1-type and resulted in CD4+ T cells producing IFN-gamma and IL-2 with markedly reduced levels of Th2-type cytokines.Interestingly, oral rmIL-12 did not result in significant levels of serum IL-12 nor altered S-IgA Ab responses and resulted in higher levels of some Th2-type cytokines both in vitro and in vivo when compared with parenteral IL-12.Our results show that the shifts in systemic immune responses with intact S-IgA Abs which occur after oral delivery of IL-12-liposomes are due to cytokine effects in the Peyer's patches and suggest new strategies for the targeted manipulation of Th1- and Th2-type responses to mucosal vaccines.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Alabama at Birmingham 35294-2170, USA.

ABSTRACT
Our past studies have shown that the mucosal adjuvant cholera toxin (CT) induces T helper type 2 (Th2) responses with systemic IgG1, IgE and mucosal secretory IgA (S-IgA) antibodies (Abs). In this study, recombinant murine IL-12 (rmIL-12) was given either parenterally or orally to mice orally immunized with tetanus toxoid (TT) and CT to determine whether this cytokine could redirect the CT-induced Th2-type responses and what effect this shift would have on S-IgA Ab responses. Intraperitoneal administration of rmIL-12 shifted TT-specific responses toward Th1-type and resulted in CD4+ T cells producing IFN-gamma and IL-2 with markedly reduced levels of Th2-type cytokines. This cytokine profile was accompanied by increased delayed-type hypersensitivity (DTH) and shifts in serum IgG1 to IgG2a and IgG3 anti-TT Ab responses. Further, serum IgE and S-IgA Ab responses were markedly reduced by parenteral IL-12. When IL-12 complexed to liposomes was given orally both shifts to IgG2a and IgG3 and low IgE Abs again occurred concomitant with enhanced serum IFN-gamma and DTH responses. Interestingly, oral rmIL-12 did not result in significant levels of serum IL-12 nor altered S-IgA Ab responses and resulted in higher levels of some Th2-type cytokines both in vitro and in vivo when compared with parenteral IL-12. Our results show that the shifts in systemic immune responses with intact S-IgA Abs which occur after oral delivery of IL-12-liposomes are due to cytokine effects in the Peyer's patches and suggest new strategies for the targeted manipulation of Th1- and Th2-type responses to mucosal vaccines.

Show MeSH
Related in: MedlinePlus