The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/2/415/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 3, February 3, 1997 415-428

Articles

Oral but Not Parenteral Interleukin (IL)-12 Redirects T Helper 2 (Th2)-type Responses to an Oral Vaccine Without Altering Mucosal IgA Responses

Mariarosaria Marinaro*, Prosper N. Boyaka*, Fred D. Finkelman{ddagger}, Hiroshi Kiyono*,§, Raymond J. Jackson*, Emilio Jirillo, and Jerry R. McGhee*

From the * Departments of Microbiology and Oral Biology, The Immunobiology Vaccine Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294-2170; {ddagger} Department of Internal Medicine, Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0563; § Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan 565; and Department of Microbiology and Immunology, University of Bari, Bari, Italy

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.

Address correspondence to Jerry R. McGhee, Department of Microbiology, The Immunobiology Vaccine Center, University of Alabama at Birmingham, Bevill Biomedical Research Building, Room 761, 845 19th St. South, Birmingham, Alabama 35294-2170.

This work was supported by National Institutes of Health grants AI 18958, DK 44240, DE 04217, AI 35344, DE 09837, and NIAID-DMID contract N01 AI 65299.

1 Abbreviations used in this paper: AFC, antibody-forming cells; CMI, cellmediated immunity; CT, cholera toxin; ELISPOT, enzyme-linked spot; GALT, gut-associated lymphoreticular tissue; GI, gastrointestinal; LPL, lamina propria lymphocytes; PCA, passive cutaneous anaphylaxis; PP, Peyer's patches; S-IgA, secretory IgA; SP, spleen; TMB, 3,3',5,5'-tetramethylbenzidine; TT, tetanus toxoid.


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