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*
Thomas E. Starzl Transplantation Institute and Departments of Surgery and
Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15213; and
Immunex Corp., Seattle, WA 98101
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-17 induces activation of the transcription factor NF-
B in a
variety of cell types (9) and stimulates stromal elements, such as
fibroblasts, endothelial cells, and epithelial cells to secrete IL-6,
IL-8, granulocyte CSF (G-CSF), and PGE2, a process that can
be blocked by anti-IL-17 mAb. In addition, IL-17 induces the
secretion of IL-1ß and TNF-
by human macrophages (10) and enhances
IL-1-induced IL-6 and leukemia inhibitory factor production by
rheumatoid synoviocytes (11). Besides inducing proinflammatory cytokine
production, IL-17 exhibits indirect hemopoietic activity by enhancing
the ability of fibroblasts to sustain the growth of CD34+
hemopoietic progenitors and directing their maturation into neutrophils
(9). IL-17 also augments mature T cell proliferation induced by
suboptimal concentrations of PHA. Recently, an IL-17 antagonist,
soluble mIL-17R:Fc fusion protein, has been found to inhibit IL-2
production and T cell proliferation induced by PHA, Con A, anti-TCR
mAb, or anti-CD28 mAb, suggesting a key role for endogenously
produced IL-17 in T cell growth (4, 5).
We hypothesized that IL-17 might play a role in the generation of alloimmune responses, and we have tested the influence of mIL-17R:Fc on alloimmune reactivity, both in vitro and in vivo. In view of the capacity of IL-17 to exhibit hemopoietic activity and to further explore its immunologic role, we also examined the influence of IL-17 on the in vitro differentiation and function of bone marrow-derived dendritic cells (DC), potentially the most potent donor-derived APC for T cell activation and proliferation (12). The results reveal effects of IL-17 on the maturation of DC progenitors, allogeneic T cell proliferation, and the expression of alloimmune reactivity. They also suggest that IL-17 plays a role in organ allograft rejection, and that IL-17 antagonism may have potential for antirejection therapy, either alone or in combination with other immunosuppressive agents exhibiting complementary modes of action.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C57BL/10J (B10; H2b) and C3H (H2k) mice, 8–10 wk of age, were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in the Central Animal Facility of the University of Pittsburgh Medical Center. BALB/c (H2d) and C57BL/6 (B6; H2b) mice were obtained from Taconic Farms (Germantown, NY) and were bred and housed at Immunex Corp. (Seattle, WA). All animals were maintained under specific pathogen-free conditions.
Recombinant mIL-17R:Fc
A soluble rmIL-17R:Fc fusion protein constructed by fusing the extracellular domain (residues 1–323) of IL-17R to the Fc portion of huIgG1 (4) was reconstituted in sterile HBSS (Life Technologies, Grand Island, NY). For in vivo use, it was injected i.p. Controls received human or rat IgG (Sigma, St. Louis, MO).
Recombinant huIL-17 and mIL-17R mAb
Recombinant huIL-17 was purchased from R&D Systems (Minneapolis, MN). Purified rat IgG mAb against the mIL-17R (M177) was provided by Immunex Corp.
Nonvascularized heart transplantation
Neonatal (day 1) B6 hearts were transplanted into the ear pinnae of adult BALB/c recipients, using the method of Fulmer et al. (13), with modifications as previously described (14). Following transplantation, the mice were assigned to four different groups, with four animals in each group. Groups 1 and 2 received IL-17R:Fc or huIgG at 100 µg/day i.p. on days 0–2, where day 0 was the day of transplant. Groups 3 and 4 received rmIL-17R:Fc or rat IgG at 100 µg/day i.p. on days 0–3 post-transplant. The heart grafts were monitored for contractile activity on a daily basis by a blinded observer using a stereomicroscope. Rejection was determined as cessation of heartbeat.
Vascularized heart transplantation
Heterotopic heart transplantation was performed in the B10 to C3H combination (MHC class I, class II, and multiple non-MHC Ag disparities) using techniques adapted from the rat procedure of Ono and Lindsey (15). The heart was transplanted into the abdomen with end-to-end anastomosis of aorta to aorta and pulmonary artery to vena cava. Immediately following transplantation, the animals were treated with varying doses of IL-17R:Fc (100–500 µg/day) for different periods of time, and graft survival was evaluated. Control mice received no treatment. Rejection was defined by the cessation of cardiac contraction after daily palpation through the abdominal wall.
Mixed leukocyte reactions
Either bulk splenocytes or spleen cells that were highly T cell enriched by passing them through a nylon wool column at 37°C in 5% CO2 in air for 30 min were set up (2 x 105 cells/well) as responders in 96-well microtiter plates (Corning, Corning, NY). They were cocultured with graded concentrations of gamma-irradiated (20 Gy) stimulator cells in RPMI 1640 (Life Technologies) complete medium, containing 10% (v/v) heat-inactivated FBS (Life Technologies), 2 mM L-glutamine, 50 U/ml penicillin and streptomycin, and 2 mM nonessential aa for 3–4 days at 37°C in 5% CO2 in air. Sixteen to eighteen hours before the end of the culture period, individual wells were pulse labeled with 1 µCi of [3H]thymidine. The plates were harvested, and the amount of radioisotope incorporated into the cells was determined using a beta scintillation counter. Results are expressed as the mean counts per minute ± 1 SD and are representative of experiments performed at least twice.
Propagation of DC progenitors from bone marrow
B10 mouse bone marrow cells were isolated and DC progenitors were propagated using the procedure described initially by Inaba et al. (16), with modifications as previously described (17). Briefly, 2 x 106 bone marrow cells were cultured in 24-well plates in 2 ml of RPMI 1640 complete medium containing various concentrations of rmGM-CSF (1, 2, or 4 ng/ml) with or without rm IL-4 (1000 U/ml; cytokines from Schering-Plough Research Institute, Kenilworth, NJ). On day 2 of culture, the medium was gently removed and spun down, and 1 ml of this old medium along with 1 ml of fresh medium containing cytokines were added to the culture. This step allowed the depletion of nonadherent granulocytes without dislodging clusters of DC progenitors that were loosely attached to a monolayer of plastic-adhered macrophages. On day 5, floating cells (many of which exhibited typical DC morphology) were harvested and incubated overnight (18 h) in medium containing either no cytokine or various concentrations of rhuIL-17. At the end of the culture period, the cells were harvested, and phenotypic analyses were performed. The functional capacity of the cells was tested by adding them as stimulators to either C3H spleen cells or purified T cell responders in a one-way MLR.
Staining for cell surface Ags
The surface phenotype of the bone marrow-derived cells was analyzed after gating for DC by cytofluorography, using an EPICS Elite flow cytometer (Coulter, Hialeah, FL). Before staining with the relevant mAb, the cells were incubated with 10% (v/v) normal goat serum (Vector Laboratories, Burlingame, CA) in HBSS at 4°C for 30 min to eliminate nonspecific binding. The cells were then washed once in HBSS containing 0.1% (v/v) BSA (Sigma) and analyzed using FITC-labeled Abs (PharMingen, San Diego, CA) for expression of the murine DC-restricted marker CD11c, costimulatory molecules (CD40, CD80, and CD86), and MHC class II Ag (I-Ab). Ig isotype controls were included for each mAb. After staining, the cells were fixed in 1% (v/v) paraformaldehyde in saline before analysis. Five thousand events were accumulated for each sample. In the same experiments, two-color staining for CD11c and other Ags of interest was performed using phycoerythrin- and FITC-labeled mAbs, respectively. Data are presented as percentages of positive cells, after deduction of appropriate isotype control values.
Statistics
The significances of differences were determined using the nonparametric Wilcoxon rank-sum test (graft survival data) or Student’s t test, as appropriate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To test for a role for IL-17 in alloimmune responses in vitro,
variable numbers of gamma-irradiated normal allogeneic (B10) stimulator
splenocytes were added to a fixed number of C3H bulk spleen cells
together with varying doses of rmIL-17R:Fc (50–200 µg/ml) and
cultured for 4 days. As shown in Fig. 1
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each dose of the IL-17 antagonist tested markedly inhibited T cell
proliferation compared with Ig isotype-treated controls. These findings
suggest a role for IL-17 in the generation of allogeneic T cell
responses and indicate the immunosuppressive potential of IL-17R:Fc.
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B6 recipients of day 1 BALB/c heart grafts injected with 100
µg/day rmIL-17R:Fc on days 0–2 post-transplant exhibited
significantly prolonged graft survival compared with control animals
that received hu IgG (Table I). Graft
median survival time (MST) was prolonged from 13 to 20 days
(p < 0.005). Similarly, B6 recipients treated
with the same dose of fusion protein from days 0–3 post-transplant
exhibited prolonged graft survival compared with controls. However,
increasing the duration of treatment from 2 to 4 days post-transplant
did not further extend graft survival time. The increase in MST
observed following administration of IL-17R:Fc strongly implicates
endogenous IL-17 in the generation and/or expression of anti-donor
immune reactivity.
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We next evaluated the influence of rmIL-17R:Fc on vascularized
heart allograft survival. Different strains were used from those used
for the nonvascularized grafts, to test whether the therapeutic effect
could be observed in another MHC-disparate combination. Administration
of rmIL-17R:Fc (500 µg/day) to C3H recipients of B10 cardiac
allografts on days 0–6 post-transplant resulted in prolonged graft MST
from 10.5 to 19 days (p < 0.001) (Table II). A lower dose of the fusion protein
(200 µg/day) administered for varying periods post-transplant did not
significantly affect graft survival. Overall, these findings using two
experimental models indicate that by blocking the effects of IL-17,
IL-17R:Fc can inhibit organ allograft rejection.
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Bone marrow-derived DC are crucial APC for the activation of naive
T cells (12). In normal heart and other nonlymphoid tissues, the
interstitial DC are thought to be at an immature stage of phenotypic
and functional development (18, 19, 20). After organ transplantation, these
cells migrate to lymphoid tissue (17, 21, 22) where, as mature
interstitial DC in T-dependent areas, they instigate allogeneic T cell
activation and proliferation (20, 21). To determine whether IL-17 might
influence the maturation of DC progenitors, rhuIL-17 was added to
cultures of GM-CSF-stimulated bone marrow-derived cells, and its
influence on their phenotype and function was determined. Cells
propagated in 4 ng/ml GM-CSF for 5 days, as described in
Materials and Methods, were exposed to IL-17 (10 or 20
ng/ml) in the absence of other exogenous cytokines for 18 h. They
were then analyzed for the expression of various cell surface markers
by single color flow cytometry. As shown in Fig. 2, IL-17 treatment increased the
intensity of staining for CD11c, CD40, and MHC class II
(I-Ab) and, more strikingly, up-regulated CD80 and CD86
expression. This maturation-promoting effect of IL-17 was observed
consistently in five separate experiments. It was also observed when DC
progenitors were propagated in a reduced concentration of GM-CSF (1 or
2 ng/ml) and 1000 U/ml IL-4, and then exposed to IL-17 under conditions
identical with those described above (Fig. 3).
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To ascertain whether IL-17 might affect more fully differentiated
bone marrow-derived DC, 5-day cultures stimulated with 4 ng/ml GM-CSF
and 1000 U/ml IL-4 and expressing comparatively high levels of CD11c,
costimulatory molecules, and MHC class II were treated with IL-17 for
18 h. They were then analyzed by flow cytometry. In contrast to
the effects on the immature cell population, the expression of key cell
surface functional molecules was not significantly affected by exposure
to IL-17 (Fig. 4).
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To confirm that the changes in cell surface phenotype induced by
IL-17 occurred on DC, two-color flow analysis of CD80, CD86, or MHC
class II and the DC-restricted Ag CD11c was performed. Cells propagated
in various concentrations of GM-CSF (1, 2, or 4 ng/ml) in the absence
or the presence of IL-4 (1000 U/ml) for 5 days, then exposed overnight
(18 h) to IL-17 (20 ng/ml), were harvested, stained, gated for DC, and
analyzed. As shown in Table III, IL-17
up-regulated the expression of CD80 and CD86 on CD11c+
cells at all concentrations of GM-CSF tested (with or without IL-4).
Up-regulation of IAb (MHC class II) expression, however,
was only evident at comparatively low concentrations of GM-CSF.
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Since responsiveness of DC to IL-17 may be dependent on cell
surface expression of the IL-17R, 5-day cultures of either
GM-CSF-stimulated or GM-CSF- plus IL-4-stimulated cells were analyzed
by two-color flow staining for coexpression of CD11c and IL-17R. As
shown in the results of a representative experiment (Fig. 5A), 18% of the
GM-CSF-stimulated CD11c+ cells were IL-17R+;
culture in GM-CSF and IL-4 resulted in a lower incidence of
CD11c+ DC expressing surface IL-17R (8%). Also shown in
Fig. 5, B and C, are the results of staining
for IL-17R on normal, resting, and Con A-activated bulk splenocytes
and T cells. The incidence of positive cells was increased following
their activation, suggesting that activated T cells in culture may be
responsive to IL-17.
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The influence of exposure to IL-17 on the allostimulatory capacity
of cultured DC progenitors was determined by adding various
concentrations of rhuIL-17 (10–40 ng/ml) to bulk splenocytes at the
start of primary (3-day) MLR induced by 5-day GM-CSF (4
ng/ml)-stimulated cells. As shown in Fig. 6 and consistent with its influence on
the phenotypic maturation of these comparatively immature cells (Fig. 2
), IL-17 increased the T cell proliferative response induced by DC
progenitors in a dose-related manner. These data are consistent with a
stimulatory action of IL-17 on allogeneic T cell responses mediated at
least in part by promotion of the functional maturation of bone
marrow-derived APC (DC).
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To exclude the possibility that IL-17 may augment T cell
proliferative responses by a direct action on T cells rather than by a
maturation-inducing effect on DC progenitors, we investigated the
allostimulatory properties of DC progenitors pre-exposed to IL-17.
Cells propagated in GM-CSF (1 ng/ml) for 5 days and then either left
untreated or exposed to IL-17 (20 ng/ml) for an additional 18 h
were used as stimulators of purified T cells in 3-day MLR. Cocultures
of IL-17-pre-exposed DC progenitors and allogeneic T cells were also
set up, with addition of IL-17 at the start of the MLR. Purified T
cells were used as responders. As shown in Fig. 7A, pre-exposure of DC
progenitors grown in a low concentration of GM-CSF (1 ng/ml) to IL-17
significantly augmented their allostimulatory activity (by
approximately twofold) at all DC:T cell ratios tested
(p < 0.05). This effect was more marked,
although not consistently so over all DC:T cell ratios, when additional
IL-17 (20 ng/ml) was added at the start of the MLR. When more fully
differentiated DC (grown in 1 ng/ml GM-CSF and 1000 U/ml IL-4) were
pre-exposed to IL-17 and used as stimulators, no significant effect of
IL-17 pretreatment on their potent T cell stimulatory response was
observed (Fig. 7B). Of interest was that further exposure of
these highly stimulatory APC to IL-17 during the MLR tended to reduce
their effect on T cell proliferation (p < 0.02
compared with untreated DC at the maximal response), suggesting a
feedback regulatory mechanism.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-17 also acts in concert with other cytokines to induce
proinflammatory responses in various cell types. Both TNF- and
IFN-
synergize with IL-17 to augment IL-17-induced secretion of IL-6
by rheumatoid synoviocytes (4, 5). Lotz et al. (33) have found IL-17 to
promote synovial inflammation and cartilage degradation. Thus, IL-17
stimulated the expression of various genes (inducible cyclo-oxygenase,
inducible nitric oxide synthase, IL-6, stromelysin, and collagenase) in
normal human chondrocytes and augmented IL-1, IL-6, macrophage
chemotactic protein-1, and inducible cyclo-oxygenase gene expression in
synoviocytes. In addition, the joint tissues of patients with
rheumatoid arthritis, psoriatic arthritis, or osteoarthritis revealed
message for this cytokine (33). Yao et al. (5) have reported that
together with TNF-, IL-17 induces GM-CSF production by synovial
fibroblasts. This functional interrelationship between IL-17 and
numerous other cytokines (IL-1, IL-6, IL-8, macrophage chemotactic
protein-1, GM-CSF, TNF-, and IFN-) suggests a role for IL-17 in
the induction and/or expression of alloimmune reactivity. Moreover,
previous studies have shown that IL-17 augments T cell proliferation
induced by a suboptimal mitogenic costimulus (PHA). In addition, the
IL-17 antagonist IL-17R:Fc can inhibit IL-2 production and T cell
proliferation induced by phytomitogens or anti-TCR or anti-CD28
mAbs (4). These observations suggest a role for endogenously produced
IL-17 in the induction of proinflammatory cytokine release and T cell
proliferation, with implications for effects on immune reactivity.
The present study shows for the first time that blocking the effects of IL-17 using IL-17R:Fc not only inhibits proliferative responses of T cells to alloantigens in vitro, but also significantly prolongs MHC-mismatched nonvascularized and vascularized cardiac allograft survival. In the nonvascularized heart transplant model, treatment of the recipients with 100 µg/day of fusion protein for only 3 days led to a significant increase in graft MST compared with that in control (huIgG-treated) animals. In the vascularized model, however, a larger dose of IL-17R:Fc (500 µg/day for 7 days post-transplant) was required to significantly prolong heart graft survival. This difference may have been due both to the use of different strain combinations in the two models and to the apparent greater immunogenicity of the vascularized heart grafts, which survived for a shorter time than the nonvascularized grafts in unmodified hosts. Thus, higher levels of IL-17 as well as other cytokines may have been involved in the immune responses generated to the vascularized allografts, and hence, a higher dose of the fusion protein was required to achieve a protective effect. In vitro, the ability of IL-17R:Fc to inhibit allogeneic T cell proliferative responses further indicates a role for IL-17 in T cell activation and/or growth. The finding that IL-17R:Fc can enhance organ allograft survival as well as suppress allogeneic T cell alloresponses in vitro suggests that IL-17 is a proinflammatory cytokine with significant effects in the process of organ allograft rejection.
A number of different mechanisms have been proposed by which cytokines
mediate graft destruction. IFN- and TNF-ß are directly cytotoxic
to the graft, IL-2 and IL-4 promote the expansion and differentiation
of mature cytotoxic T cells, whereas IL-4, IL-5, and IL-6 promote B
cell maturation and the development of specific, anti-graft
alloantibodies (23, 24, 34, 35). Rejection is characterized by the
infiltration of lymphocytes into the graft. While the CD4+
subset elaborates cytokines, CD8+ cells are primarily
cytotoxic effector cells. It is reasonable to propose that IL-17 is
elaborated by graft-infiltrating T lymphocytes, and that it plays a
role (either directly or indirectly) in intensifying the local
inflammatory response by acting on various cell types, such as T cells
and fibroblasts, and by recruiting additional cells, including APCs,
into the graft site. This may be achieved by inducing cytokines such as
IL-8 and GM-CSF and by up-regulation of adhesion molecule expression. A
subset of such recruited cells is likely to be DC progenitors, with the
important characteristics of motility and migratory capacity (12, 20),
enabling these cells to move from peripheral tissues (including the
allograft) to regional lymphoid organs (21, 22). It is thus of interest
that combination of IL-17 with TNF- is effective in inducing the
release of GM-CSF (9), a key growth- and maturation-inducing factor for
myeloid DC (16).
Bone marrow-derived DC present in organ allografts, such as heart or liver, are believed to be in an immature state of development (18, 19) and to be influenced by various factors (such as Ags and the cytokine milieu) to migrate and undergo maturation. The present finding that IL-17 can serve to promote the phenotypic and functional maturation of DC progenitors suggests a mechanism by which this cytokine may promote host T cell sensitization (allostimulation) and consequent graft rejection. Whether these effects on DC progenitors (and possibly other APC) may be mediated directly or indirectly is at present uncertain. We observed that approximately 20% of bone marrow-derived DC progenitors expressed IL-17R, as determined by flow cytometric analysis, and that expression of the receptor appeared to be reduced on more mature DC. Thus, it is likely that in the present studies, only a minor population of DC progenitors was directly responsive to IL-17. Since IL-17 is known to promote the secretion of a variety of cytokines, including hemopoietic growth factors from stromal cells and macrophages, its stimulatory effects on DC progenitors in vitro and its presumed influence on these cells in vivo may be mediated in part by an indirect action on stromal cell elements, such as endothelial cells and fibroblasts. The relative inability of more fully differentiated, highly stimulating DC to respond to IL-17 and its capacity to exert a negative effect on T cell proliferation when added at the start of vigorous MLRs may reflect the refractoriness of potent APC and/or T cells to the cytokine and perhaps feedback inhibition mediated via IL-17-IL-17R interaction.
Taken together, the findings clearly indicate the effects of the IL-17/IL-17R pathway on alloimmune responses. The capacity of the IL-17R:Fc fusion protein to prolong organ allograft survival suggests that IL-17 antagonism may have potential for therapy of transplant rejection and perhaps other immune-mediated disorders, possibly in conjunction with immunosuppressive agents with complementary modes of action.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mary A. Antonysamy or Dr. Angus W. Thomson, Department of Surgery, University of Pittsburgh Medical Center, W1540C Biomedical Science Tower, Terrace and Lothrop St., Pittsburgh, PA 15213.
3 Abbreviations used in this paper: CTLA-8, cytotoxic T lymphocyte-associated Ag-8; m, mouse; aa, amino acids; hu, human; G-CSF, granulocyte CSF; DC, dendritic cell; rm, recombinant mouse; rhu, recombinant human; GM-CSF, granulocyte-macrophage CSF; MST, median survival time.
Received for publication March 27, 1998. Accepted for publication September 14, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß TCR+CD4-CD8- T cells. J. Interferon Cytokine Res. 16:611.[Medline]
, by human macrophages. J. Immunol. 160:3513. may suppress allograft reactivity by T lymphocytes in vitro and in vivo. Science 229:176.This article has been cited by other articles:
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 J. Li, E. Simeoni, S. Fleury, J. Dudler, E. Fiorini, L. Kappenberger, L. K. von Segesser, and G. Vassalli Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model. Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 779 - 783. [Abstract] [Full Text] [PDF]
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P. G. Fallon, S. J. Ballantyne, N. E. Mangan, J. L. Barlow, A. Dasvarma, D. R. Hewett, A. McIlgorm, H. E. Jolin, and A. N.J. McKenzie Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion J. Exp. Med., April 17, 2006; 203(4): 1105 - 1116. [Abstract] [Full Text] [PDF]
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E. Lubberts, P. Schwarzenberger, W. Huang, J. R. Schurr, J. J. Peschon, W. B. van den Berg, and J. K. Kolls Requirement of IL-17 Receptor Signaling in Radiation-Resistant Cells in the Joint for Full Progression of Destructive Synovitis J. Immunol., September 1, 2005; 175(5): 3360 - 3368. [Abstract] [Full Text] [PDF]
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 D. T. Nardelli, M. A. Burchill, D. M. England, J. Torrealba, S. M. Callister, and R. F. Schell Association of CD4+ CD25+ T Cells with Prevention of Severe Destructive Arthritis in Borrelia burgdorferi-Vaccinated and Challenged Gamma Interferon-Deficient Mice Treated with Anti-Interleukin-17 Antibody Clin. Vaccine Immunol., November 1, 2004; 11(6): 1075 - 1084. [Abstract] [Full Text] [PDF]
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G. Vassalli, S. Fleury, J. Li, J.-J. Goy, L. Kappenberger, and L. K. von Segesser Gene transfer of cytoprotective and immunomodulatory molecules for prevention of cardiac allograft rejection Eur. J. Cardiothorac. Surg., November 1, 2003; 24(5): 794 - 806. [Abstract] [Full Text] [PDF]
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 R.-B. Yang, C. K. D. Ng, S. M. Wasserman, L. G. Komuves, M. E. Gerritsen, and J. N. Topper A Novel Interleukin-17 Receptor-like Protein Identified in Human Umbilical Vein Endothelial Cells Antagonizes Basic Fibroblast Growth Factor-induced Signaling J. Biol. Chem., August 29, 2003; 278(35): 33232 - 33238. [Abstract] [Full Text] [PDF]
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S. Nakae, S. Saijo, R. Horai, K. Sudo, S. Mori, and Y. Iwakura IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist PNAS, May 13, 2003; 100(10): 5986 - 5990. [Abstract] [Full Text] [PDF]
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Y. Chen, P. Thai, Y.-H. Zhao, Y.-S. Ho, M. M. DeSouza, and R. Wu Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop J. Biol. Chem., May 2, 2003; 278(19): 17036 - 17043. [Abstract] [Full Text] [PDF]
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 H.-R. Jiang, E. Muckersie, M. Robertson, and J. V. Forrester Antigen-Specific Inhibition of Experimental Autoimmune Uveoretinitis by Bone Marrow-Derived Immature Dendritic Cells Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1598 - 1607. [Abstract] [Full Text] [PDF]
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S. Ferretti, O. Bonneau, G. R. Dubois, C. E. Jones, and A. Trifilieff IL-17, Produced by Lymphocytes and Neutrophils, Is Necessary for Lipopolysaccharide-Induced Airway Neutrophilia: IL-15 as a Possible Trigger J. Immunol., February 15, 2003; 170(4): 2106 - 2112. [Abstract] [Full Text] [PDF]
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S. Aggarwal, N. Ghilardi, M.-H. Xie, F. J. de Sauvage, and A. L. Gurney Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17 J. Biol. Chem., January 10, 2003; 278(3): 1910 - 1914. [Abstract] [Full Text] [PDF]
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 P. W. Hellings, A. Kasran, Z. Liu, P. Vandekerckhove, A. Wuyts, L. Overbergh, C. Mathieu, and J. L. Ceuppens Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 42 - 50. [Abstract] [Full Text] [PDF]
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M. R. Kim, R. Manoukian, R. Yeh, S. M. Silbiger, D. M. Danilenko, S. Scully, J. Sun, M. L. DeRose, M. Stolina, D. Chang, et al. Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production Blood, September 18, 2002; 100(7): 2330 - 2340. [Abstract] [Full Text] [PDF]
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T. Starnes, H. E. Broxmeyer, M. J. Robertson, and R. Hromas Cutting Edge: IL-17D, a Novel Member of the IL-17 Family, Stimulates Cytokine Production and Inhibits Hemopoiesis J. Immunol., July 15, 2002; 169(2): 642 - 646. [Abstract] [Full Text] [PDF]
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F. Benchetrit, A. Ciree, V. Vives, G. Warnier, A. Gey, C. Sautes-Fridman, F. Fossiez, N. Haicheur, W. H. Fridman, and E. Tartour Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism Blood, March 15, 2002; 99(6): 2114 - 2121. [Abstract] [Full Text] [PDF]
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D. Haudenschild, T. Moseley, L. Rose, and A. H. Reddi Soluble and Transmembrane Isoforms of Novel Interleukin-17 Receptor-like Protein by RNA Splicing and Expression in Prostate Cancer J. Biol. Chem., February 1, 2002; 277(6): 4309 - 4316. [Abstract] [Full Text] [PDF]
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 S. Aggarwal and A. L. Gurney IL-17: prototype member of an emerging cytokine family J. Leukoc. Biol., January 1, 2002; 71(1): 1 - 8. [Abstract] [Full Text] [PDF]
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P. Ye, F. H. Rodriguez, S. Kanaly, K. L. Stocking, J. Schurr, P. Schwarzenberger, P. Oliver, W. Huang, P. Zhang, J. Zhang, et al. Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense J. Exp. Med., August 20, 2001; 194(4): 519 - 528. [Abstract] [Full Text] [PDF]
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E. Lubberts, L. A. B. Joosten, B. Oppers, L. van den Bersselaar, C. J. J. Coenen-de Roo, J. K. Kolls, P. Schwarzenberger, F. A. J. van de Loo, and W. B. van den Berg IL-1-Independent Role of IL-17 in Synovial Inflammation and Joint Destruction During Collagen-Induced Arthritis J. Immunol., July 15, 2001; 167(2): 1004 - 1013. [Abstract] [Full Text] [PDF]
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C. Infante-Duarte, H. F. Horton, M. C. Byrne, and T. Kamradt Microbial Lipopeptides Induce the Production of IL-17 in Th Cells J. Immunol., December 1, 2000; 165(11): 6107 - 6115. [Abstract] [Full Text] [PDF]
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J. Witowski, K. Pawlaczyk, A. Breborowicz, A. Scheuren, M. Kuzlan-Pawlaczyk, J. Wisniewska, A. Polubinska, H. Friess, G. M. Gahl, U. Frei, et al. IL-17 Stimulates Intraperitoneal Neutrophil Infiltration Through the Release of GRO{alpha} Chemokine from Mesothelial Cells J. Immunol., November 15, 2000; 165(10): 5814 - 5821. [Abstract] [Full Text] [PDF]
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 A. M. WOLTMAN, S. DE HAIJ, J. G. BOONSTRA, S. J.P. GOBIN, M. R. DAHA, and C. V. KOOTEN Interleukin-17 and CD40-Ligand Synergistically Enhance Cytokine and Chemokine Production by Renal Epithelial Cells J. Am. Soc. Nephrol., November 1, 2000; 11(11): 2044 - 2055. [Abstract] [Full Text]
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A. E. Morelli, M. A. Antonysamy, T. Takayama, H. Hackstein, Z. Chen, S. Qian, N. B. Zurowski, and A. W. Thomson Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus J. Immunol., July 1, 2000; 165(1): 226 - 237. [Abstract] [Full Text] [PDF]
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R. Schwandner, K. Yamaguchi, and Z. Cao Requirement of Tumor Necrosis Factor Receptor-Associated Factor (Traf)6 in Interleukin 17 Signal Transduction J. Exp. Med., April 3, 2000; 191(7): 1233 - 1240. [Abstract] [Full Text] [PDF]
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J. Lee, W.-H. Ho, M. Maruoka, R. T. Corpuz, D. T. Baldwin, J. S. Foster, A. D. Goddard, D. G. Yansura, R. L. Vandlen, W. I. Wood, et al. IL-17E, a Novel Proinflammatory Ligand for the IL-17 Receptor Homolog IL-17Rh1 J. Biol. Chem., January 5, 2001; 276(2): 1660 - 1664. [Abstract] [Full Text] [PDF]
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Y. Shi, S. J. Ullrich, J. Zhang, K. Connolly, K. J. Grzegorzewski, M. C. Barber, W. Wang, K. Wathen, V. Hodge, C. L. Fisher, et al. A Novel Cytokine Receptor-Ligand Pair. IDENTIFICATION, MOLECULAR CHARACTERIZATION, AND IN VIVO IMMUNOMODULATORY ACTIVITY J. Biol. Chem., June 16, 2000; 275(25): 19167 - 19176. [Abstract] [Full Text] [PDF]
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