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*
Department of Immunology, University of Glasgow, Western Infirmary, Glasgow, Scotland, United Kingdom;
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Department of Microbiology and Immunology, University of California, San Francisco, CA 94122;
§
Department of Immunology, University of Cape Town, Cape Town, South Africa; and
¶
Department of Immunology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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or Stat6. The Th2
responses observed could not be due to IL-13 as IL-13 responses are
also impaired in IL-4R- and Stat6-deficient mice. We also detected
higher levels of IL-4 in IL-4R gene-deficient, though not
Stat6-deficient, mice compared with their wild-type counterparts. The
increased levels of IL-4 could be explained by the IL-4R being
unavailable to neutralize this cytokine in IL-4R-deficient mice.
While levels of IL-5 production in IL-4R- or Stat6-deficient mice
were similar to IL-4-deficient and wild-type mice, other type
2-associated responses, which are largely or wholly IL-4 dependent,
such as the production of IgG1 or IgE Abs, were either reduced or
absent. We conclude that alum adjuvants can induce IL-4 production and
Th2 responses independently of IL-4 or IL-13, negating the requirement
for an early source of IL-4 in the Th2 response induced by this
adjuvant. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit and the subsequent activation of Stat6
(9, 10, 11). We have recently described the generation of mice
lacking the IL-4R gene, which lack IL-4- or IL-13-mediated responses
(12). Similarly, the previously described Stat6-deficient
mice also fail to mediate effective signaling induced by either IL-4 or
IL-13 (13, 14). To determine whether IL-13 plays a role in
producing Th2 responses in the absence of IL-4 signaling, we have
compared the ability of alum to induce Th2 responses in mice lacking
Stat6 or IL-4R genes with IL-4-deficient and wild-type
mice. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Alhydrogel (alum), purchased from Superfos Biosector (Vedbaek, Denmark), was mixed with a predetermined quantity of OVA (grade V; Sigma, Poole, U.K.) and incubated at room temperature for 20 min. A sample of the mixture was centrifuged at 14, 000 x g for 10 min, and the supernatant was checked for unbound protein by bicinchoninic acid assay (Pierce, Rockford, IL).
Animals and inoculations
IL-4-/- and
IL-4R-/- mice were generated as described
previously (12, 15). These, and wild-type control animals
(BALB/c), were bred at the Max Planck Institute for Immunobiology and
maintained at the University of Strathclyde.
Stat6-/- mice (14) were a gift
from Professor J. Ihle; these and B6/129 control mice were bred and
maintained at the University of Pennsylvania. Eight- to 10-wk-old
female mice were inoculated s.c. with 0.1 ml of OVA (100 µg) adsorbed
to alum and boosting inoculations administered in the same fashion 2 wk
later.
Determination of plasma Ab titers
Blood was sampled from mice for Ab determination 2 wk (IgG1 and IgG2a) and 4 wk (IgE) following boosting inoculations. ELISA were performed as described previously (1) to detect Ag-specific IgG1 and IgG2a and total or specific IgE in plasma. Results are expressed as endpoint dilutions where the endpoint is determined as the final plasma dilution that yields a higher absorbance than a negative control plasma sample included in the assay. Comparisons between groups were performed using a Mann-Whitney U test.
Spleen cell responses
Spleens were aseptically removed 5 wk following the second inoculations with alum-adsorbed OVA, and cell suspensions were prepared by gently teasing apart in RPMI 1640 supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 0.05 mM 2-ME, and 10% FCS (Life Technologies, Paisley, U.K.). RBCs were depleted by incubation in 0.17 M Tris and 0.16 M ammonium chloride (16) at 37°C for 5 min followed by washing. Viable cells were enumerated by trypan blue exclusion, and 100-µl aliquots of cell suspension containing 5 x 105 cells were added to 96-well flat-bottom tissue culture plates (Costar, Cambridge, MA). Triplicate aliquots (100 µl per well) of Con A (5 µg/ml) or OVA (from 0 to 1000 µg/ml) were added as appropriate. IL-4R neutralizing Ab (M1; kindly provided by Dr. M. Widmer, Immunex, Seattle, WA) or isotype-control IgG (PharMingen, San Diego, CA) were also added at this stage where required (17, 18). Following incubation for 60 h at 37°C, 5% CO2, 150-µl aliquots of cell-culture supernatants were removed and stored at -70°C for cytokine assay.
Cytokine assays
IFN-
, IL-4 (Genzyme, Cambridge, MA), and IL-5 (PharMingen)
were detected by capture ELISA according to the manufacturers
instructions. Cytokine concentrations in the cell cultures were
determined from the standard curve (regression coefficient,
r = 0.990 or better). Comparisons between groups were
made using Student’s t test.
Cell depletions
Spleen cell suspensions were prepared from three
IL-4R-/- mice inoculated with alum/OVA,
pooled, and passed through sterile 100-µm monofilament filter cloth
(Nitex; Cadisch Precision Meshes, London, U.K.). Cells were washed,
resuspended in 1 ml of PBS, pH 7.2 (Life Technologies), with 0.5% BSA
(Sigma), and T cell subset depletion was performed on 5 x
107 spleen cells using magnetic beads according
to the manufacturer’s instructions (Miltenyi Biotec, Auburn, CA).
Briefly, CD8+ cells were labeled with primary rat
anti-CD8 Ab (YTS105.18), and magnetic depletion was conducted with
rat IgG microbeads (Miltenyi Biotec). CD4+ cells
were directly depleted with mouse CD4 (L3T4) microbeads.
CD4+CD8+ depletions were
conducted simultaneously on cells previously labeled with anti-CD8
(YTS105.18) as described above. Cells were adjusted to 5 x
106 cells/ml, and 100-µl samples were incubated
with Ag as described above.
Depletion of T cell subsets was confirmed by flow cytometry
analysis of samples taken from both depleted cell suspensions as well
as from undepleted IL-4R-/- splenocyte
suspensions. All samples were incubated at 4°C with PE-labeled
anti-CD4 mAb (L3T4) and FITC-labeled anti-CD8 (YTS105.18; both
from PharMingen). Ten thousand events were collected for each sample on
a FACScan flow cytometer (Becton Dickinson, Mountain View, CA) and
analyzed using CellQuest software (Becton Dickinson).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As demonstrated previously, inoculation of BALB/c or B6/129
mice with Ag prepared in alum produced high titers of Ag-specific IgG1
(Fig. 1
, a and b),
but negligible amounts of IgG2a (Fig. 1, c and
d), a pattern indicative of a polarized Th2 response. Also
as previously demonstrated (Fig. 1, a and c),
IL-4-deficient mice (IL-4-/-) produced levels
of IgG1 that were slightly, though significantly, reduced
(p 
0.025) and IgG2a titers that were greatly
increased compared with wild-type mice (p
0.01). In the present study, IL-4R-deficient mice
(IL-4R-/-) also produced a shift in Ab
subclass responses, and IgG1 and IgG2a titers were similar to those
observed in IL-4-/- mice (Fig. 1, a
and c), again demonstrating increased Th1 responses compared
with wild-type mice. Likewise, Stat6-deficient mice
(Stat6-/-) had reduced OVA-specific IgG1 titers
(p 0.01; Fig. 1b) and increased
IgG2a levels (p 0.01; Fig. 1d)
compared with control B6/129 mice. Four weeks following secondary
inoculations with alum/OVA, significant levels of total or OVA-specific
IgE could be detected in BALB/c or B6/129 mice, respectively (Fig. 1e, p 0.01; Fig. 1f,
p 0.01). However, this Ab isotype was undetectable
in plasma prepared from similarly treated
Stat6-/-, IL-4R-/-,
or IL-4-/- mice.
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When splenocytes from wild-type, IL-4-/-,
and IL-4R-/- mice inoculated with alum/OVA
were restimulated with Ag in vitro, no significant differences in the
proliferative responses were detected between the groups (data not
shown). While levels of IL-4 were undetectable in Ag-stimulated spleen
cells from IL-4-/- mice (Fig. 2a), spleen cells from
IL-4R-/- mice produced significant levels of
this cytokine compared with unstimulated control cells
(p 0.01). Spleen cells from alum-inoculated
BALB/c control mice also produced significant amounts of IL-4, although
these levels were significantly less than those detected in
IL-4R-/- mice (p
0.01). Although spleen cells from alum/OVA-inoculated
Stat6-/- mice also produced significant levels
of IL-4 (Fig. 2b, p 0.01), unlike
IL-4R-/- mice, the levels of IL-4 detected
in Ag-stimulated spleen cell cultures were not significantly greater
than those observed in spleen cells from wild-type mice.
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-/- as well as
IL-4-/- mice could also be stimulated in vitro
with OVA to produce significant levels of IL-5
(p 0.01), which were equivalent to those
found using splenocytes from wild-type mice (Fig. 2
c).
Similar levels of IL-5 were also found in Ag-stimulated spleen cell
cultures from Stat6-/- and wild-type B6/129
mice (Fig. 2d).
As demonstrated previously, spleen cells from alum/OVA-inoculated
BALB/c mice did not produce significant levels of IFN-; however,
cells from IL-4-/- and
IL-4R-/- mice did produce significant levels
of this cytokine on Ag restimulation in vitro
(p 0.01 in both cases). Similarly,
Stat6-/- mice produced significantly higher
levels of IFN- compared with wild-type control mice
(p 0.05).
Neutralization of soluble IL-4R in vitro
Spleen cells from alum/OVA-inoculated mice were restimulated with
Ag in the presence of an anti-IL-4R-neutralizing Ab or
isotype-matched control Ab (Fig. 3).
While the addition of the anti-IL-4R Ab produced significant
increases in detectable levels of IL-4 in spleen cells from both B6/129
mice (Fig. 3a, p 0.05) and
Stat6-/- mice (Fig. 3b,
p 0.05) this was not the case with
IL-4R-/- cells. The addition of
IL-4R-neutralizing Abs to spleen cells from
IL-4R-/- mice did not affect Ag-induced IL-4
production, whereas similar treatment of spleen cells from control
BALB/c mice significantly increased detectable levels of IL-4
(p 0.01; Fig. 3, c and
d). In fact, in the presence of anti-IL-4R Ab, levels of
detectable IL-4 were similar in Ag-stimulated spleen cells from both
wild-type and IL-4R-/- mice.
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To determine the source of IL-4 production in alum/OVA-inoculated
IL-4R-/- mice, mixed spleen cell
preparations were depleted of either CD4+ or
CD4+ and CD8+ T cells (Fig. 4). As described above, Ag restimulation
of IL-4R-/- spleen cells resulted in IL-4
production. However, depletion of CD4+ T cells
resulted in complete ablation of IL-4 production, clearly demonstrating
that CD4+ T cells were the source of IL-4
production in mixed cultures (Fig. 4a). Analysis of the cell
suspensions by flow cytometry demonstrated that depletion using
magnetic beads was 
99% effective (Fig. 4, b–d).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production, but could also continue to induce a Th2
response characterized by the production of IL-5 by Ag-restimulated
splenocytes (1). In other models of Th2 induction, such as
the inductive phase of schistosome egg-induced granuloma, IL-5 has been
thought to play an important, though indirect, role in Th2 induction
via the recruitment of eosinophils and the subsequent production of
IL-4 (18). However, we did not observe any reduction in
the Th2 response following administration of alum/OVA to IL-5-deficient
mice compared with wild-type control mice (data not shown). Similarly,
more recent data has shown that there is no alteration in Th2 induction
in the schistosome egg model in IL-5-/- mice
(19). Thus, we hypothesized that this residual Th2
response, produced in the absence of IL-4, may be mediated by the
compensatory action of IL-13, a cytokine that has been associated with
mediating some of the effects of Th2 cells (20, 21).
Nonetheless, analyses of alum-induced Th2 responses in IL-4-deficient
mice were clearly limited due to the inability to analyze the
production of IL-4, the key Th2 cytokine in these mice. Our current
approach using IL-4R-deficient (12) and Stat6-deficient
(14) mice has allowed analysis of IL-4 production by alum,
not only in the absence of functional IL-4, but also in the absence of
functional IL-13 signaling. This is due to the critical role that Stat6
plays in mediating signaling via IL-4R, a common component of both
the IL-4 and IL-13 receptor complexes (12).
Most strikingly, these results demonstrate that in the absence of IL-4-
or IL-13-mediated signaling, alum continues to prime splenocytes to
produce IL-4 on Ag restimulation in vitro. This is intriguing as early
studies of the growth of Th clones in vitro clearly describe IL-4 as a
prerequisite autocrine growth factor for Th2 cells (22, 23). On this basis, a number of studies have established sources
of this cytokine from cells of the innate and adaptive immune
responses, which could act as prime movers in providing the initial
source of IL-4 required to initiate Th2 responses in vivo. These cell
types include NK1.1+ CD4+ T
cells (24, 25), NK1.1-
CD4+ T cells (26, 27), eosinophils
(18, 28), and cells of the mast cell/basophil lineage
(29). However, in the present study we have demonstrated
that using alum as an adjuvant can induce Th2 responses independently
of IL-4, dispensing with the requirement for an initial source for IL-4
in the alum-induced Th2 response. The source of IL-4 in these present
studies was clearly CD4+ T cells as depletion of
this subset of lymphocytes was sufficient to completely ablate
Ag-dependent IL-4 production in spleen cells from IL-4R-deficient
mice. Furthermore, as IL-4R-deficient mice also lack IL-13-mediated
signaling, the present study therefore produces a dilemma as to how Th2
responses are initiated in vivo and what effects of alum, independently
of IL-4 or IL-13, mediate the development of Th2 responses. Previous
studies in IL-4R- and Stat6-deficient mice have also described
IL-4-independent pathways for IL-4 production. In studies of infection
with the nematode parasite N. brasiliensis,
IL-4R-deficient mice could produce reduced, though significant,
levels of IL-4 compared with wild-type mice (30).
CD4+ spleen cells from IL-4R-deficient mice
could also be induced to produce IL-4 upon stimulation with
anti-CD3 Ab, and this activity could subsequently be isolated to a
population of CD62Llow,
CD4+ T cells. Further analysis demonstrated that
ß2-microglobulin
(ß2m)-deficient mice, which lack NK1.1 cells,
failed to produce IL-4 on stimulation with anti-CD3 in vivo,
suggesting that the source of IL-4 in IL-4R-deficient mice was
NK1.1+ CD4+ T cells.
However, previous work has demonstrated that alum/OVA can induce IL-4
production and Th2 responses in ß2m-deficient
mice (31), indicating that NK T cell populations do not
appear to be the source of the IL-4 response induced following in vivo
inoculation with alum. A similar conclusion was made in studies where
anti-IgD, another potent Th2-inducing stimulus, was administered to
ß2m-deficient mice and Stat6-deficient mice
(32). As significant levels of IL-4 could be induced in
both of these strains of mice, these studies indicate that an
IL-4-independent mechanism of priming CD4+ T
cells for IL-4 production must exist in vivo.
Despite the significant levels of IL-4 detected in in
vitro-restimulated spleen cells from OVA/alum-inoculated
IL-4R-deficient mice, plasma IgG1 and IgE and spleen cell IL-5
production in these mice were similar to those found in IL-4-deficient
mice. This would be consistent with the concept that in the absence of
IL-4, IL-13 has no direct effect on these Th2 responses
(12). Furthermore, as levels of IFN- in IL-4-deficient
and IL-4R-deficient mice were similar, IL-13 does not appear to be
able to mediate inhibition of IFN- production in the absence of
IL-4. Thus, although it is clear that Th2 induction can continue
independently of IL-4 production, there still remains the question of
how alum inhibits Th1 responses in intact animals. Our previous studies
(1), as well as those shown here, clearly demonstrate that
this is dependent on the production of IL-4; however, the source of
this cytokine remains to be defined. Therefore, further studies to
address this question are being planned.
We were also intrigued why IL-4R-deficient mice should have greatly
increased production of IL-4 compared with wild-type BALB/c mice. This
was not the case in Stat6-deficient mice, where levels of IL-4 produced
by in vitro-restimulated spleen cells were similar to levels found in
spleen cells from OVA/alum-inoculated wild-type mice. One hypothesis
that we tested was that IL-4R-deficient mice had increased levels of
IL-4 due to the lack of neutralization of IL-4 by the IL-4R. An
alternatively spliced variant of the IL-4R can also be transcribed and
shed from the surface of lymphocytes as a soluble receptor. This
soluble receptor also sequesters and neutralizes IL-4
(33), consequently preventing IL-4 detection by
conventional methods (18). This could explain why
Stat6-deficient mice, which also lack IL-4-mediated signaling, but do
have the IL-4R, did not have increased IL-4 levels in spleen cell
cultures compared with wild-type mice. To allow IL-4 detection in the
presence of the IL-4R, we treated splenocyte cultures with a mAb that
blocks the receptor, thereby preventing neutralization of IL-4
(28). When BALB/c mice spleen cells were treated with the
IL-4R-neutralizing mAb, similar levels of IL-4 to those produced in
untreated or treated IL-4R-deficient mice were detected. In
contrast, treatment of spleen cells from Stat6-deficient mice or their
wild-type counterparts with the neutralizing Ab produced significant
increases in detectable IL-4 in both strains of mice. Therefore, this
would suggest that the lack of the cell-bound receptor, or the soluble
receptor, is responsible for the increase in detectable IL-4 observed
in IL-4R-deficient mice.
In conclusion, our data clearly demonstrate that alum can induce Th2 responses, as characterized by IL-4 and IL-5 production, independently of IL-4- or IL-13-mediated signaling. The mechanism by which alum adjuvants can achieve this remains unclear. However, the requirement for an early source of IL-4 in mediating this Th2 response is clearly unnecessary. Thus, according to this and our previous studies (1), the major effect of IL-4 production mediated by the use of alum adjuvants is not to induce Th2-type responses but to down-regulate Ag-specific Th1 responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. James M. Brewer, Department of Immunology, University of Glasgow, Western Infirmary, Glasgow, G11 6NT, U.K. E-mail address:
3 Abbreviations used in this paper: alum, aluminium hydroxide gel (Alhydrogel); ß2m, ß2-microglobulin.
Received for publication June 30, 1999. Accepted for publication October 1, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. J. Immunol. 162:7302.8 CD4+ T cells instructs Th2 development and susceptibility to Leishmania major in BALB/c mice. Immunity 6:541.[Medline]
RI+ cells. J. Exp. Med. 53:1.
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 K. E. Hooper-McGrevy, B. N. Wilkie, and J. F. Prescott Immunoglobulin G Subisotype Responses of Pneumonic and Healthy, Exposed Foals and Adult Horses to Rhodococcus equi Virulence-Associated Proteins Clin. Vaccine Immunol., May 1, 2003; 10(3): 345 - 351. [Abstract] [Full Text] [PDF]
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S. Nakae, Y. Komiyama, H. Yokoyama, A. Nambu, M. Umeda, M. Iwase, I. Homma, K. Sudo, R. Horai, M. Asano, et al. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response Int. Immunol., April 1, 2003; 15(4): 483 - 490. [Abstract] [Full Text] [PDF]
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S. Kusam, L. M. Toney, H. Sato, and A. L. Dent Inhibition of Th2 Differentiation and GATA-3 Expression by BCL-6 J. Immunol., March 1, 2003; 170(5): 2435 - 2441. [Abstract] [Full Text] [PDF]
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 A. Suto, H. Nakajima, K. Hirose, K. Suzuki, S.-i. Kagami, Y. Seto, A. Hoshimoto, Y. Saito, D. C. Foster, and I. Iwamoto Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cepsilon transcription of IL-4-stimulated B cells Blood, December 15, 2002; 100(13): 4565 - 4573. [Abstract] [Full Text] [PDF]
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B. M. Naiman, S. Blumerman, D. Alt, C. A. Bolin, R. Brown, R. Zuerner, and C. L. Baldwin Evaluation of Type 1 Immune Response in Naive and Vaccinated Animals following Challenge with Leptospira borgpetersenii Serovar Hardjo: Involvement of WC1+{gamma}{delta} and CD4 T Cells Infect. Immun., November 1, 2002; 70(11): 6147 - 6157. [Abstract] [Full Text] [PDF]
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 T. Ito, K. Inouye, H. Fujimaki, C. Tohyama, and K. Nohara Mechanism of TCDD-Induced Suppression of Antibody Production: Effect on T Cell-Derived Cytokine Production in the Primary Immune Reaction of Mice Toxicol. Sci., November 1, 2002; 70(1): 46 - 54. [Abstract] [Full Text] [PDF]
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M. Taneichi, S. Naito, H. Kato, Y. Tanaka, M. Mori, Y. Nakano, H. Yamamura, H. Ishida, K. Komuro, and T. Uchida T Cell-Independent Regulation of IgE Antibody Production Induced by Surface-Linked Liposomal Antigen J. Immunol., October 15, 2002; 169(8): 4246 - 4252. [Abstract] [Full Text] [PDF]
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 S. A. Ritz, M. J. Cundall, B. U. Gajewska, D. Alvarez, J.-C. Gutierrez-Ramos, A. J. Coyle, A. N. J. McKenzie, M. R. Stampfli, and M. Jordana Granulocyte Macrophage Colony-Stimulating Factor-Driven Respiratory Mucosal Sensitization Induces Th2 Differentiation and Function Independently of Interleukin-4 Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 428 - 435. [Abstract] [Full Text] [PDF]
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 H. Plotnicky-Gilquin, D. Cyblat-Chanal, J.-P. Aubry, T. Champion, A. Beck, T. Nguyen, J.-Y. Bonnefoy, and N. Corvaia Gamma Interferon-Dependent Protection of the Mouse Upper Respiratory Tract following Parenteral Immunization with a Respiratory Syncytial Virus G Protein Fragment J. Virol., September 11, 2002; 76(20): 10203 - 10210. [Abstract] [Full Text] [PDF]
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Q. He, A. Mitchell, T. Morcol, and S. J. D. Bell Calcium Phosphate Nanoparticles Induce Mucosal Immunity and Protection against Herpes Simplex Virus Type 2 Clin. Vaccine Immunol., September 1, 2002; 9(5): 1021 - 1024. [Abstract] [Full Text] [PDF]
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E. A. M. Lee, D. R. Palmer, K. L. Flanagan, W. H. H. Reece, K. Odhiambo, K. Marsh, M. Pinder, M. B. Gravenor, W. A. Keitel, K. E. Kester, et al. Induction of T Helper Type 1 and 2 Responses to 19-Kilodalton Merozoite Surface Protein 1 in Vaccinated Healthy Volunteers and Adults Naturally Exposed to Malaria Infect. Immun., March 1, 2002; 70(3): 1417 - 1421. [Abstract] [Full Text] [PDF]
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K. A. Near, A. W. Stowers, D. Jankovic, and D. C. Kaslow Improved Immunogenicity and Efficacy of the Recombinant 19-Kilodalton Merozoite Surface Protein 1 by the Addition of Oligodeoxynucleotide and Aluminum Hydroxide Gel in a Murine Malaria Vaccine Model Infect. Immun., February 1, 2002; 70(2): 692 - 701. [Abstract] [Full Text] [PDF]
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B. M. Naiman, D. Alt, C. A. Bolin, R. Zuerner, and C. L. Baldwin Protective Killed Leptospira borgpetersenii Vaccine Induces Potent Th1 Immunity Comprising Responses by CD4 and gamma delta T Lymphocytes Infect. Immun., December 1, 2001; 69(12): 7550 - 7558. [Abstract] [Full Text] [PDF]
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 R. K. Gherardi, M. Coquet, P. Cherin, L. Belec, P. Moretto, P. A. Dreyfus, J.-F. Pellissier, P. Chariot, and F.-J. Authier Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle Brain, September 1, 2001; 124(9): 1821 - 1831. [Abstract] [Full Text] [PDF]
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J. Mattes, M. Yang, A. Siqueira, K. Clark, J. MacKenzie, A. N. J. McKenzie, D. C. Webb, K. I. Matthaei, and P. S. Foster IL-13 Induces Airways Hyperreactivity Independently of the IL-4R{alpha} Chain in the Allergic Lung J. Immunol., August 1, 2001; 167(3): 1683 - 1692. [Abstract] [Full Text] [PDF]
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S. Nakae, M. Asano, R. Horai, N. Sakaguchi, and Y. Iwakura IL-1 Enhances T Cell-Dependent Antibody Production Through Induction of CD40 Ligand and OX40 on T Cells J. Immunol., July 1, 2001; 167(1): 90 - 97. [Abstract] [Full Text] [PDF]
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K. G. Tournoy, J. C. Kips, and R. A. Pauwels The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent J. Immunol., June 1, 2001; 166(11): 6982 - 6991. [Abstract] [Full Text] [PDF]
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M. Ulanova, A. Tarkowski, M. Hahn-Zoric, and L. A. Hanson The Common Vaccine Adjuvant Aluminum Hydroxide Up-Regulates Accessory Properties of Human Monocytes via an Interleukin-4-Dependent Mechanism Infect. Immun., February 1, 2001; 69(2): 1151 - 1159. [Abstract] [Full Text] [PDF]
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A. P. Mountford, K. G. Hogg, P. S. Coulson, and F. Brombacher Signaling via Interleukin-4 Receptor {alpha} Chain Is Required for Successful Vaccination against Schistosomiasis in BALB/c Mice Infect. Immun., January 1, 2001; 69(1): 228 - 236. [Abstract] [Full Text] [PDF]
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E. L. Faquim-Mauro and M. S. Macedo Induction of IL-4-dependent, anaphylactic-type and IL-4-Independent, non-anaphylactic-type IgG1 antibodies is modulated by adjuvants Int. Immunol., December 1, 2000; 12(12): 1733 - 1740. [Abstract] [Full Text] [PDF]
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