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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 (IL-2 and IFN-γ) and  Th2-type (IL-4, IL-5, IL-6, and  IL-10) cytokine secretion by  CD4+ T cells isolated from mucosally immunized mice which  had been given oral (shaded) or  parenteral (striped) rmIL-12. SP  and PP CD4+ T cells, were purified from mice receiving the  combined oral vaccine only (unshaded) or combined vaccine together with rmIL-12 orally (six  times, 1,000 ng/dose) or parenterally (15 times, 100 ng/dose)  and were restimulated in vitro  for 6 d in the presence of feeder  cells and TT-coated beads. Th1type (A) and Th2-type (B) cytokine production in culture supernatants were analyzed by  ELISA. Cytokine levels are representative of three separate experiments.
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Figure 5: The induction of Th1-type (IL-2 and IFN-γ) and Th2-type (IL-4, IL-5, IL-6, and IL-10) cytokine secretion by CD4+ T cells isolated from mucosally immunized mice which had been given oral (shaded) or parenteral (striped) rmIL-12. SP and PP CD4+ T cells, were purified from mice receiving the combined oral vaccine only (unshaded) or combined vaccine together with rmIL-12 orally (six times, 1,000 ng/dose) or parenterally (15 times, 100 ng/dose) and were restimulated in vitro for 6 d in the presence of feeder cells and TT-coated beads. Th1type (A) and Th2-type (B) cytokine production in culture supernatants were analyzed by ELISA. Cytokine levels are representative of three separate experiments.

Mentions: It was important to determine cytokine profiles exhibited by TT-specific CD4+ T cells from both peripheral (SP) and mucosal (PP) immune compartments since mice treated parenterally or orally with rmIL-12 exhibited comparable effects on serum Ab responses but different effects on mucosal IgA Ab responses. Culture supernatants from PP and SP CD4+ T cells restimulated with Ag in vitro revealed that T cells from mice treated either orally or parenterally with rmIL-12 secreted more IFN-γ than did T cells from mice orally immunized with TT and CT only (Fig. 5 A). The two different treatment routes both led to induction of comparable IFN-γ synthesis at the mucosal level (PP) and in SP. IL-12 treatment also increased IL-2 secretion by splenic T cells and to a lesser extent by PP T cells. Levels of IL-4, IL-5, IL-6, and IL-10 assessed in culture supernatants of TT-specific CD4+ T cells from SP and PP were significantly downregulated after parenteral administration of rmIL-12 (Fig. 5 B). Oral rmIL-12–liposomes downregulated IL-4 secretion but reduced IL-5, IL-6, and IL-10 secretion by SP and PP CD4+ T cells less markedly (Fig. 5 B).


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 (IL-2 and IFN-γ) and  Th2-type (IL-4, IL-5, IL-6, and  IL-10) cytokine secretion by  CD4+ T cells isolated from mucosally immunized mice which  had been given oral (shaded) or  parenteral (striped) rmIL-12. SP  and PP CD4+ T cells, were purified from mice receiving the  combined oral vaccine only (unshaded) or combined vaccine together with rmIL-12 orally (six  times, 1,000 ng/dose) or parenterally (15 times, 100 ng/dose)  and were restimulated in vitro  for 6 d in the presence of feeder  cells and TT-coated beads. Th1type (A) and Th2-type (B) cytokine production in culture supernatants were analyzed by  ELISA. Cytokine levels are representative of three separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196042&req=5

Figure 5: The induction of Th1-type (IL-2 and IFN-γ) and Th2-type (IL-4, IL-5, IL-6, and IL-10) cytokine secretion by CD4+ T cells isolated from mucosally immunized mice which had been given oral (shaded) or parenteral (striped) rmIL-12. SP and PP CD4+ T cells, were purified from mice receiving the combined oral vaccine only (unshaded) or combined vaccine together with rmIL-12 orally (six times, 1,000 ng/dose) or parenterally (15 times, 100 ng/dose) and were restimulated in vitro for 6 d in the presence of feeder cells and TT-coated beads. Th1type (A) and Th2-type (B) cytokine production in culture supernatants were analyzed by ELISA. Cytokine levels are representative of three separate experiments.
Mentions: It was important to determine cytokine profiles exhibited by TT-specific CD4+ T cells from both peripheral (SP) and mucosal (PP) immune compartments since mice treated parenterally or orally with rmIL-12 exhibited comparable effects on serum Ab responses but different effects on mucosal IgA Ab responses. Culture supernatants from PP and SP CD4+ T cells restimulated with Ag in vitro revealed that T cells from mice treated either orally or parenterally with rmIL-12 secreted more IFN-γ than did T cells from mice orally immunized with TT and CT only (Fig. 5 A). The two different treatment routes both led to induction of comparable IFN-γ synthesis at the mucosal level (PP) and in SP. IL-12 treatment also increased IL-2 secretion by splenic T cells and to a lesser extent by PP T cells. Levels of IL-4, IL-5, IL-6, and IL-10 assessed in culture supernatants of TT-specific CD4+ T cells from SP and PP were significantly downregulated after parenteral administration of rmIL-12 (Fig. 5 B). Oral rmIL-12–liposomes downregulated IL-4 secretion but reduced IL-5, IL-6, and IL-10 secretion by SP and PP CD4+ T cells less markedly (Fig. 5 B).

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