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. 2002 Jan;76(2):517-24.
doi: 10.1128/jvi.76.2.517-524.2002.

Cytokines as adjuvants for the induction of anti-human immunodeficiency virus peptide immunoglobulin G (IgG) and IgA antibodies in serum and mucosal secretions after nasal immunization

Curtis P Bradney  1 , Gregory D Sempowski, Hua-Xin Liao, Barton F Haynes, Herman F Staats
Affiliations

Cytokines as adjuvants for the induction of anti-human immunodeficiency virus peptide immunoglobulin G (IgG) and IgA antibodies in serum and mucosal secretions after nasal immunization

Curtis P Bradney et al. J Virol. 2002 Jan.

Abstract

Safe and potent new adjuvants are needed for vaccines that are administered to mucosal surfaces. This study was performed to determine if interleukin-1alpha (IL-1alpha) combined with other proinflammatory cytokines provided mucosal adjuvant activity for induction of systemic and mucosal anti-human immunodeficiency virus (HIV) peptide antibody when intranasally administered with an HIV peptide immunogen. Nasal immunization of BALB/c mice with 10 microg of an HIV env peptide immunogen with IL-1alpha, IL-12, and IL-18 on days 0, 7, 14, and 28 induced peak serum anti-HIV peptide immunoglobulin G1 (IgG1) and IgA titers of 1:131,072 and 1:7,131, respectively (P = 0.05 versus no adjuvant). The use of cholera toxin (CT) as a mucosal adjuvant induced serum IgG1 and IgA titers of 1:32,768 and 1:776, respectively. The adjuvant combination of IL-1alpha, IL-12, and IL-18 induced anti-HIV peptide IgA titers of 1:1,176, 1:7,131, and 1:4,705 in saliva, fecal extracts and vaginal lavage, respectively. Titers induced by the use of CT as an adjuvant were 1:223, 1:1,176, and 1:675, respectively. These results indicate that the proinflammatory cytokines IL-1alpha, IL-12, and IL-18 can replace CT as a mucosal adjuvant for antibody induction and are important candidates for use as mucosal adjuvants with HIV and other vaccines.

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Figures

FIG. 1.
FIG. 1.
Serum antipeptide IgG anti-C4-V3 MN geometric mean titers after nasal immunization with 10 μg of C4-V3 MN immunogen with and without adjuvants. Female BALB/c mice were nasally immunized with 10 μg of C4-V3 MN peptide immunogen alone or combined with 1 μg of CT, 4 μg of IL-1α, 4 μg of GM-CSF, 100 ng of IL-12, 400 ng of IL-18, 20 ng of IL-12 and 400 ng of IL-18, 4 μg of IL-1α and 4 μg of GM-CSF, 4 μg of IL-1α and 100 ng of IL-12, 4 μg of IL-1α and 400 ng of IL-18, or 4 μg of IL-1α and 20 ng of IL-12 and 400 ng of IL-18. On day 35, serum samples were collected and tested via ELISA for the presence of anti-HIV peptide IgG endpoint titers. There were three mice per group. Letters above the bars indicate significance: a, greater than nasal immunization with no adjuvant, P < 0.05; b, greater than nasal immunization with GM-CSF adjuvant, P < 0.05; c, greater than nasal immunization with IL-1α adjuvant, P < 0.05; d, greater than nasal immunization with IL-18 adjuvant, P < 0.05; e, greater than nasal immunization with IL-12 plus IL-18 adjuvant, P < 0.05; f, greater than nasal immunization with CT adjuvant, P < 0.05.
FIG. 2.
FIG. 2.
Serum antipeptide IgG1, IgG2a, and IgA geometric mean titers after immunization with 10 μg of C4E9V-V3 89.6P peptide with and without adjuvant. Female BALB/c mice were nasally immunized with 10 μg of C4E9V-V3 89.6P peptide immunogen alone or combined with1 μg of CT; 4 μg of IL-1α and 100 ng of IL-12 and 4 μg of GM-CSF; 4 μg of IL-1α and 20 ng of IL-12 and 400 ng of IL-18; 4 μg of IL-1α and 20 ng of IL-12 and 400 ng of IL-18 and 4 μg of GM-CSF on days 0, 7, 14, and 28. Control animals were immunized on the same schedule via the subcutaneous route with 10 μg of peptide formulated with alum or alum and 4 μg of IL-1α and 100 ng of IL-12 and 4 μg of GM-CSF. Serum samples were collected on day 35 and assayed via ELISA for the presence of anti-HIV IgG and IgA. There were five mice per group. Letters above the bars indicate significance:a, greater than nasal immunization with no adjuvant, P < 0.05; b, greater than nasal immunization with CT adjuvant, P < 0.05; c, greater than subcutaneous immunization with alum adjuvant, P < 0.05; d, greater than subcutaneous immunization with alum plus IL-1α, IL-12, and GM-CSF adjuvants, P < 0.05.
FIG. 3.
FIG. 3.
Vaginal antipeptide IgG and IgA geometric mean titers after immunization with 10 μg of C4E9V-V3 89.6P peptide with and without adjuvant. Immunization and sample collections were performed as described in the legend to Fig. 2. There were five mice per group. Letters above the bars indicate significance: a, greater than nasal immunization with no adjuvant, P < 0.05; b, greater than nasal immunization with CT adjuvant, P < 0.05; c, greater than subcutaneous immunization with alum adjuvant, P < 0.05; d, greater than subcutaneous immunization with alum plus IL-1α, IL-12, and GM-CSF adjuvants, P < 0.05.
FIG. 4.
FIG. 4.
Fecal antipeptide IgG and IgA geometric mean titers after immunization with 10 μg of C4E9V-V3 89.6P peptide with and without adjuvant. Immunization and sample collections were performed as described in the legend for Fig. 2. There were five mice per group. Letters above the bars indicate significance: a, greater than nasal immunization with no adjuvant, P < 0.05; b, greater than nasal immunization with CT adjuvant, P < 0.05; c, greater than subcutaneous immunization with alum adjuvant, P < 0.05; d, greater than subcutaneous immunization with alum plus IL-1α, IL-12, and GM-CSF adjuvants, P < 0.05.
FIG. 5.
FIG. 5.
Salivary antipeptide IgG and IgA geometric mean titers after immunization with 10 μg of C4E9V-V3 89.6P peptide with and without adjuvant. Immunization and sample collections were performed as described in the legend for Fig. 2. There were five mice per group. Letters above the bars indicate significance: a, greater than nasal immunization with no adjuvant, P < 0.05; b, greater than nasal immunization with CT adjuvant, P < 0.05; c, greater than subcutaneous immunization with alum adjuvant, P < 0.05; d, greater than subcutaneous immunization with alum plus IL-1α, IL-12, and GM-CSF adjuvants, P < 0.05.
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