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Departments of Medicine and Immunology, Center for AIDS Research, Duke University Medical Center, Durham, NC 27710
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß for their ability to serve as mucosal adjuvants
when intranasally administered with soluble protein Ags. IL-1 and
IL-1ß were as effective as CT for the induction of Ag-specific serum
IgG, vaginal IgG and IgA, systemic delayed-type hypersensitivity, and
lymphocyte proliferative responses when intranasally administered with
soluble protein Ag. Our results indicate that IL-1 and IL-1ß may
be useful as mucosal vaccine adjuvants. Such an adjuvant may be useful,
and possibly required, for vaccine-mediated protection against
pathogens that infect via the mucosal surfaces of the host such as
HIV. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The most potent and best-studied mucosal adjuvant is CT (13, 16, 17, 18, 19). However, CT is not safe for use as a mucosal adjuvant in humans because as little as 5 µg of CT causes massive diarrhea when intragastrically administered to human volunteers (20). Although the use of CT as a mucosal adjuvant in research animals is generally well tolerated, in some cases the use of CT was associated with the production of Ag-specific IgE responses and lethal anaphylactic reactions (21, 22). To repress the toxicity associated with toxin adjuvants, mutant CT, LT, and PT molecules have been produced that exhibit reduced or undetectable toxic activity while maintaining mucosal adjuvant activity (15, 23, 24, 25, 26, 27, 28). Although these molecules possess potent adjuvant activity in the absence of toxicity, they maintain immunogenic properties when administered to experimental animals (23, 29, 30). Unfortunately, the immunogenicity of these mutant toxin molecules may also prevent their widespread repeated use as mucosal adjuvants because pre-existing immunity to CT reduces its adjuvant activity (31, 32).
Exactly how CT (or LT or PT) acts as a mucosal adjuvant is not
completely understood. When used as a mucosal adjuvant, CT has been
reported to facilitate Ag access to the mucosal immune system (31),
enhance the induction of Ag-specific T and B cells (33, 34), and
up-regulate the expression of the costimulatory molecule B7.2 on
mucosal APC (35). The adjuvant activity of CT has also been associated
with its ability to induce cytokine secretion by a variety of cell
types (Table I
). For example, treatment
of the P388D1 M* cell line with CT enhanced the production of IL-1 and
the APC activity of the cells in an alloreactive T cell proliferation
assay (36). Treatment of CT-stimulated P388D1 cells with
anti-IL-1 completely abrogated the CT-enhanced APC activity
(36). CT also enhanced IgA production in surface IgA-
spleen B cells, and CT-enhanced IgA production could be blocked by
anti-TGF-ß Abs (37). Therefore, CT-enhanced APC activity in
macrophages and IgA production by B cells can be attributed to
CT-stimulated production of IL-1 and TGF-ß, respectively (36, 37).
Additionally, the CT-induced cytokines IL-1 and TGF-ß may duplicate
many responses induced by CT (37, 38, 39, 40, 41, 42, 43, 44) (Table I).
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), our hypothesis
is that the adjuvanticity of CT is due to its ability to induce the
local production of proinflammatory cytokines that create an
immunological microenvironment suitable for the induction of systemic
and mucosal immune responses. Because IL-1 secretion was induced by CT,
IL-1 was responsible for CT-enhanced APC function of macrophages, IL-1
duplicates many of the activities of CT, and IL-1 is a potent
proinflammatory cytokine that induces the production of many additional
cytokines, we formed the additional hypothesis that coadministration of
IL-1 with soluble protein Ags by the nasal route will induce
Ag-specific systemic and mucosal immune responses. The present study
was performed to determine whether IL-1 and IL-1ß exhibited
mucosal adjuvant activity when intranasally administered with soluble
protein Ags. Our results indicated that IL-1 and IL-1ß were as
effective as cholera toxin for the induction of Ag-specific systemic
and mucosal immune responses. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c and C57BL/6 mice, 16–18 g, were purchased from Frederick Cancer Research and Developmental Center, National Cancer Institute (Frederick, MD). Animals were housed in filter-top cages and provided food and water ad libitum. All procedures for use and care of mice were approved by Duke University’s institutional animal care and use committee.
Immunization
Mice were intranasally immunized as previously described (10, 11, 14). Briefly, mice (three or four mice per group) were intranasally
immunized with the indicated concentration (Table II) of OVA (A-5503, Sigma, St. Louis, MO)
or tetanus toxoid (TT; provided by Drs. Dennis Katkocin and John
Eldridge, Wyeth-Lederle Vaccines and Pediatrics, Pearl River, NY) and
the indicated adjuvant in a total volume of 15 µl (7.5 µl/nostril).
The mucosal adjuvant CT was obtained from List Biological Laboratories
(Campbell, CA). Recombinant human IL-1 and IL-1ß were obtained
from the National Cancer Institute Biological Resources Branch,
Division of Cancer Treatment, Frederick Cancer Research and Development
Center. The recombinant human IL-1 had a sp. act. of 3.0 x
108 U/mg, while recombinant human IL-1ß had a sp. act. of
1.81 x 107 U/mg. Ag preparations were diluted to the
appropriate concentration in sterile distilled water, and 7.5 µl of
the Ag mixture was introduced into each nostril while mice were under
isoflurane anesthesia (IsoFlo, USP, Solvay Animal Health, Mendota
Heights, MN).
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Blood was collected from the retro-orbital plexus using a heparinized Natelson capillary tube (Baxter Healthcare, McGaw Park, IL) while mice were under ketamine/xylazine anesthesia. Vaginal wash samples were collected by washing the vaginal cavity with 100 µl of sterile PBS while mice were anesthetized with ketamine/xylazine. This procedure resulted in an approximately 10-fold dilution of vaginal samples (10). All samples were stored at -20°C until assayed for Ag-specific Abs.
ELISA
An ELISA was used to determine the presence of Ag-specific Abs in serum and vaginal wash samples. The ELISA was performed as previously reported (10, 11), except that ELISA plates were coated with OVA or TT at 5 µg/ml. The end-point titer represents the reciprocal log2 dilution of the last sample whose OD was at least 2-fold higher than the OD of a corresponding naive sample. The geometric mean titer and SD were calculated using the log2 end-point titers and then were transformed to the antilog for figures and tables. All statistical evaluations were performed with the log2 data. Due to the small vaginal lavage sample sizes, vaginal IgG and IgA responses are reported as end-point ELISA titers instead of standardizing them based on total IgG and IgA concentrations (10, 11). Detection reagents for the ELISA were purchased from Southern Biotechnology Associates (Birmingham, AL). IgG subclass detection reagents were specific for the indicated IgG subclass (i.e., there was no cross-reactivity among the IgG subclass reagents).
Cell isolation and proliferation assay
Spleens were aseptically removed, and single-cell suspensions
were produced by cutting the spleen into small pieces (
5 mm x
5 mm) and expressing the cells from the splenic capsule with the
sterile end of a 5-cc syringe plunger. RBC were removed by
centrifugation over Cappel Lymphocyte Separation Medium (ICN, Aurora,
OH). Cells were adjusted to 2 x 106 cells/ml in
complete T cell medium (RPMI 1640, 10% FBS, HEPES, Pen/Strep, and
2-ME). To an equal volume of cells was added an equal volume of
complete T cell medium or medium containing 0.2 µg/ml of the
appropriate Ag (OVA or TT) to give a final cell density of 1 x
106 cells/ml and Ag at 0.1 µg/ml. Cells (100 µl) were
added to round-bottom 96-well microtiter plates in triplicate and were
incubated in a 37°C, 10% CO2 in air, humidified
environment for 5 days. Four to six hours before harvesting, 0.5 µCi
of [3H]thymidine (New England Nuclear Research Products,
Boston, MA) was added to each well. Cells were harvested onto glass
filters using a PHD sample harvester (Cambridge Technology,
Watertown, MA). Incorporation was determined by placing the filters
in ScintiVerse BD scintillation fluid (Fisher, Pittsburgh, PA) and
counting with a 2000CA Tri-Carb liquid scintillation analyzer (Packard,
Downers Grove, IL).
Delayed-type hypersensitivity (DTH)
For the measurement of DTH responses, an ear swelling assay was employed as previously described (10, 11). Briefly, 25 µg of immunization Ag was injected into the right ear in 10 µl of sterile PBS while 10 µl of sterile PBS was injected into the left ear as a control. Ear swelling was measured 24–48 h after injection with a dial thickness gauge (Mitutoyo thickness cage #7326, Kawasaki, Japan). Ag-specific ear swelling was calculated by subtracting the ear swelling of the PBS-injected ear from the swelling of the Ag-injected ear. DTH ear-swelling units are 10-4 inches (i.e., 1 DTH unit = 1 x 10-4 inches).
Statistical analysis
Statistical significance was determined using ANOVA, with comparison of multiple means using Bonferroni’s (Dunn) t tests, Sidak’s t tests, and Tukey’s Studentized range test on SAS software (SAS Institute, Cary, NC). A difference was considered significantly different if two of three tests indicated a significant difference. The level of significance used was 0.05. Error bars represent the SD.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß enhance serum Ag-specific IgG responses when
intranasally administered with soluble protein Ags
To determine whether IL-1 or IL-1ß possessed mucosal adjuvant
activity, BALB/c or C57BL/6 mice were intranasally immunized with Ag
alone or with Ag in the presence of CT, IL-1, or IL-1ß (Table II).
In Expt. 1, BALB/c mice were intranasally immunized with 100 µg of
OVA on days 0, 14, and 28 in the absence of adjuvants or in the
presence of 1 µg of CT, 4 µg of IL-1, or 4 µg of IL-1ß
administered with all immunizations or with the first immunization only
(Table II). Both IL-1 and IL-1ß were able to serve as mucosal
adjuvants when intranasally administered with OVA with all
immunizations (three times) or with the first immunization only
(p < 0.05 compared with no adjuvant control).
When coadministered with all three immunizations, the day 42 serum
anti-OVA IgG titers for the IL-1, IL-1ß, and CT groups were
1/262,144, 1/104,031, and 1/13,004, respectively (Fig. 1, Expt. 1). IL-1 and IL-1ß were
also effective adjuvants when administered with the first immunization
only, resulting in serum anti-OVA IgG titers of 1/26,008 and
1/13,004, respectively. Anti-OVA IgG titers were <1/100 in the sera
collected from mice immunized with no adjuvant or with CT administered
with the first immunization only (Fig. 1, Expt. 1). IL-1 and IL-1ß
were also tested at a 1.3-µg dose (3-fold dilution of 4 µg)
administered with all three nasal immunizations (days 0, 14, and 28).
IL-1 at 1.3 µg induced a day 42 serum anti-OVA IgG end-point
titer of 1/46,341, while IL-1ß at 1.3 µg induced a day 42 serum
anti-OVA IgG end-point titer of 1/2,048 (data not shown). Because
IL-1 and IL-1ß were more effective at the 4-µg dose, subsequent
studies used only the 4-µg dose.
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and/or IL-1ß exhibited mucosal adjuvant
activity when coadministered with a more relevant vaccine Ag, C57BL/6
(Expt. 2) or BALB/c (Expt. 3) mice were intranasally immunized with 50
µg of TT alone or in the presence of adjuvants (Table II). To comply
with other published mucosal immunization protocols (9, 22), mice were
immunized on days 0, 7, and 14 for Expt. 2 and 3 (Table II). IL-1
and IL-1ß were effective mucosal adjuvants when intranasally
administered with 50 µg of TT on days 0, 7, and 14 in both C57BL/6
(Expt. 2) and BALB/c (Expt. 3) mice (p < 0.05
compared with no adjuvant control). When administered with all three
immunizations, day 21 serum anti-TT titers for IL-1 and IL-1ß
groups were 1/155,872 and 1/208,064 for C57BL/6 mice, respectively, and
1/165,140 and 1/208,064, respectively, for BALB/c mice (Fig. 1, Expt. 2
and 3). IL-1 also exhibited significant adjuvant activity when
intranasally administered to BALB/c mice with TT on day 0 only
(p < 0.05 compared with no adjuvant control).
Within the same experiment, there were no significant differences
between any of the CT, IL-1, or IL-1ß adjuvant groups.
Ag-specific IgG subclass end-point titers were measured to compare the
Ag-specific IgG subclass responses induced by IL-1 and IL-1ß to
those induced by CT. The Ag-specific IgG subclass profiles associated
with the use of IL-1 or IL-1ß as a mucosal adjuvant were
comparable to those induced by the use of CT as a mucosal adjuvant
(Table III).
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and IL-1ß induce mucosal IgA responses when used as a
mucosal adjuvant
Vaginal lavage samples were monitored for the presence of
Ag-specific IgG and IgA to determine whether IL-1 or IL-1ß could
induce Ag-specific IgA responses when used as a mucosal vaccine
adjuvant. In all experiments IL-1 and IL-1ß were as effective as
CT in their ability to induce the production of Ag-specific mucosal IgA
and IgG responses (Fig. 2). In Expt. 1
when the adjuvants were used with all three immunizations, the day 42
vaginal anti-OVA IgA titers for the IL-1 and IL-1ß groups were
1/32 and 1/128, respectively, compared with an undetectable
anti-OVA IgA response in the CT group (Fig. 2, Expt. 1). Even when
used with the first immunization only, IL-1 and IL-1ß induced
anti-OVA IgA responses that were detectable in vaginal lavage
samples (Fig. 2, Expt. 1). In Expt. 2 and 3, the use of IL-1 and
IL-1ß with all immunizations consistently induced Ag-specific vaginal
IgA titers that were 2- to 8-fold higher than those induced by CT (Fig. 2, Expt. 2 and 3). When administered with TT for the first immunization
only, IL-1 (Expt. 3) and IL-1ß (Expt. 2 and 3) induced the
production of anti-TT vaginal IgA responses.
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and IL-1ß induce cell-mediated immune responses when used
as a mucosal adjuvant
Ear-swelling DTH responses were used as in indicator of in vivo
cell-mediated immune responses after intranasal immunization with
soluble protein Ags alone or in the presence of CT, IL-1, or
IL-1ß. When intranasally administered with OVA for all three
immunizations (Expt. 1), IL-1 and IL-1ß induced DTH ear-swelling
responses (114 ± 8.9 and 106 ± 7.6 DTH units, respectively) that
were significantly greater than those induced by any other group
(p < 0.05; Fig. 3). In subsequent studies, IL-1 (Expt.
3) and IL-1ß (Expt. 2) induced DTH ear-swelling responses that were
significantly greater than those induced by immunization in the absence
of adjuvant (p < 0.05) and were comparable to
those induced by CT. The use of IL-1 with the first immunization only
did not induce significantly elevated DTH ear-swelling responses.
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and IL-1ß induced lymphocyte proliferative responses comparable to
those induced by CT (Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß
are able to serve as mucosal adjuvants when intranasally administered
with soluble protein Ags. IL-1 and IL-1ß were as effective as CT
for the induction of Ag-specific serum IgG, vaginal IgA, as well as in
vivo and in vitro cell-mediated immune responses. Although numerous
reports have indicated that IL-1 is able to serve as an adjuvant for
the induction of systemic Ag-specific immune responses (45, 46, 47, 48, 49, 50, 51), this
is the first report demonstrating mucosal adjuvant activity for IL-1
when intranasally administered with soluble protein Ags. A number of observations support the hypothesis that the production and release of IL-1 by CT-stimulated mucosal epithelial cells are critically involved in the mucosal adjuvant activity of CT. CT and the related LT are heterohexameric proteins with a m.w. of approximately 85,000 (52). The toxin is composed of one CT-A subunit noncovalently associated with five CT-B subunits. CT-B is responsible for binding to its receptor, ganglioside GM1, while the CT-A subunit possesses the toxic ADP-ribosyltransferase activity (52). Our hypothesis for CT-induced, IL-1-mediated mucosal adjuvant activity is as follows. After mucosal administration as an adjuvant, CT binds to its specific receptor on the surface of mucosal epithelial cells. Indeed, orally administered LT-B (similar to CT-B) bound to the brush border of villous enterocytes as well as epithelial cells overlying the Peyer’s patches (53). After binding to GM1, CT induces the production and/or secretion of IL-1 from mucosal epithelial cells (54). CT-induced IL-1 binds to type I IL-1R on mucosal epithelial cells (55, 56) and stimulates the production of more IL-1 as well as other cytokines (IL-6, IL-8, TGF-ß) that affect both mucosal epithelial cells and other cell types (fibroblasts, macrophages, dendritic cells) and enhance the induction of mucosal and systemic immune responses. IL-1 stimulation down-regulates type I IL-1R expression on mucosal epithelial cells (57) and therefore limits the proinflammatory action of IL-1 induced by mucosal administration of CT. Indeed, mucosal adjuvant activity was observed when CT was coadministered with specific Ag, but not when it was administered 24 h before or after Ag dosing (58).
IL-1 and IL-1ß are proinflammatory cytokines produced by many cell
types including macrophages, PBMC, fibroblasts, and intestinal
epithelial cell lines (36, 54, 59, 60, 61, 62). IL-1 and IL-1ß use the
same cell surface receptors, type I and type II, although only the type
I IL-1R transduces a signal in response to ligation of the receptor
with IL-1 (59, 63, 64). IL-1 induces the gene expression of itself as
well as a large number of other proteins, including IL-2, IL-3, IL-4,
IL-5, IL-6, IL-7, IL-8, IL-12, TGF-ß3, TNF-, TNF-ß, GM-CSF,
G-CSF, M-CSF, and the IL-2R (59, 61). Because of its ability to induce
the production of cytokines involved in the induction of immune
responses, the potential of IL-1 as a vaccine adjuvant is apparent.
IL-1 has been extensively studied in humans and has been found to be
extremely toxic after i.v. administration (61, 65, 66, 67, 68, 69, 70). With both
IL-1 and IL-1ß, the predominant side effects observed were fever,
chills, hypotension, and nausea. In these human studies, IL-1 was
administered by the i.v. route and was administered daily for 4–14
days. In published murine studies, systemic administration of IL-1
and IL-1ß also exhibited adverse side effects, such as fever and
weight loss (71, 72, 73). The use of other cytokines as systemically
administered adjuvants has also been reported to have adverse side
effects in murine models. For example, i.p. injection of IL-12 and
IL-18 was lethal when tested as an anti-tumor therapy at the doses
of 0.01 and 1.0 µg, respectively, although a protective, nonlethal
effect was observed at doses of 0.01 and 0.2 µg, respectively (74).
In the present murine study, noticeable side effects were not observed
after nasal administration of IL-1 or IL-1ß (i.e., no
cytokine-induced mortality, no obvious weight loss or abnormal
behavior). Additionally, IL-1 and IL-1ß were administered locally
and were effective adjuvants when administered at weekly (Expt. 2 and
3) or biweekly intervals (Expt. 1). In some cases, IL-1 was an
effective adjuvant when administered with only the first immunization
in a series of immunizations. Because IL-1 stimulation of mucosal
epithelial cells down-regulates expression of the type I IL-1R, the
inflammatory activity of IL-1 used as a mucosal adjuvant may be
minimized (57). Additional studies to carefully monitor the effects of
nasally administered IL-1 and IL-1ß on body temperature, body
weight, and histology of the upper respiratory tract are currently
being performed in our laboratory.
IL-1 and IL-1ß may be superior to CT and related molecules as
mucosal adjuvants because they are self proteins. Although CT is a
potent mucosal adjuvant, the fact that it is very immunogenic in
addition to being toxic may diminish its effectiveness when repeatedly
used as a mucosal adjuvant. Indeed, pre-existing immunity to CT reduces
its effectiveness as a mucosal adjuvant (31, 32). Despite having
reduced toxicity in the presence of adjuvant activity, mutant CT
molecules maintain their immunogenicity, which may reduce their
effectiveness when repeatedly used as mucosal adjuvants in humans (23, 29, 30). In contrast to CT, IL-1 and IL-1ß are self proteins and
therefore nonimmunogenic. This quality may allow IL-1 or IL-1ß to
be repeatedly used as an effective mucosal adjuvant. Because human
IL-1 and IL-1ß were used in the present study and are expected to
be immunogenic in mice, it is impossible to determine what effect, if
any, host immunity to the mucosal adjuvants (CT, IL-1, IL-1ß) had
on the induction of systemic and mucosal immune responses in this
study. Additional studies are being performed with CT and recombinant
murine IL-1 and IL-1ß (expected to be nonimmunogenic in mice) to
determine whether the repeated use of host proteins (i.e., IL-1)
is superior to the use of foreign proteins as mucosal adjuvants.
The development of safe and effective mucosal adjuvants is critical to
the development of mucosal vaccines for use in humans. Of particular
interest to our laboratory is the development of vaccines that induce
mucosal anti-HIV humoral and cell-mediated immune responses (10, 11, 14). The results from the present study suggest that 1) IL-1 and
IL-1ß are effective mucosal adjuvants for the induction of systemic
and mucosal immune responses and 2) cytokines are biologically active
when intranasally administered. The use of recombinant cytokines as
mucosal adjuvants may prove useful for the induction of systemic and
mucosal anti-HIV immune responses in humans. Studies are being
performed to evaluate the use of IL-1 and IL-1ß as vaccine
adjuvants when intranasally administered with HIV peptide and protein
immunogens.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Herman F. Staats, Box 3307, Department of Medicine, Duke University Medical Center, Durham, NC 27710. E-mail address:
3 Abbreviations used in this paper: CT, cholera toxin; PT, pertussis toxin; LT, heat-labile toxin; TT, tetanus toxoid; DTH, delayed-type hypersensitivity.
Received for publication November 2, 1998. Accepted for publication February 26, 1999.
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E. Williamson, G. M. Westrich, and J. L. Viney Modulating Dendritic Cells to Optimize Mucosal Immunization Protocols J. Immunol., October 1, 1999; 163(7): 3668 - 3675. [Abstract] [Full Text] [PDF]
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