title: Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses.
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.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham 35294-2170, USA.
authors.forename: M
authors.initials: M
authors.lastname: Marinaro
authors.forename: P N
authors.initials: PN
authors.lastname: Boyaka
authors.forename: F D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: H
authors.initials: H
authors.lastname: Kiyono
authors.forename: R J
authors.initials: RJ
authors.lastname: Jackson
authors.forename: E
authors.initials: E
authors.lastname: Jirillo
authors.forename: J R
authors.initials: JR
authors.lastname: McGhee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002772:Cholera Toxin / Q000276:immunology; D016207:Cytokines / Q000097:blood; D006968:Hypersensitivity, Delayed; D018928:Immunity, Mucosal; D007071:Immunoglobulin A, Secretory / Q000096:biosynthesis*; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage*; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage; D013745:Tetanus Toxoid / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D014612:Vaccines / Q000008:administration & dosage*
chemical_list: D016207:Cytokines; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; D008081:Liposomes; D011994:Recombinant Proteins; D013745:Tetanus Toxoid; D014612:Vaccines; D018664:Interleukin-12; D007073:Immunoglobulin E; D002772:Cholera Toxin