Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses.
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.
Marinaro
M
M
Department of Microbiology, University of Alabama at Birmingham 35294-2170, USA.
Boyaka
P N
PN
Finkelman
F D
FD
Kiyono
H
H
Jackson
R J
RJ
Jirillo
E
E
McGhee
J R
JR
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*
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