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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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Induction of delayed-type hypersensitivity responses in  rmIL-12–treated mice given the combined oral vaccine. Three groups of  mice were assessed and included combined oral vaccine only (unshaded),  those receiving combined oral vaccine and rmIL-12 by the i.p. (striped; 15  times 100 ng/dose) route, or mice given rmIL-12 by the oral route  (shaded; six times 1,000 ng/dose). The results are expressed as the mean ±  one SD of the difference in the ear swelling between the TT-injected and  OVA-injected ear pinna and are representative of three separate experiments.
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Figure 7: Induction of delayed-type hypersensitivity responses in rmIL-12–treated mice given the combined oral vaccine. Three groups of mice were assessed and included combined oral vaccine only (unshaded), those receiving combined oral vaccine and rmIL-12 by the i.p. (striped; 15 times 100 ng/dose) route, or mice given rmIL-12 by the oral route (shaded; six times 1,000 ng/dose). The results are expressed as the mean ± one SD of the difference in the ear swelling between the TT-injected and OVA-injected ear pinna and are representative of three separate experiments.

Mentions: To assess changes in CMI responses resulting from the shift in cytokine production, we measured DTH responses to TT in mice orally or parenterally treated with rmIL-12. Mice given the combined oral vaccine alone did not develop significant DTH responses, supporting the presence of a predominant Th2-type immune response (Fig. 7). In contrast, mice treated either orally or parenterally with rmIL-12 during the immunization protocol exhibited significantly higher DTH responses 24 h after TT challenge when compared with mice receiving the oral vaccine and adjuvant only.


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)

Induction of delayed-type hypersensitivity responses in  rmIL-12–treated mice given the combined oral vaccine. Three groups of  mice were assessed and included combined oral vaccine only (unshaded),  those receiving combined oral vaccine and rmIL-12 by the i.p. (striped; 15  times 100 ng/dose) route, or mice given rmIL-12 by the oral route  (shaded; six times 1,000 ng/dose). The results are expressed as the mean ±  one SD of the difference in the ear swelling between the TT-injected and  OVA-injected ear pinna and are representative of three separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Induction of delayed-type hypersensitivity responses in rmIL-12–treated mice given the combined oral vaccine. Three groups of mice were assessed and included combined oral vaccine only (unshaded), those receiving combined oral vaccine and rmIL-12 by the i.p. (striped; 15 times 100 ng/dose) route, or mice given rmIL-12 by the oral route (shaded; six times 1,000 ng/dose). The results are expressed as the mean ± one SD of the difference in the ear swelling between the TT-injected and OVA-injected ear pinna and are representative of three separate experiments.
Mentions: To assess changes in CMI responses resulting from the shift in cytokine production, we measured DTH responses to TT in mice orally or parenterally treated with rmIL-12. Mice given the combined oral vaccine alone did not develop significant DTH responses, supporting the presence of a predominant Th2-type immune response (Fig. 7). In contrast, mice treated either orally or parenterally with rmIL-12 during the immunization protocol exhibited significantly higher DTH responses 24 h after TT challenge when compared with mice receiving the oral vaccine and adjuvant only.

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