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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 effect of oral and parenteral administration of rmIL-12 on mucosal IgA responses  to an oral vaccine consisting of TT and CT as mucosal adjuvant. TT-specific S-IgA Ab titers in fecal  extracts were measured on day 21 by ELISA. The  frequency of TT-specific IgA AFCs in LPLs was  determined on day 21 by ELISPOT. Mice received  the oral vaccine alone (unshaded) or together with  rmIL-12 by i.p. injection (striped, 100 ng/dose) or  six oral administrations (shaded, 1,000 ng/dose). The  results are expressed as the mean ± one SD from  four different experiments (five mice per group).
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Figure 4: The effect of oral and parenteral administration of rmIL-12 on mucosal IgA responses to an oral vaccine consisting of TT and CT as mucosal adjuvant. TT-specific S-IgA Ab titers in fecal extracts were measured on day 21 by ELISA. The frequency of TT-specific IgA AFCs in LPLs was determined on day 21 by ELISPOT. Mice received the oral vaccine alone (unshaded) or together with rmIL-12 by i.p. injection (striped, 100 ng/dose) or six oral administrations (shaded, 1,000 ng/dose). The results are expressed as the mean ± one SD from four different experiments (five mice per group).

Mentions: We next compared the effect of rmIL-12 given i.p. or orally on TT-specific mucosal IgA Ab responses to oral TT plus CT as adjuvant. Three oral doses of TT with CT at weekly intervals led to brisk fecal IgA Abs and elevated numbers of IgA anti-TT AFC in isolated lamina propria lymphocytes (LPLs) (Fig. 4, A and B). Intraperitoneal delivery of rmIL-12 resulted in an eightfold decrease in IgA Ab titers, which correlated with an ∼50% reduction in IgA AFC in isolated LPLs (Fig. 4, A and B). In sharp contrast to the significant inhibition of mucosal IgA anti-TT Ab responses induced by parenteral rmIL-12, neither IgA anti-TT Abs nor numbers of IgA AFC in isolated LPLs were affected by oral delivery of rmIL-12 (Fig. 4, A and B). Thus, both oral and parenteral rmIL-12 reduced IgE responses and induced shifts from IgG1 to IgG2a and IgG3 anti-TT Ab responses in serum, while only the oral route of delivery allowed mucosal IgA anti-TT Ab responses.


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 effect of oral and parenteral administration of rmIL-12 on mucosal IgA responses  to an oral vaccine consisting of TT and CT as mucosal adjuvant. TT-specific S-IgA Ab titers in fecal  extracts were measured on day 21 by ELISA. The  frequency of TT-specific IgA AFCs in LPLs was  determined on day 21 by ELISPOT. Mice received  the oral vaccine alone (unshaded) or together with  rmIL-12 by i.p. injection (striped, 100 ng/dose) or  six oral administrations (shaded, 1,000 ng/dose). The  results are expressed as the mean ± one SD from  four different experiments (five mice per group).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: The effect of oral and parenteral administration of rmIL-12 on mucosal IgA responses to an oral vaccine consisting of TT and CT as mucosal adjuvant. TT-specific S-IgA Ab titers in fecal extracts were measured on day 21 by ELISA. The frequency of TT-specific IgA AFCs in LPLs was determined on day 21 by ELISPOT. Mice received the oral vaccine alone (unshaded) or together with rmIL-12 by i.p. injection (striped, 100 ng/dose) or six oral administrations (shaded, 1,000 ng/dose). The results are expressed as the mean ± one SD from four different experiments (five mice per group).
Mentions: We next compared the effect of rmIL-12 given i.p. or orally on TT-specific mucosal IgA Ab responses to oral TT plus CT as adjuvant. Three oral doses of TT with CT at weekly intervals led to brisk fecal IgA Abs and elevated numbers of IgA anti-TT AFC in isolated lamina propria lymphocytes (LPLs) (Fig. 4, A and B). Intraperitoneal delivery of rmIL-12 resulted in an eightfold decrease in IgA Ab titers, which correlated with an ∼50% reduction in IgA AFC in isolated LPLs (Fig. 4, A and B). In sharp contrast to the significant inhibition of mucosal IgA anti-TT Ab responses induced by parenteral rmIL-12, neither IgA anti-TT Abs nor numbers of IgA AFC in isolated LPLs were affected by oral delivery of rmIL-12 (Fig. 4, A and B). Thus, both oral and parenteral rmIL-12 reduced IgE responses and induced shifts from IgG1 to IgG2a and IgG3 anti-TT Ab responses in serum, while only the oral route of delivery allowed mucosal IgA anti-TT Ab responses.

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