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,
,
,¶,¶,¶,¶
Departments of
*
Medicine,
Immunology, and
Pathology,
Human Vaccine Institute, and
¶ Center For AIDS Research, Duke University Medical Center, Durham, NC 27710; and
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Harvard Medical School, and Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215
Cholera toxin (CT) is frequently used as an experimental adjuvant
intranasally for the induction of systemic and mucosal immunity.
However, CT is highly reactogenic and not approved for use in humans.
To define the cytokine requirements for the nasal activation of the
systemic and mucosal immune system, and to design new adjuvants with
efficacy similar to CT, we defined the cytokines that were able to
replace CT as a nasal adjuvant for the induction of CTL. BALB/c mice
were nasally immunized with an HIV immunogen that contains an MHC class
I-restricted CTL epitope ± cytokines and tested for HIV-specific
immune responses. We found that combinations of IL-1
plus IL-18,
IL-1 plus IL-12, and IL-1 plus IL-12 plus GM-CSF each induced
optimal splenocyte anti-HIV CTL responses in immunized mice (range
60–71% peptide-specific 51Cr release). Peak
H-2Dd-peptide tetramer-binding T cell responses induced by
cytokine combinations were up to 5.5% of CD8+ PBMC. Nasal
immunization with HIV immunogen and IL-1, IL-12, and GM-CSF also
induced Ag-specific IFN-
-secreting cells in the draining cervical
lymph node and the lung. The use of IL-1, IL-12, and GM-CSF as nasal
adjuvants was associated with an increased expression of MHC class II
and B7.1 on nonlymphocytes within the nasal-associated lymphoid
tissue/nasal mucosa. Thus, IL-1, IL-12, IL-18, and GM-CSF are
critical cytokines for the induction of systemic and mucosal CTL after
nasal immunization. Moreover, these cytokines may serve as effective
adjuvants for nasal vaccine delivery.
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