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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  administration of rmIL-12 on  polyclonal and TT-specific serum Ab responses. Mice received  the oral combined vaccine alone  (unshaded) or vaccine together  with rmIL-12 complexed to liposomes by the oral route  (striped, 1,000 ng/dose three  times and shaded, 1,000 ng/dose  six times). (A) Polyclonal and  TT-specific serum IgE Abs were  measured on day 14 by ELISA  and PCA assays, respectively. (B)  The distribution of TT-specific  serum IgG subclasses were determined on day 21 by ELISA. (C)  Serum TT-specific IgM, IgA,  and IgG Abs were measured by  ELISA on day 21. Results are  expressed as the mean ± one SD  from four different experiments  (five mice per group).
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Figure 3: The effect of oral administration of rmIL-12 on polyclonal and TT-specific serum Ab responses. Mice received the oral combined vaccine alone (unshaded) or vaccine together with rmIL-12 complexed to liposomes by the oral route (striped, 1,000 ng/dose three times and shaded, 1,000 ng/dose six times). (A) Polyclonal and TT-specific serum IgE Abs were measured on day 14 by ELISA and PCA assays, respectively. (B) The distribution of TT-specific serum IgG subclasses were determined on day 21 by ELISA. (C) Serum TT-specific IgM, IgA, and IgG Abs were measured by ELISA on day 21. Results are expressed as the mean ± one SD from four different experiments (five mice per group).

Mentions: We next determined if rmIL-12 could be given by the oral route. To obviate potential degradation in the gastrointestinal (GI) tract, mice were given 1,000 ng of rmIL-12/dose complexed to liposomes. The efficacy of oral rmIL-12-liposomes was assessed in two schedules, both of which included the time of oral immunization (Fig. 1), since it has been shown that shifts toward Th1-type responses require IL-12 delivery at the time of antigen administration (15, 42). Analysis of serum IgE responses in mice orally immunized with TT plus CT and receiving oral rmIL-12–liposomes showed that three doses (days 0, 7, and 14) of rmIL-12 significantly downregulated both polyclonal and TT-specific IgE responses, an effect which was further increased when six oral doses (days 0, 3, 7, 10, 14, and 17) of rmIL-12–liposomes were given (Fig. 3 A). Administration of three doses of rmIL-12 also resulted in moderate increases in serum IgG2a and IgG3 anti-TT Ab responses (see Fig. 3 B); however, six oral doses of rmIL-12– liposomes elicited high IgG2a and IgG3 anti-TT Ab titers and downregulated TT-specific IgG1 Ab responses (see Fig. 3 B). Interestingly, the inhibition of serum IgE responses and the changes in IgG subclass responses after administration of six oral doses of rmIL-12–liposomes (1,000 ng/dose) were comparable to or greater than those observed after parenteral rmIL-12 (100 ng/dose) (Fig. 2). Despite the effects of rmIL-12 on IgG subclass responses, the total levels of serum IgG, IgM and IgA were not significantly affected by oral administration of this cytokine (Fig. 3 C).


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  administration of rmIL-12 on  polyclonal and TT-specific serum Ab responses. Mice received  the oral combined vaccine alone  (unshaded) or vaccine together  with rmIL-12 complexed to liposomes by the oral route  (striped, 1,000 ng/dose three  times and shaded, 1,000 ng/dose  six times). (A) Polyclonal and  TT-specific serum IgE Abs were  measured on day 14 by ELISA  and PCA assays, respectively. (B)  The distribution of TT-specific  serum IgG subclasses were determined on day 21 by ELISA. (C)  Serum TT-specific IgM, IgA,  and IgG Abs were measured by  ELISA on day 21. 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 3: The effect of oral administration of rmIL-12 on polyclonal and TT-specific serum Ab responses. Mice received the oral combined vaccine alone (unshaded) or vaccine together with rmIL-12 complexed to liposomes by the oral route (striped, 1,000 ng/dose three times and shaded, 1,000 ng/dose six times). (A) Polyclonal and TT-specific serum IgE Abs were measured on day 14 by ELISA and PCA assays, respectively. (B) The distribution of TT-specific serum IgG subclasses were determined on day 21 by ELISA. (C) Serum TT-specific IgM, IgA, and IgG Abs were measured by ELISA on day 21. Results are expressed as the mean ± one SD from four different experiments (five mice per group).
Mentions: We next determined if rmIL-12 could be given by the oral route. To obviate potential degradation in the gastrointestinal (GI) tract, mice were given 1,000 ng of rmIL-12/dose complexed to liposomes. The efficacy of oral rmIL-12-liposomes was assessed in two schedules, both of which included the time of oral immunization (Fig. 1), since it has been shown that shifts toward Th1-type responses require IL-12 delivery at the time of antigen administration (15, 42). Analysis of serum IgE responses in mice orally immunized with TT plus CT and receiving oral rmIL-12–liposomes showed that three doses (days 0, 7, and 14) of rmIL-12 significantly downregulated both polyclonal and TT-specific IgE responses, an effect which was further increased when six oral doses (days 0, 3, 7, 10, 14, and 17) of rmIL-12–liposomes were given (Fig. 3 A). Administration of three doses of rmIL-12 also resulted in moderate increases in serum IgG2a and IgG3 anti-TT Ab responses (see Fig. 3 B); however, six oral doses of rmIL-12– liposomes elicited high IgG2a and IgG3 anti-TT Ab titers and downregulated TT-specific IgG1 Ab responses (see Fig. 3 B). Interestingly, the inhibition of serum IgE responses and the changes in IgG subclass responses after administration of six oral doses of rmIL-12–liposomes (1,000 ng/dose) were comparable to or greater than those observed after parenteral rmIL-12 (100 ng/dose) (Fig. 2). Despite the effects of rmIL-12 on IgG subclass responses, the total levels of serum IgG, IgM and IgA were not significantly affected by oral administration of this cytokine (Fig. 3 C).

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