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*
Department of Dermatology, Johns Hopkins University, Baltimore, MD 21287; and
Department of Dermatology, University G. d’Annunzio, Chieti, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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following in vitro IL-12 stimulation, which could be
partially blocked by anti-IL-18 Ab, suggesting a synergistic role
for endogenous IL-18 in IFN- production by LN cells. Because mature
IL-18 requires cleavage of immature precursors by caspase-1, we further
examined IL-12-induced IFN- production in caspase-1-/-
LN cells. An impaired IFN- production was seen in
caspase-1-/- LN cells, which could be restored by
addition of exogenous IL-18, supporting a role for caspase-1-cleaved,
mature IL-18 in IFN- production. Finally, in vivo studies showed
that CHS responses were significantly inhibited in mice treated with
neutralizing IL-18 Ab as well as in caspase-1-/- mice
deficient in mature IL-18, indicating functional relevance for IL-18 in
CHS. Taken together, our studies demonstrate that LC-derived IL-18
significantly contributes to CHS initiation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Contact hypersensitivity (CHS), clinically presenting as allergic
contact dermatitis, is one of the most frequent and vexing
dermatological problems. The CHS response, traditionally used as a
classic model for delayed-type hypersensitivity, is mediated by
IFN--producing type 1 T cells (i.e., CD4+ Th1
and/or CD8+ type 1 cytotoxic T (Tc1) cells)
(3, 4, 5). It has been demonstrated that LC play a central
role in CHS. Depending on the allergen, LC can either bind haptens
directly to MHC molecules on their surface or process the hapten
internally into a complete Ag (6). LC then migrate via
afferent lymphatic vessels into skin-draining regional lymph nodes (LN)
to position in T cell areas, where they present the haptenated peptide
to naive T cells (7, 8, 9). During Ag presentation, LC
secrete high levels of IL-12 to drive T cell development toward a Th1
type (10, 11). IL-12 promotes Th1 responses by selective
up-regulation of IFN- in T cells (12). Moreover, IL-12
induces Tc1 cell development and potentiates the cytotoxic
activity of CTL (13, 14). In vivo studies have
demonstrated that IL-12 serves as a mediator and adjuvant for the
induction of CHS (15, 16).
IL-18, initially described as IFN--inducing factor, is a new member
of the IL-1 family (17, 18). IL-18 has also been termed
IL-1 due to its structural homology to IL-1
, with both cytokines
having a unique, all--pleated structure (19, 20).
Similar to IL-1, IL-18 is synthesized as a precursor lacking a
typical signal peptide. Both IL-1 and IL-18 require caspase-1 (also
known as IL-1-converting enzyme) for cleavage and release of their
mature active molecules from the immature precursors
(21, 22, 23). Furthermore, the IL-18R system and its signal
transduction pathway are analogous to those of the IL-1R (24, 25). Recently, Toll-like receptors have been identified that use
signaling pathways shared with IL-1R and IL-18R (26, 27).
This has resulted in the defining of a new receptor superfamily, known
as the IL-1R/Toll-like receptor superfamily.
Despite the similarities between IL-18 and IL-1, functionally IL-18
shares biological properties with IL-12, such as induction of IFN-,
enhancement of NK cell cytotoxicity, and promotion of activated T cell
proliferation (28, 29). In addition, like IL-12, IL-18 is
mainly derived from activated macrophages and DC, including LC
(30, 31). IL-18 synergizes with IL-12 to stimulate IFN-
production by differentiating and committed Th1 cells and is required
for significant expression of the Th1 phenotype (32, 33).
IL-18 itself does not induce Th1 cell differentiation but serves as a
strong costimulatory factor in the activation of Th1 cells stimulated
by Ag (34). IL-18 up-regulates IL-12R expression and
thereby enhances IL-12-mediated Th1 development (35).
Furthermore, IL-18 induces the development of naive
CD8+ T cells into Tc1 effector cells
(36).
Because LC are a significant source of IL-18, we sought to determine
whether LC-derived IL-18 is involved in the initiation of CHS. In this
study we examined IL-18 gene expression and protein production by
migratory LC in skin-draining LN during the induction phase of CHS. To
investigate whether IL-18 plays a synergistic role with IL-12 in
IFN- production in LN cells (LNC), we performed anti-IL-18 Ab
blocking studies. Furthermore, we examined whether caspase-1 deficiency
affects the IL-12-induced IFN- production in LNC due to the lack of
mature IL-18. Finally, to further investigate whether endogenous IL-18
is functionally relevant to the initiation of CHS in vivo, we examined
CHS responses in mice treated with neutralizing IL-18 Ab and in
caspase-1-/- mice deficient in mature IL-18.
Our results suggest that endogenous, caspase-1-dependent IL-18
significantly contributes to CHS initiation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Murine rIL-12 was purchased from BD PharMingen (Mississauga, Ontario, Canada), and murine rIL-18 was purchased from PeproTech (Rocky Hill, NJ). Anti-Ia, anti-DEC-205 (NLDC-145), isotype controls, normal rabbit IgG, goat anti-mouse IgM/biotin, goat anti-rat IgG/biotin, streptavidin/FITC, and streptavidin/Texas Red were purchased from Cedarlane Laboratories (Hornby, Ontario, Canada). Oxazolone, collagenase IV, Con A, and metrizamide were purchased from Sigma-Aldrich (St. Louis, MO). DNase I was purchased from Roche (Mannheim, Germany). Anti-IL-18 Ab was a gift from Dr. C. A. Dinarello (University of Colorado Health Science Center, Denver, CO); it was obtained from a New Zealand rabbit immunized by intradermal injection of murine rIL-18, followed by several booster injections (22). This IL-18 antiserum has been used in various mouse models in vivo for specific neutralization of endogenous IL-18 activity (22, 23, 37, 38, 39, 40, 41).
Mice
Caspase-1-deficient (capase-1-/-) mice were obtained from The Jackson Laboratory (Bar Harbor, ME) (42). C57BL/6 mice were purchased from Charles River Breeding Laboratories (Saint Constant, Quebec, Canada). Six- to 8-wk-old mice were used for the experiments. Each experimental group contained four to six mice. The animal protocol was approved by the institutional animal care and use committee.
XS52 cell line
The XS52 cells, a murine LC-like cell line, were provided by Dr. A. Takashima (University of Texas Southwestern Medical Center, Dallas, TX) (43). The cells were propagated in complete RPMI 1640 medium supplemented with murine rGM-CSF (2 ng/ml) and 10% NS47 cell culture supernatant.
Preparation of LNC
Mice were sensitized with 150 µl 3% oxazolone on the shaved abdomen and four paws, and 24 h later the skin-draining LN (i.e., axillary and inguinal) were collected. To prepare single-cell suspensions, LN were gently disrupted by rubbing between the frosted ends of two microscope slides. The stromal fragments were digested with a collagenase IV/DNase I solution at room temperature for 25 min, and the cells were filtered through nylon mesh (44).
Isolation of migratory hpLC
The migratory hapten-modified LC (hpLC) were isolated from LNC using a metrizamide gradient, as described by Bigby et al. (45). Briefly, skin-draining LN were collected 24 h after oxazolone sensitization. LNC suspensions (5 ml; at 5 x 106 cells/ml) were layered onto 2 ml 14.5% metrizamide and gradient-centrifuged at 1200 rpm for 15 min. Cells at the interface were collected, washed once, and resuspended in RPMI 1640 medium. Consistent with previous reports, immunolabeling studies demonstrated that 50–80% of this fraction was Ia+DEC-205+ DCs (5, 45).
RNA isolation and cDNA synthesis
The total RNA from LNC, hpLC, and hpLC-free LNC was extracted by a single-step method using RNA STAT-60 (Tel-Test, Friendswood, TX). Then, 2 µl total RNA, 1 µg oligo(dT)12–18 primers, and 500 U Moloney murine leukemia virus reverse transcriptase were used for the synthesis of oligo(dT)-primed cDNA. The RT reaction was stopped by heating at 95°C for 5 min, and 2 µl cDNA was used for each PCR (46).
PCR analysis
The primer sequences were as follows: IL-18: upstream,
5'-ACTGTACAACCGCAGTAATACGG-3'; downstream,
5'-AGTGAACATTACAGATTTATCCC-3' (47); and -actin:
upstream,
5'-GTGGGCCGCTCTAGGCACCAA-3'; downstream, 5'-CTCTTTGATGTCACGCACGATTTC-3'.PCR
products were size-fractionated in agarose gel containing ethidium
bromide and photographed under UV light. For relative quantitation,
amounts of PCR products were determined by scanning photo negatives
using a laser densitometer, and then the densitometry value of IL-18
was normalized to that of the housekeeping gene, -actin.
Quantitation of IL-18 protein in vitro
The hpLC, hpLC-free LNC, and XS52 cells were cultured at 5 x 106 cells/ml in 24-well plates in RPMI 1640 medium for 48 h, and supernatants were collected. IL-18 was quantitated by a sandwich ELISA with a murine IL-18 ELISA kit (R&D Systems, Minneapolis, MN). Each supernatant was analyzed in duplicate.
IL-18 bioassay
IL-18 activity in hpLC culture supernatants was assessed by its
ability to induce IFN- production in T cells (31).
Briefly, the mouse spleen was removed, and cell suspensions were
prepared. Spleen cells were resuspended in RPMI 1640 medium
supplemented with 10% FBS and cultured at 5 x
106 cells/ml in 24-well plates. Cultures were
incubated for 48 h with Con A (0.5 µg/ml) in combination with
culture supernatants from hpLC, hpLC-free LNC, and XS52 cells. As a
specificity control, supernatants were preincubated with either
anti-IL-18 Ab (50 µg/ml) or normal rabbit IgG (50 µg/ml). The
amount of IFN- produced was measured by a murine IFN- ELISA kit
(Genzyme, Cambridge, MA).
Assay for IL-12-induced IFN- production
Skin-draining LN were obtained from mice 24 h following
oxazolone sensitization. LNC were prepared from C57BL/6 mice and
cultured at 5 x 106 cells/ml in 24-well
plates in RPMI 1640 medium containing murine rIL-12 (10 ng/ml) in the
presence of either anti-IL-18 Ab or normal rabbit IgG (50 µg/ml)
(23). Caspase-1-/- LNC were
prepared from caspase-1-/- mice and cultured in
RPMI 1640 medium containing murine rIL-12 (10 ng/ml) in the presence or
the absence of murine rIL-18 (30 ng/ml). After 48-h culture,
supernatants were collected. IFN- was quantitated by ELISA.
Epidermal sheet preparation and immunolabeling
The density of epidermal LC was examined by anti-Ia in situ immunolabeling. Epidermal sheets were obtained from the ears of caspase-1-/- and wild-type (WT) mice using 0.5 M ammonium thiocyanate. Acetone-fixed epidermal sheets were labeled with anti-Ia in a three-step immunolabeling procedure (48). Ia+ cells (LC) were counted using a micrometer grid.
Induction of CHS
Mice were sensitized with 150 µl 3% oxazolone in alcohol/acetone (3/1) applied to the shaved abdomen and four paws. Five days later mice were challenged by applying 25 µl 1% oxazolone in olive oil/acetone (3/1) on the dorsal and ventral sides of the right ear. As a control, the left ear was painted with an identical amount of vehicle. The CHS response was determined by measuring the degree of ear swelling of the oxazolone-exposed ear compared with that of the vehicle-treated contralateral ear at 24, 48, and 72 h after challenge using a micrometer (49).
In vivo neutralizing IL-18 Ab blocking studies
To study whether IL-18 is involved in the induction phase of CHS, endogenous IL-18 was neutralized by i.p. injection of 100 µl anti-IL-18 antiserum (70 mg/ml) into mice 24 and 2 h before oxazolone sensitization. As a control, equivalent amounts of normal rabbit serum were used.
Statistical analysis
Data are expressed as the mean ± SEM. The statistical significance of differences between the means was determined by applying Student’s t test. A difference was considered statistically significant at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine IL-18 gene expression in LN during the induction phase
of CHS, RNA was extracted from the skin-draining LN in
hapten-sensitized mice and naive mice and subjected to RT-PCR analysis.
IL-18 mRNA was constitutively expressed in LN of naive mice. However, a
significantly up-regulated expression of IL-18 mRNA was seen in LN of
sensitized mice 12–48 h following epicutaneous hapten application.
Maximal expression of IL-18 mRNA was seen at 24 h, and levels
returned to baseline by 72 h (Fig. 1
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Because IL-18 is an LC-derived cytokine, we examined whether LC
were the main cellular source for the increased IL-18 mRNA expression
in skin-draining LN. Migratory hpLC were enriched from LNC and
subjected to RT-PCR analysis. Results revealed that the level of IL-18
mRNA was significantly higher in the hpLC compared with hpLC-free LNC
and total LNC (Fig. 2). To determine
whether LC are able to secrete IL-18 protein, hpLC, hpLC-free LNC, and
XS52 cells were cultured for 48 h, and culture supernatants were
subjected to ELISA analysis (Fig. 3). A
significant amount of IL-18 protein was detected from XS52 cells and
hpLC, but not from hpLC-free LNC. To further examine whether LC-derived
IL-18 is functionally active, we performed an IL-18 bioassay. IL-18
activity in cell culture supernatants was assayed for its ability to
induce IFN- production in Con A-stimulated T cells. IL-18-induced
IFN- production was detected from the supernatants of XS52 cells and
hpLC, but not from hpLC-free LNC (Fig. 4). The IFN--inducing activity was
significantly blocked (60%) when cells were preincubated with
neutralizing anti-IL-18 Ab (data not shown). Importantly, the
supernatants of hpLC derived from caspase-1-/-
mice showed a significantly lower level of IFN--inducing activity,
and addition of anti-IL-18 serum did not block IFN- production
(data not shown). This confirmed that
caspase-1-/- mice do not produce functional
IL-18.
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production by LNC is partially blocked by
anti-IL-18 Ab
To induce LNC to produce IFN-, LNC were incubated with rIL-12
at 10 ng/ml for 48 h. The quantity of IFN- protein in the
supernatants was examined by ELISA (Fig. 5). IL-12 induced LNC to produce
significant amounts of IFN-. To examine whether endogenous IL-18
plays a synergistic role in the IL-12-induced IFN- production, LNC
were incubated with IL-12 (10 ng/ml) in the presence or the absence of
neutralizing anti-IL-18 Ab (50 µg/ml) for 48 h. ELISA
analysis on the culture supernatants showed that neutralization of
IL-18 significantly reduced IFN- production. In contrast, control
rabbit IgG did not reduce IL-12-induced IFN- production in
LNC.
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production is decreased in caspase-1-/- LNC
but restored by exogenous IL-18
To confirm the synergistic role of IL-18 in the induction of
IFN- by IL-12, we further examined whether caspase-1 deficiency
impairs IL-12-induced IFN- production due to the absence of mature
IL-18. LNC were obtained from caspase-1-/- and
WT mice and incubated with IL-12 for 48 h. Culture supernatants
were subjected to ELISA analysis (Fig. 6). The IFN- concentration was
significantly lower in caspase-1-/- LNC
compared with WT LNC. However, the addition of exogenous IL-18 restored
IFN- production.
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To investigate whether IL-18 is functionally relevant to the
induction of CHS, endogenous IL-18 was neutralized by the
administration of anti-IL-18 Ab. C57BL/6 mice were injected i.p.
with anti-IL-18 Ab 24 and 2 h before hapten sensitization.
Blockage of endogenous IL-18 led to suppression of CHS responses by
50% (Fig. 7). On the contrary,
pretreatment with normal rabbit serum did not significantly alter the
ear swelling response.
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To further confirm the functional relevance of endogenous IL-18 to
CHS, we investigated whether caspase-1 deficiency could impair CHS
responses due to the absence of mature IL-18. Before CHS assays, we
examined the density of epidermal LC in the epidermal sheets and
demonstrated a normal number of LC present in
caspase-1-/- mice (data not shown). When
caspase-1-/- and WT mice were sensitized to
oxazolone, a significantly reduced CHS response was seen in
caspase-1-/- mice compared with WT mice (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-2, and TNF-
, which promote
cell-mediated inflammatory reactions, while Th2 cells synthesize IL-4,
IL-5, IL-10, and IL-13, which promote humoral Ab-driven responses.
Although populations of T cells may simultaneously produce both
cytokine subsets, effective cellular or humoral responses require the
selective activation of polarized Th1 or Th2 cells, respectively. While T cells respond to Ag-derived peptides presented in the context of MHC molecules expressed by APC, the shift of the balance between Th1 and Th2 cytokines is highly determined by APC-associated factors. APC provide T cells not only with an Ag-specific stimulatory signal (signal 1) and a series of costimulatory signals (signal 2), but also with polarizing signals (signal 3, i.e., IL-12) (50).
APC-derived IL-12 is the most potent polarizing cytokine for Th1 cells.
IL-12 promotes Th1 cell responses by the selective up-regulation of
IFN- in T cells. In addition to IL-12, other cytokines, such as
IL-1 and TNF-, are recognized to contribute to Th1 polarization
(51). Differential actions of IL-1 on T cell subsets have
long been recognized (52). This recognition foreshadowed
identification of additional IL-1 family members that can significantly
contribute to the biological regulation of Th1 and Th2 cells.
IL-18, a new member of the IL-1 family, has been shown to be a
selective activator of IFN- in Th1, but not Th2, cells. This is
supported by the observation that IL-18 and IL-12 act synergistically
on the development of Th1 cells and induction of IFN- production by
these cells (32). Furthermore, the effects of IL-18 as a
costimulator for IFN- are selectively targeted toward Th1 cells but
not Th2 cells (33). An important role for IL-18 in vivo
has been shown by targeted disruption of the IL-18 gene.
IL-18-deficient mice were found to have a significant reduction in
LPS-induced IFN- production and a decreased Th1 response to
intracellular bacteria and parasites (53). While many
studies indicate that IL-18 cannot induce a Th1 response in the absence
of IL-12, other evidence suggests that IL-18 has IL-12-independent
effects. This was shown for Th1-directed, delayed-type
hypersensitivity-mediated crescentic glomerulonephritis and cutaneous
delayed-type hypersensitivity in mice (54). Moreover,
recent studies reveal that IL-18 can stimulate Th2 immune responses in
the absence of IL-12 (55). Further elucidation of the
molecular mechanisms of IL-18 on Th1 and Th2 immune responses may
provide a novel approach for controlling Th1/Th2 balance at the
transcriptional level.
CHS represents a classic Th1 immune response in the skin. Although Th2
cytokines may also mediate CHS in certain cases, it is clear that the
Th1 cytokine IFN- is the main effector cytokine for CHS (56, 57). The critical role of LC and LC-derived IL-12 in the
initiation of CHS has been well documented. For the present studies we
investigated whether another LC-derived cytokine, IL-18, plays a role
in the induction of CHS. First we demonstrate that during the induction
phase of CHS, migratory LC in the skin-draining LN express high levels
of IL-18 mRNA and secrete functional IL-18 protein. Examination of
IL-18 gene expression in skin-draining LN with RT-PCR showed a
significant up-regulation of IL-18 mRNA in LN following hapten
sensitization. Further analysis of IL-18 mRNA levels in different
fractions of LNC revealed that migratory hapten-modified LC were the
main cellular source for the increased IL-18 mRNA expression in
skin-draining LN. Moreover, ELISA analysis demonstrated that migratory
LC were able to secrete significant amounts of IL-18 protein, which was
functionally active, as shown by its ability to induce IFN-
production in Con A-stimulated T cells.
We also demonstrate a synergistic role for LC-derived IL-18 in
IL-12-induced IFN- production by LNC. IL-12 induced LNC to produce
significant amounts of IFN-; however, neutralizing IL-18 Ab could
block IFN- production by 50%. IL-12-induced IFN- production
was also significantly lower in caspase-1-/-
LNC compared with WT LNC. This impaired IFN- induction appeared to
be due to the absence of mature IL-18, because IFN- production could
be restored by treatment with exogenous IL-18.
Finally, we used in vivo experiments to demonstrate functional relevance for IL-18 production during the induction phase of CHS. To neutralize endogenous IL-18, mice were injected with anti-IL-18 Ab before hapten sensitization. Anti-IL-18 Ab-treated mice showed a reduced CHS response. Additionally, we examined CHS responses in caspase-1-/- mice that could not produce the mature form of IL-18. Caspase-1-/- mice also exhibited reduced CHS responses. Recently, Antonopoulos et al. (58) demonstrated decreased LC migration associated with reduced CHS responses in caspase-1-/- mice. Our observation of a decreased CHS response in caspase-1-/- mice is consistent with their report.
Collectively, the present study demonstrates that during the induction
phase of CHS, migratory LC in the LN produce significant amounts of
functional IL-18, which acts synergistically with IL-12 to induce
IFN- production and significantly contributes to CHS initiation. Our
results are also consistent with the observations of Wildbaum et al.
(59), who recently demonstrated a crucial role for IL-18
in the induction phase of experimental autoimmune encephalomyelitis, a
Th1 autoimmune disease of the CNS. They reported that treatment of rats
with anti-IL-18 Ab during the induction phase of experimental
autoimmune encephalomyelitis resulted in significant inhibition of
disease and Ag-specific IFN- production (59). However,
recent studies also suggest that IL-18 can modulate inflammation at
multiple checkpoints, acting not only on initiation of putative
autoreactive Th1/Tc1 responses, but also during perpetuation of
inflammation. In fact, elevated IL-18 expression has been reported in
mouse skin during the elicitation phase of CHS (60).
Up-regulated IL-18 expression has also been reported in other Th1
immune/inflammatory responses, such as Crohn’s disease, rheumatoid
arthritis, psoriasis, and sarcoidosis (61, 62, 63, 64). Our
studies presented here support a need for better understanding the
molecular mechanisms of IL-18 functions. Further defining
IL-18-dependent signaling mechanisms in immune/inflammatory responses
may provide a rationale for anti-IL-18-based treatment of
inflammatory conditions.
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cell; CHS, contact hypersensitivity; LC, Langerhans cell; hpLC, hapten-modified LC; LN, lymph node; LNC, LN cell; Tc1, type 1 cytotoxic T; WT, wild type.
Received for publication October 29, 2001. Accepted for publication January 30, 2002.
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References |
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  C. Antonopoulos, M. Cumberbatch, J. B. Mee, R. J. Dearman, X.-Q. Wei, F. Y. Liew, I. Kimber, and R. W. Groves IL-18 is a key proximal mediator of contact hypersensitivity and allergen-induced Langerhans cell migration in murine epidermis J. Leukoc. Biol., February 1, 2008; 83(2): 361 - 367. [Abstract] [Full Text] [PDF]
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 C. L. Bennett, M. Noordegraaf, C. A. E. Martina, and B. E. Clausen Langerhans Cells Are Required for Efficient Presentation of Topically Applied Hapten to T Cells J. Immunol., November 15, 2007; 179(10): 6830 - 6835. [Abstract] [Full Text] [PDF]
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 R. Watanabe, M. Fujimoto, N. Ishiura, Y. Kuwano, H. Nakashima, N. Yazawa, H. Okochi, S. Sato, T. F. Tedder, and K. Tamaki CD19 Expression in B Cells Is Important for Suppression of Contact Hypersensitivity Am. J. Pathol., August 1, 2007; 171(2): 560 - 570. [Abstract] [Full Text] [PDF]
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 W. Wannamaker, R. Davies, M. Namchuk, J. Pollard, P. Ford, G. Ku, C. Decker, P. Charifson, P. Weber, U. A. Germann, et al. (S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an Orally Available Selective Interleukin (IL)-Converting Enzyme/Caspase-1 Inhibitor, Exhibits Potent Anti-Inflammatory Activities by Inhibiting the Release of IL-1beta and IL-18 J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 509 - 516. [Abstract] [Full Text] [PDF]
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 E. Garaczi, M. Szell, T. Janossy, A. Koreck, A. Pivarcsi, E. Buzas, Z. Pos, A. Falus, A. Dobozy, and L. Kemeny Negative regulatory effect of histamine in DNFB-induced contact hypersensitivity Int. Immunol., December 1, 2004; 16(12): 1781 - 1788. [Abstract] [Full Text] [PDF]
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 K. G. Hogg, S. Kumkate, S. Anderson, and A. P. Mountford Interleukin-12 p40 Secretion by Cutaneous CD11c+ and F4/80+ Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity to Schistosomamansoni Infect. Immun., June 1, 2003; 71(6): 3563 - 3571. [Abstract] [Full Text] [PDF]
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