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Mucosal Immunology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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is about 10-fold greater in
mucosal than in peripheral lymphoid tissue. Our results show that
activated mucosal T cells expand and up-regulate cytokine mRNA in
response to luminal exposure to SEB, suggesting a role for the
gut-associated lymphoid tissue in the gastrointestinal manifestations
of enterotoxic poisoning. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The toxic syndromes and foodborne illness (4, 5) associated with the SEs have been linked to the high levels of cytokine secretion induced by the simultaneous stimulation of large populations of T cells (6). It has been assumed that these toxic effects of SEs are due to their dissemination, via the blood, to T cells in the peripheral lymphoid tissues. The primary manifestations of foodborne enterotoxic poisoning, i.e., vomiting and diarrhea, are associated with the gastrointestinal tract and usually occur within 24 h after the ingestion of the toxin. If the SEs exert their toxic effects through the secretion of cytokines, the activation of large numbers of potentially responsive T cells present in the gut-associated lymphoid tissue (GALT) in the organized lymphoid tissues in the mesenteric lymph node (MLN) and Peyer’s patch (PP), as well as in the intestinal epithelium and lamina propria, might be expected to play an important role. Yet, to our knowledge, the responses of T cells in the GALT to either systemic or i.g. administration of SEB in vivo have not previously been examined.
Systemic administration of SEB by i.p. or i.v. injection results in an
early (2–3 day) expansion of the responsive Vß8+ T
cells, which are subsequently deleted at 7–10 days (7, 8, 9). We have
found that intragastric (i.g.) administration of SEB rapidly (within
4 h) leads to the expansion and activation of both
CD4+ and CD8+ Vß8+ T cells in the
PP and MLN. Analysis of cytokine mRNA in purified Vß8+ T
cells by competitive RT-PCR showed that, 4 h after i.g.
administration of SEB, the induction of mRNA for IL-2 and IFN- was
about 10-fold greater in mucosal than in peripheral lymphoid tissue.
SE-elicited secretion of IFN- and TNF from lymphocytes has been
shown to lead to epithelial transport and barrier abnormalities (10).
Taken together, our results suggest that the rapid expansion of mucosal
T cells, and concomitant cytokine release, induced by the presence of
SEs in the intestinal lumen could contribute directly to the acute
intestinal symptoms at the site of SEB uptake, i.e., the diarrhea and
vomiting that are the hallmark of food poisoning.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/cBy J mice (6–12 wk of age) were purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained under specific viral pathogen-free conditions at an American Association for the Accreditation of Laboratory Animal Care accredited facility at Massachusetts General Hospital.
SEB treatment and flow cytometric analysis
Mice were anesthetized and fed i.g. with 50 µg of
staphylococcal enterotoxin B (SEB; Sigma, St. Louis, MO) mixed with 400
µg of soybean trypsin inhibitor (STI; Sigma) in 500 µl of PBS using
a ball-tipped feeding needle. Controls were fed PBS and STI alone.
Another group of mice received 50 µg of SEB dissolved in 500 µl of
PBS and administered i.p. Single-cell suspensions were prepared by
pressing the tissues through a 70-µM nylon cell strainer (Falcon,
Lincoln Park, NJ). Spleen cell suspensions were depleted of RBCs by
lysis with Tris-buffered ammonium chloride. Each of the cell
suspensions was then incubated with the following fluorescently
conjugated, activation marker-specific Abs: CD69 (phycoerythrin
(PE)-labeled H1.2F3, hamster Ig, PharMingen, San Diego, CA); CD25
(IL-2R 
-chain, PE-labeled PC61 5.3, rat IgG1, Caltag, San Francisco,
CA); and L-selectin/CD62L (PE-labeled MEL14, rat IgG2a, Phar-
Mingen). PE-labeled hamster Ig, rat IgG1, and rat IgG2a (all
purchased from PharMingen) were used as isotype controls. The T cell
subpopulations of interest were identified using FITC-labeled Abs
directed against CD4 (RM4-5) and CD8 (53-6.7), both purchased from
Caltag. SEB-responsive Vß8+ T cells were identified using
a biotin-conjugated Ab against Vß8.1, -8.2, and -8.3 (F23.1,
PharMingen). In preliminary experiments, an Ab against Vß9 (MR10-2)
was used as an additional specificity control. Detection of the the
biotinylated Abs with streptavidin-conjugated PerCP (Becton Dickinson,
San Jose, CA) enabled us to analyze these samples by three-color flow
cytometric analysis on a Becton Dickinson FACScan with CellQuest
software. Dead cells and debris were excluded from analysis by gates
set on forward and side angle light scatter. For each stained aliquot
of cells, 50,000–200,000 events were acquired, gating on all cells
with the forward and side scatter properties of lymphocytes.
6000–10000 events were analyzed for activation marker expression in
the gated CD4+ or CD8+ Vß8+
populations.
T cell purification
In some experiments, Vß8+ T cells were purified from the single-cell suspensions obtained from spleen, MLN, and PP using the VarioMACS system (Miltenyi Biotec, Auburn, CA) following the manufacturer’s protocol. Cells were incubated with biotinylated anti-Vß8.1,2,3 (F23.1, PharMingen), for 25 min at 4°C, washed, and incubated with streptavidin-conjugated magnetic microbeads (Miltenyi Biotec) for an additional 25 min at 4°C. Streptavidin-conjugated PE (PharMingen) was also added as a tracer to assess the purity of the resulting cell preparations by flow cytometric analysis. The cells were then washed again and passed through a MACS VS separator column. The purity of the magnetically sorted Vß8+ T cells was >95% for cells derived from the spleen and MLN and equivalent for cell populations prepared from PBS- or SEB-treated mice. Multiple experiments (for a total of 30–40 mice) were required for the preparation of an enriched population of Vß8+ cells from the PP of PBS- and SEB-treated mice. The lymphocytes in the various preparations ranged in purity from 50–90% Vß8+ and were pooled together (estimated final purity, 75–90%) for the preparation of RNA for analysis by RT-PCR.
Semiquantitative and competitive RT-PCR
Total RNA was extracted from whole tissue preparations or from
purified Vß8+ T cells isolated from the spleen, MLN, and
PP of SEB-treated mice and PBS controls using TRIzol (Life
Technologies, Gaithersburg, MD) according to the manufacturer’s
instructions. In a 60-µl total reaction mixture, 10 µg of total RNA
was reverse transcribed using 0.5 µM random hexamer primers, 0.67 mM
dNTP, 50 U of murine leukemia virus reverse transcriptase, and 20 U of
RNase inhibitor (all purchased from Perkin-Elmer, Foster City, CA). The
cDNA was then amplified by PCR with specific primers for the
housekeeping gene HPRT (5'-GTTGGATACAGGCCAGACTTTGTTG,
5'-GAGGGTAGGCTGGCCTATGGCT) and cytokine-specific primers for IL-2
(5'-TCCACTTCAAGCTCTACAG, 5'-GAGTCAAATCCAGAACATGCC), IFN-
(5'-CATTGAAAGCCTAGAAAGTCTG, 5'-CTCATGAATGCATCCTTTTTCG), IL-4
(5'-CATCGGCATTTTGAACGAGGTCA, 5'-CTTATCGATGAATCCAGGCATCG), and
IL-10 (5'-CCAGTTTTACCTGGTAGAAGTGATG,
5'-TGTCTAGGTCCTGGAGTCCAGCAGACTCAA) derived from published
sequences (11). TNF- cDNA was amplified using an RT-PCR
Amplimer Set from Clontech (Palo Alto, CA). PCR reactions were
performed in a programmable Thermal Cycler (MJ Research, Watertown, MA)
for 35 cycles. Preliminary experiments established that amplification
for 35 cycles was within the linear range. The PCR reaction mixtures
contained 5 µl of buffer A (100 mM Tris-HCl, pH 8.3, 500 mM KCl, 15
mM MgCl2, 0.01% w/v gelatin; Fisher Scientific,
Pittsburgh, PA), 1 µl of dNTP (10 mM; Perkin-Elmer), and 0.25 µl of
Taq polymerase (Fisher Scientific). Each cycle was 95°C,
30 s; 58°C, 60 s; 75°C, 60 s; and a final extension
of 72°C, 5 min. In each experiment the initial PCR reaction was
performed using 4 µl of cDNA and HPRT-specific primers. The PCR
products were separated by electrophoresis on a 1.5% agarose gel and
visualized by EtBr staining and UV light. The amount of cDNA to be
added to each cytokine-specific reaction mixture was then adjusted so
that each experimental sample would contain equivalent amounts of DNA
for the housekeeping gene. After HPRT normalization, each experimental
sample was amplified using cytokine-specific primers. Twenty
microliters of the total (50 µl) cytokine-specific PCR product from
each reaction was separated by electrophoresis in a 1.5% agarose gel
and visualized by EtBr staining and UV light.
For competitive PCR for IL-2 and IFN-, 10-fold or 3-fold dilutions
(in the pg/ml range) of the polycompetitor cytokine plasmid PQRS (Ref.
11; generously provided by Dr. Steven Reiner, University of Chicago,
IL) were added to a constant, HPRT-normalized amount of experimental
cDNA for the PCR reaction with each cytokine-specific primer.
Competitive PCR for TNF- was performed using serial 10-fold and
3-fold dilutions of TNF- PCR MIMIC (Clontech). PCR products were
separated on agarose gels. The point at which the competitor and
experimental bands are of equivalent intensity is designated as the
concentration of experimental mRNA for the cytokine-specific gene.
Statistical analysis
Statistical differences in percentages of CD4+ and CD8+Vß8+ T cells for groups of mice given SEB i.p. or i.g. in comparison with PBS-treated controls were determined using a two-tailed Student’s t test with StatView software (Abacus Concepts, Berkeley, CA). A p value < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Systemic administration of SEB by i.p. or i.v. injection results
in a characteristic and well-documented early (2–3 day) expansion of
the responsive Vß8+ T cells in peripheral blood and
spleen followed by deletion at 7–10 days (7, 8, 9). This is sometimes
accompanied by an early loss of SEB-responsive cells within the first
24 h (12). Fig. 1
shows that i.p.
injection of SEB results in a significant loss of responsive
CD4+Vß8+ T cells in the spleen at 12 h
followed by a marked expansion by 48 h, as expected.
CD8+Vß8+ T cells in the spleen are expanded
at 48 h as well. The expansion of CD4+ and
CD8+Vß8+ T cells noted in the spleen at
48 h after systemic administration of SEB also occurs in the MLN,
albeit to a lesser extent. The response of T cells in the PP to i.p.
SEB differs from that in the spleen and MLN;
CD4+Vß8+ T cells are expanded by 48 h,
whereas CD8+Vß8+ T cells are markedly reduced
at 12 h and have only returned to baseline levels by 48 h.
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Mucosal T cells are activated during the first 48 h after i.g. administration of SEB
This pattern of responsiveness suggested that i.g. administration
of SEB resulted in the activation of mucosal T cells. Accordingly, we
examined the induction of well-known early markers of cellular
activation on both CD4+Vß8+ and
CD8+Vß8+ T cells from the spleen, MLN, and PP
during the first 48 h after oral or i.p. injection of SEB. The
first phenotypic change evidenced by Vß8+ T cells after
systemic administration of SEB in vivo is a marked down-regulation of
L-selectin expression on T cells in the draining lymph nodes, which
peaks at 4 h after SEB injection and returns to normal levels
within 48 h (15). Fig. 2 shows that
systemic, i.p. administration of SEB leads to down-regulation of
L-selectin on CD4+ T cells in the spleen as well as on
mucosal CD4+ T cells in the MLN and PP. The subsequent
up-regulation of L-selectin on these cells is delayed compared with
that noted for SEB-responsive T cells in the spleen during the first
48 h. The magnitude and kinetics of induction of the early
activation marker CD69 and the IL-2R -chain (CD25) are similar on
CD4+Vß8+ T cells in all three tissues. The
response of CD8+Vß8+ T cells paralleled that
of CD4+Vß8+ T cells during the first 48
h after i.p. administered SEB (data not shown). It is interesting to
note that some of the Vß8+CD4+ and
CD8+ T cells in the PP express a constitutively activated
phenotype, since 
20% are L-selectinlow and
CD69+ before SEB treatment (Fig. 2 and 16 .
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-chain is not up-regulated on
CD4+Vß8+ T cells after oral administration of
SEB in any of the three tissues examined. A somewhat different response
pattern emerged when CD8+Vß8+ T cells were
examined (data not shown). Although CD69 was highly up-regulated on T
cells in the PP, L-selectin was only partially down-regulated. There
was no evidence for activation of CD8+Vß8+ T
cells in the MLN or spleen within the first 48 h. When we examined the percentages of Vß8+CD4+ and CD8+ T cells in both mucosal and peripheral tissues 10 days after i.p. or i.g. administration of SEB, we found that i.p. injection of SEB resulted in a marked depletion of CD4+Vß8+ T cells in all sites examined, as reported (7, 8, 9). However, i.g. administration of two different doses (50 and 200 µg) of SEB resulted in little depletion of CD4+ or CD8+Vß8+ T cells in the spleen; significant depletion in the PBL was detected only at the higher (200 µg) dose, in agreement with a previous report (Ref. 14; data not shown). CD4+Vß8+ T cells were, however, significantly depleted in both of the mucosal sites examined after i.g. SE, although the depletion was less marked than that seen after i.p. administration of SEB (data not shown).
mRNA for Th1 cytokines is rapidly up-regulated in mucosal lymphoid tissue after i.g. administration of SEB
We next analyzed the induction of mRNA for both Th1 and Th2
cytokines after i.g. administration of SEB, using semiquantitative
RT-PCR. Fig. 3 shows that IL-2, IFN-,
and TNF- mRNA are rapidly induced in the PP and MLN within 1.5
h. mRNA for each of these Th1 cytokines declines in the PP by 12
h, but can still be seen in the MLN. When we looked at cytokine
induction outside of the GALT, we found that a small amount of IL-2
mRNA is present in the spleen at 4 h; IFN- and TNF- mRNA are
not detectable in the spleen at any time point. mRNA from MLN and
spleen cells prepared 4 h after i.p. administration of SEB is also
included as a positive control for induction of cytokine mRNA. No clear
induction of Th2 cytokine mRNA was noted after i.g. administration of
SEB, although both IL-4 and IL-10 were detectable in the spleen and MLN
after SEB was given i.p.. Although Th1 cytokine responses are typically
associated with the response to the SEs, other work has shown that,
after i.v. administration of SEB, both Th2 (IL-4 and IL-10) and Th1
(IFN- and IL-2) cytokines can be detected in the serum within 90 min
(17).
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, and
TNF- using 10-fold dilutions of competitor. We chose to examine the
4-h time point because this was the peak for IL-2 and IFN- mRNA
induction in all of the tissues examined (see Fig. 3
). Fig. 4A shows that, in the MLN,
4 h after i.g. administration of SEB, mRNA for IL-2 is increased
by 100-fold and IFN- is increased 20-fold. In the spleen (Fig. 4B), mRNA induction for each of these cytokines is
10-fold lower than in the MLN. mRNA for IL-2 is increased 10-fold,
while IFN- is increased only 5-fold. We then examined mRNA for both
Th1 and Th2 cytokines in Vß8-enriched PP T cells by competitive
RT-PCR, using a narrower (3-fold) range of competitor dilutions. Fig. 5 shows that mRNA for the Th1 cytokines
IL-2 and IFN- is undetectable in Vß8+ T cells from the
PP of PBS-fed mice and increases to 0.07 pg/ml in Vß8+ T
cells in the PP of mice fed SEB 4 h previously. Since the
detection limit of the assay is .01 pg/ml this represents at least a
7 fold increase over background levels. Competitive RT-PCR also showed
that i.g. administration of SEB did not result in any increase in
TNF- mRNA in purified Vß8+ T cells from the PP, MLN,
and spleen at this 4-h time point (data not shown) suggesting that the
TNF- mRNA detectable in unfractionated PP and MLN in Fig. 3 is
derived from non-T cell sources. In contrast to the induction seen
after i.p. administration of SEB (Fig. 3), no induction of mRNA for the
Th2 cytokines IL-4 or IL-10 was detectable in the PP.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent work has shown that SEB can bind to a class II-negative
human intestinal epithelial cell line in vitro and can cross the
epithelium in an immunologically intact form (14). Our data extend
these results by showing that i.g. administration of SEB can also
activate mucosal T cells. As in mice, SE-mediated shock in man is
accompanied by T cell expansion and cytokine release (20, 21). Mice,
however, are more resistant to the toxic effects of the SEs than
humans, but at higher doses, they exhibit symptoms associated with T
cell cytokine release such as weight loss and thymic involution (6, 22). The differences in susceptibility between mice and humans may be
related to the magnitude of the response induced, since SEB binds with
higher affinity to human than murine MHC class II (1). Indeed, mice
treated with D-galactosamine to impair liver metabolism
succumb to a T cell-mediated lethal shock after administration of small
(2–20 µg) doses of SEB (22, 23). Our results in mice might therefore
be extrapolated to propose a model for the role of T cells in the GALT
in human enterotoxic poisoning. Toxins such as SEB may gain access to T
cells in the PP by binding to specialized epithelial cells called M
cells, which transport Ags from the intestinal lumen into the PP (24)
and, at least some of which, express MHC class II (25). SE-elicited
secretion of IFN- and TNF from lymphocytes has been shown to lead to
epithelial transport and barrier abnormalities (10). Our results would
then suggest that the rapid expansion of mucosal T cells, and
concomitant cytokine release, induced by the presence of SEs in the
intestinal lumen could contribute directly to the acute intestinal
symptoms at the site of SEB uptake, i.e., the diarrhea that is the
hallmark of food poisoning. The 50-µg dose used in this study has
enabled us to detect mucosal T cell responses in the absence of
substantial peripheral T cell activation. At higher doses, or in
D-galactosamine treated mice (22, 23), extraintestinal
manifestations of enterotoxic shock that involve the central nervous
system may result from the uptake of toxin into the bloodstream. Our
data indicate that a self-limited local T cell response may explain
some acute forms of enterotoxic poisoning.
The response of Vß8+ T cells in the PP differed
markedly depending on the route of toxin administration.
Intraperitoneal administration of SEB led to a marked depletion of
CD4+ and CD8+ Vß8+ cells in the
PP 12 h later, whereas these subsets are expanded 12 h after
i.g. administration of SEB (Fig. 1). It is not yet clear whether this
early expansion reflects recruitment of Vß8+ T cells from
other sites (e.g., MLN) or proliferation within the PP itself. The
absence of IL-2R (CD25) up-regulation on Vß8+ T cells in
the PP after i.g. SEB (see Fig. 2) may suggest that at least some of
this expansion is due to chemokine-induced migration rather than
IL-2-driven proliferation.
There have only been a few other studies that have examined Ag-specific
T cell responses without in vitro stimulation. Litton et al. showed
that i.p. administration of SEB leads to the induction of TNF and IL-2
synthesis in peripheral lymph nodes within 1 h (26).
Semiquantitative RT-PCR analysis of lymph node cells showed that IL-2
mRNA peaked at 4 h, while IFN- mRNA (produced primarily by
CD8+ T cells) peaked at 12 h after i.p. injection.
Cytokine expression preceded clonal expansion and deletion, and the
estimated frequency of cytokine producing T cells was small (2–3%)
(26). In another study, in situ hybridization showed that i.p.
administration of SEB led to up-regulation of mRNA for IL-2 and IFN-
and was limited to T cell areas in the spleen. mRNA for both cytokines
peaked at 3–4 h and was gone by 48 h (27). Similar response
patterns were noted when we analyzed the induction of IL-2 and IFN-
mRNA after i.g. administration of SEB, as shown in Fig. 3. The previous
study also reported a biphasic response for the induction of TNF-
mRNA by i.p. SEB. At early time points (before 2 h), TNF- mRNA
was restricted to T cells, while at later time points, it was expressed
mainly by macrophages. Work from other laboratories has established
that SEB can stimulate TNF- production by macrophages, presumably
via binding to MHC class II (28, 29). In agreement with Bette et al.
(27), our data on TNF- expression after i.g. SEB show that TNF-
mRNA peaks at 1.5–4 h in unfractionated PP and MLN (Fig. 3) but is not
detectable in purified Vß8+ T cells examined 4 h
after i.g. SEB (data not shown). At the later (4 h) time point, peak
expression of TNF- mRNA may occur in macrophages, which are
removed by this T cell purification protocol.
When examined quantitatively (Figs. 4 and 5), the levels of cytokine
mRNA induction we see after i.g. administration of SEB are either
greater than or of the same order of magnitude as those that have been
recently described in another model system. In that study, transgenic
OVA-specific T cells were adoptively transferred into normal mice and
visualized by in situ hybridization analysis after administration of Ag
via various routes (30). Subcutaneous immunization of these mice with
OVA led to peak induction of IL-2 mRNA in draining peripheral lymph
nodes by 8 h, with a return to baseline levels by 24 h.
Although the majority of CD4+ transgene-positive cells were
activated, as assessed by up-regulation of CD25 (IL-2R -chain) and
blast transformation, only 8.5% expressed IL-2 mRNA at the peak of the
response, i.e., an 10-fold increase over background levels. Using
this immunizing regimen, IL-2 mRNA and IL-2R -chain expression
coincide. When Ag was administered by a tolerizing route, however, the
peak of IL-2 mRNA expression preceded the peak of IL-2R -chain
up-regulation, and most of the transgene-positive population failed to
undergo blast transformation. This led the authors to suggest that the
premature induction of IL-2, before up-regulation of IL-2R is complete,
would impair the ability of T cells to utilize and produce IL-2 and
result in tolerance and/or cell death (30). Although the methodologies
are very different, several parallels can be drawn between this study
and our results using the superantigen SEB. The kinetics of IL-2 mRNA
induction (in each of the tissues examined herein) is similar to that
seen by Rogers et al. (30) with a peak between 4 and 12 h.
Interestingly, while i.p. administration of SEB resulted in marked
up-regulation of the IL-2R -chain, with a peak between 4–12 h that
coincided with peak induction of IL-2 mRNA, i.g. administration of SEB
led to IL-2 mRNA induction in the absence of IL-2R -chain
up-regulation (see Fig. 2); PP T cells, however, were clearly activated
as evidenced by their up-regulation of CD69 and down-regulation of
L-selectin. This may suggest that the early cytokine burst seen in
response to i.g. administration of SEB ultimately results in tolerance
and is in keeping with the observation that repeated oral
administration of SEB can induce tolerance to SEB as well as protection
against SEB-induced lethal shock in
D-galactosamine-sensitized mice (13, 23). Indeed, in our
hands, no IL-2 or IFN- mRNA was detectable in the spleen or MLN upon
challenge of mice rendered tolerant by repeated oral administration of
SEB (data not shown).
Superantigen-driven mucosal T cell stimulation has also been implicated in the development of the inflammatory bowel diseases, ulcerative colitis and Crohn’s disease (31, 32, 33, 34, 35). The demonstration that luminal presentation of SEB can activate large numbers of mucosal T cells lends support to this hypothesis. The dysregulation of epithelial barrier function associated with acute exposure to SEB might become chronic with prolonged superantigenic stimulation, ultimately resulting in autoimmune inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Cathryn Nagler-Anderson, Mucosal Immunology Laboratory, Massachusetts General Hospital East, 3 West, Building 149, 13th Street, Charlestown, MA 02129. E-mail address:
3 Abbreviations used in this paper: SE, staphylococcal enterotoxin; GALT, gut-associated lymphoid tissue; MLN, mesenteric lymph node; PP, Peyer’s patch; i.g., intragastric; STI, soybean trypsin inhibitor; PE, phycoerythrin; HPRT, hypoxanthine phosphoribosyltransferase.
Received for publication April 10, 1998. Accepted for publication July 13, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-: inhibition of increased permeability, but not diminished secretory responses by TGF-ß2. J. Immunol. 159:2382. and TNF-ß by staphylococcal enterotoxin A-activated human T cells. J. Immunol. 144:4663.[Abstract]
genes by MHC class II ligands. J. Immunol. 146:2310.[Abstract]
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