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-Chain Administration Prevents Murine Collagen-Induced Arthritis: A Role for IL-15 in Development of Antigen-Induced Immunopathology1
* Department of Immunology and Centre for Rheumatic Diseases, University of Glasgow, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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synthesis by macrophages via a cell contact-dependent
mechanism, suggesting a key regulatory role for IL-15. Here, we report
that the administration of a soluble fragment of IL-15R into DBA/1
mice, profoundly suppressed the development of collagen-induced
arthritis. This was accompanied in vitro by marked reductions in
Ag-specific proliferation and IFN-
synthesis by spleen cells from
treated mice compared with control mice and in vivo by a significant
reduction in serum anti-collagen Ab levels. These data directly
demonstrate a pivotal role for IL-15 in the development of inflammatory
arthritis and also suggest that antagonists to IL-15 may have
therapeutic potential in rheumatic diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(1). We
recently demonstrated that the novel cytokine, IL-15, is present in the
RA synovium, in which it may recruit and activate synovial T cells in
the relative absence of IL-2 (2, 3). Following IL-15-mediated
activation, synovial T cells both secrete TNF- directly and induce
TNF- synthesis by macrophages through cognate interactions (4, 5),
indicating an important role for IL-15 in the inflammatory cascade
within the synovium. Furthermore, IL-15 expression has recently been
detected in several diseases, including inflammatory bowel disease,
sarcoidosis, and chronic active hepatitis (6, 7, 8), suggesting that such
proinflammatory pathways may be of general importance.
IL-15 is derived from several cell types, including macrophages and
fibroblasts (9, 10). It uses the IL-2Rß and common -chain subunits
in combination with a unique -chain, IL-15R (11), through which
it induces T cell chemotaxis and activation together with B cell
maturation and isotype switching (12, 13). It enhances NK cell
cytotoxicity and cytokine production, activates neutrophils, and
modifies monokine secretion (14, 15, 16). Thus IL-15 potentially mediates
diverse effects at multiple stages of the immune response. Thus far,
however, the functional effects of the IL-15 blockade in vivo in
inflammatory models have not been explored.
Therefore, we have generated a soluble fragment of the murine IL
(mIL)-15R -chain to investigate the effect of IL-15 neutralization
on the development of inflammation in vivo. IL-15R administration
inhibited the onset of collagen-induced arthritis (CIA) in susceptible
DBA/1 mice. Parallel ex vivo studies demonstrated the suppression of
Ag-specific T cell proliferation and cytokine production as well as Ig
synthesis. Together, these observations provide the first data
implicating IL-15 in the evolution of specific immune
responses and the concomitant development of immunopathology.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(sIL-15R)
Total RNA was extracted from J774 cells that had been stimulated
for 18 h with murine rIFN- (100 U/ml, a kind gift of Dr. G.
Adolf, Bender Wien, Austria) using the TRIzol Reagent (Life
Technologies, Paisley, U.K.). The RNA was then transcribed into cDNA
using SuperScript II reverse transcriptase (Life Technologies)
according to a standard protocol. sIL-15R was cloned using nested
PCR, and two restriction sites (BamHI and
SalI) were introduced during the second amplification. The
following primer sets were designed from the published cDNA sequence of
mIL-15R (7): Set I, 5'TTG CTG CTG CTG CTG TTG CTA CTG TTG CTC CC-3';
5'-GCA CCA ACC AAG AGG ACC GAT GTA GAG ATG GC-3'. Set II, 5'-GGT
GGG ATC CGG CAC CAC GTG TCC ACC TCC CG-3'; 5'-AGA TGT
CGA CTT TCG TCA TTT AAC TGT GG3' (sequences in italics are the
BamHI and SalI site, respectively). The PCR
product was confirmed by sequencing, cloned into the pQE-30 expression
vector (Qiagen, Dorking, U.K.), and then expressed in the
Escherichia coli M15 strain (Qiagen). Following induction
with isopropyl-ß-D-thiogalactoside (Life Technologies),
sIL-15R was extracted from the bacteria under denaturing conditions
and purified as 6x histidine-tagged fusion protein using a nickel
agarose purification system (Qiagen) according to the manufacturer’s
recommendations. The purity was analyzed by SDS-PAGE following
Coomassie blue staining. The final product consisted of 193 amino acid
residues, 173 of which contained the "Sushi" domain (a
protein-binding motif also referred to as a "short consensus
repeat" or GP-I motif, 17 , linker, and Pro/Thr-rich region of
the native IL-15R. The final product was 
26 kDa in SDS-PAGE. For
Western blot analysis, affinity-purified material was electrophoresed
in 15% SDS-PAGE and transferred onto Trans-Blot medium (Bio-Rad,
Hempstead, U.K.) at 250 mA overnight. Simian rIL-15 (a gift of Immunex,
Seattle, WA) was added after blocking with 1% BSA, and binding was
detected with mouse anti-human L-15 mAb (MAB 647, R&D Systems,
Oxon, U.K.) and developed by enhanced chemiluminescence (Amersham
International, Little Chalfont, U.K.). The biologic activity of the
sIL-15R was determined by ELISA and by inhibition of IL-15-induced T
cell proliferation. For the ELISA, 96-well plates (Immulon 4, Dynatech
Laboratories, Chantilly, VA) were coated with 1 µg/ml of sIL-15R
in 0.1 M NaH2CO3 overnight at 4°C. After
blocking with 10% FCS (Life Technologies), graded concentrations of
simian rIL-15 or 500 pg/ml mIL-2 (Genzyme, Cambridge, MA) were added.
After washing with PBS/Tween-20, biotin-conjugated anti-mIL-2 or
anti-simian IL-15 (200 ng/ml) was added, respectively, followed by
avidin peroxidase, conjugated (1/1000 dilution, Sigma, Poole, U.K.),
and developed with 100 µl/well of tetramethylbenzidine substrate
(Kirkegaard and Perry, Gaithersburg, MD). To block IL-15 bioactivity,
CTLL (American Type Culture Collection (ATCC), Rockville, MD) and
D10.G4.1 (ATCC) cell lines were cultured in 96-well plates (Nunc,
Roskilde, Denmark) with 0.1 ng/ml (CTLL) or 1 ng/ml (D10) of rIL-15,
which were concentrations that had been previously titrated for optimal
proliferation. sIL-15R (200 ng/ml) was added to triplicate cultures
which were then incubated at 37°C in 5% C02 for up to
72 h. [3H]thymidine uptake over the final 6 h
of culture was measured in a beta-plate counter (Wallac Oy, Turku,
Finland).
Induction and treatment of CIA in mice
Male DBA/1 mice (6–8-wk-old, Harlan Olac, Bicester, U.K.)
received 200 µg of bovine type II collagen (Sigma) in Freund’s
complete adjuvant (Difco, Detroit, MI) by intradermal injection (day
0). Collagen (200 µg in PBS) was given again on day 21 by i.p.
injection. Daily injections of sIL-15R (10 or 40 µg/mouse/day) or
human serum albumin (HSA) (40 µg) were administered i.p. for 2 wk
starting on day 22. Mice were monitored daily for signs of arthritis,
for which severity scores were derived as follows: 0 = normal,
1 = erythema, 2 = erythema plus swelling, 3 =
extension/loss function, and total score = sum of four limbs. Paw
thickness was measured with a dial-caliper (Kroeplin, Munich, Germany).
For histologic assessment, the hind limbs from five sIL-15R
recipients and five control mice were fixed in 10% neutral-buffered
formalin, and 5-µm sections were stained with hematoxylin and eosin
(Sigma). The quantification of arthritis was performed by two
treatment-blinded observers as previously described (18).
Spleen cell culture
Spleen cells were cultured at 2 x 106 cells/ml for up to 96 h in RPMI 1640 (Life Technologies) supplemented with 2 mM L-glutamine, 100 international units/ml penicillin, 100 µg/ml streptomycin, 25 mM HEPES buffer, and 10% FCS (all from Life Technologies) at 37°C in 5% CO2. Cells were stimulated either with graded concentrations of type II collagen or with Con A (1 µg/ml, Sigma). Proliferation assays were performed in triplicate in U-bottom 96-well plates (Nunc) as previously described. Supernatants from parallel triplicate cultures were stored at -70°C until estimation of cytokine content by ELISA.
Cytokine assays
Murine TNF-, IFN-, IL-4, IL-6, and IL-10 were assayed by
ELISA using paired Abs (PharMingen, San Diego, CA) according to the
manufacturer’s instructions. Lower limits of detection were as
follows: IL-4, IL-6, and TNF- were all at 10 pg/ml; IL-10 was at 80
pg/ml; and IFN- was at 150 pg/ml.
Anti-collagen Ab ELISA
Serum anti-collagen II Ab titers in pooled sera
(n = 5) that were obtained at the end of
sIL-15R treatment were measured by ELISA. Briefly, 96-well plates
(Immulon 4, Dynatech Laboratories) were coated with 4 µg/ml bovine
type II collagen in 0.1 M NaH2CO3 overnight at
4°C, blocked, and serial dilutions of sera were added. Bound, total
IgG was detected with horseradish peroxidase-conjugated goat
anti-mouse IgG (Genzyme) or biotin-conjugated anti-mouse IgG1
or IgG2a (PharMingen), respectively, and developed as described above.
Plates were read at 630 nm.
Statistical analysis
Statistical analysis was performed using Minitab software for
Macintosh. The analyses were performed using the log-rank test,
2 test, Mann-Whitney U test, or
Student’s t test as indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To obtain a specific IL-15 antagonist for in vivo application, a
sequence corresponding to the extracellular domain of mIL-15R (Fig. 1
A) was cloned by
nested PCR from the mRNA that were prepared from an IFN--activated
murine macrophage cell line (J774). The cDNA was inserted into an
expression vector (pQE-30) and expressed in E. coli (M15).
The soluble protein was extracted and purified to homogeneity as a 6x
histidine-tagged fusion protein using a nickel-tagged agarose
purification system (Fig. 1C). Western blot analysis
against anti-IL-15 Ab following binding with simian rIL-15 showed a
single band at a molecular mass of 26 kDa (Fig. 1D).
The purified protein bound rIL-15 and neutralized its biologic activity
in a dose-dependent manner (Fig. 1, E and
F) but did not cross-react with IL-2 in parallel
assays (data not shown).
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administration prevents development of CIA
We subsequently examined whether the administration of sIL-15R
could modify CIA in susceptible DBA/1 mice, the immunopathogenesis of
which closely resembles RA (19, 20). Mice injected intradermally with
type II collagen in Freund’s complete adjuvant developed severe
arthritis when challenged i.p. 21 days later with collagen. The
incidence and severity of disease development were markedly suppressed
in mice that received daily i.p. injections of 10 or 40 µg of
sIL-15R beginning on the day after collagen challenge (day 22; Fig. 2) in comparison with controls which
received HSA. Histologic examination of the hind limb joints from
HSA-treated mice revealed massive mononuclear and polymorphonuclear
infiltration of the synovial membrane with synovial hyperplasia and
adjacent bone erosion. sIL-15R markedly suppressed each of these
parameters (Fig. 3).
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administration
To further explore the effect of sIL-15R on immunologic
responses, the spleen cells from mice that had been treated with 40
µg of sIL-15R or control HSA were harvested after 2 wk of
treatment (day 36) and cultured with type II collagen in vitro. Cells
from arthritic mice that received control protein proliferated
vigorously in response to collagen in a dose-dependent manner. This
proliferative response was significantly reduced in cultures of cells
from mice treated with sIL-15R (Fig. 4A, p <
0.001). Cells from the sIL-15R-treated mice produced less IFN-
(Fig. 4B) than cells from control HSA-treated mice,
which indicates a suppression of Th1 responses. Moreover, IL-4 was
undetectable, and IL-10 was only found at low levels (100–120 pg/ml)
that were indistinguishable between the groups (data not shown),
suggesting that the mechanism of disease suppression by sIL-15R was
not by the preferential enhancement of Th2 cells. IL-6 production was
significantly suppressed in sIL-15R-treated animals compared with
HSA controls (Fig. 4C). TNF- synthesis was not
detected, which was consistent with previous observations that the
collagen-stimulated expression of TNF- in vitro occurs primarily
during the early acute phase of CIA (21). However, the T cell mitogen,
Con A, stimulated equally high levels of both proliferation and
IFN-, IL-4, IL-10, and IL-6 production by spleen cells from both
groups of mice (data not shown), indicating that suppression of the
immune response was Ag-specific. Commensurate with the above
observations, sera from sIL-15R-treated mice contained significantly
less IFN- than those from control mice (982.8 ± 155.4 vs
1960.8 ± 51.9 pg/ml, p < 0.02). Humoral
responses were clearly modified, since serum anti-collagen Ab
concentrations were significantly reduced in sIL-15R recipients
(Fig. 5), particularly for the IgG2a
isotype and consistent with the preferential suppression of the
Th1-type immune response that predominates in CIA.
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administration facilitates disease
expression
To determine the duration of disease suppression, sIL-15R
administration was withdrawn after 14 days. CIA was detected clinically
at 5 to 7 days after the cessation of treatment, and 90% of previous
sIL-15R recipients developed CIA that was indistinguishable from the
control HSA-injected group after 10 days (data not shown). Thus,
treated mice developed acute phase CIA soon after the discontinuation
of sIL-15R injection. This observation was reflected in immune
responsiveness in vitro. At 2 wk after the cessation of treatment
(day 50), spleen cells from sIL-15R recipients produced higher
concentrations of IFN- and IL-6 to collagen (Fig. 6, A and B)
compared either with parallel cultures from HSA-treated controls, which
were in the chronic phase of CIA at that point, or with spleen cell
responses obtained earlier from littermates at the end of sIL-15R
treatment (day 36; compare with Fig. 4
, B and
C). Thus, treatment with sIL-15R clearly
suppressed the development of acute CIA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-15 expression has been detected in several human diseases including RA, pulmonary sarcoidosis, inflammatory bowel disease, and chronic active hepatitis, providing circumstantial evidence for a role in chronic immunopathology (2, 3, 6, 7, 8). The mechanisms whereby IL-15 could modify such inflammatory tissue destruction have not been clearly defined. Our current observations indicate that IL-15 expression is required for the induction of erosive inflammatory arthritis following a challenge of collagen-primed DBA/1 mice. Moreover, both the altered serum Ig levels detected and the in vitro evidence for suppressed spleen cell proliferation and cytokine production indicate that the collagen-specific response has been significantly modified. Since IL-15 induces T cell chemotaxis in vivo and in vitro (2, 12) and induces proliferation, adhesion molecule expression, and cytokine production in vitro (4, 24), it is therefore possible that IL-15 mediates effects in inflammatory arthritis, at least in part, through its activities on Ag-specific T cells. Several recent data have provided suggestive evidence for Ag-driven T cell clonal expansion in patients with long-standing RA (25, 26). Further possible explanations for our observations include the alteration of Ag-presentation or subsequent T cell costimulation, since both peripheral blood- and skin-derived dendritic cells are known to express IL-15 (27), or the modification of adjuvant activity, since IL-15 up-regulation has been detected during mycobacterial infection (28).
The CIA model provides an opportunity to study the relative
contribution of immune pathways to the development of inflammatory
arthritis. Using this approach, previous studies have demonstrated a
role for Th1 cells and several proinflammatory cytokines, including
TNF- and IL-1ß (21, 29, 30, 31, 32). Such observations in rodents are
clearly of relevance, since subsequent clinical trials with
neutralizing Abs against TNF- and soluble TNF-Rs have
demonstrated efficacy in human RA (33, 34, 35) and implied a pivotal role
for TNF- in RA pathogenesis. We recently provided evidence that
IL-15 is capable of "bystander" activation of RA synovial T cells;
after this activation, these cells may produce cytokines, including
TNF-, either directly or through cognate interaction with adjacent
macrophages (4). Thus, IL-15 could act upstream from TNF- in
orchestrating the production of inflammatory cytokines in the
chronically inflamed RA synovium. The data presented here provide
direct evidence in vivo that IL-15 can also play a pivotal role in the
development of inflammatory arthritis. Further studies are now required
to investigate the apparent dysregulation of IL-15 expression in
synovial tissues.
Besides its postulated function in innate immunity (14, 15), a critical
role in the modulation of acquired immunity is suggested for IL-15.
IL-15R administration effectively suppressed collagen-specific
responses that were measured in vivo by serum Ig and in vitro by spleen
cell responses. This finding was unexpected, since our animals were
IL-2 replete. IL-15 and IL-2 share occupancy of the IL-2/15R ß-chain
and the common -chain and transduce similar JAK1/3-STAT3/5-dependent
pathways thereafter (36), leading to the suggestion that some
functional redundancy might exist. However, the sIL-15R -chain did
not exhibit any binding to IL-2 in vitro nor did it inhibit
IL-2-mediated CTLL proliferation, making it unlikely that
cross-reactivity could explain our observations. Rather, it is likely
that early IL-15 production during Ag-challenge is necessary for the
normal development of specific immune responses. The availability of
sIL-15R will facilitate future studies to investigate the precise
relationship and functional crossover, if any, between IL-2 and
IL-15.
Thus, sIL-15R profoundly suppressed the development of CIA and
markedly inhibited the onset of the humoral and Th1 cell-mediated
anti-collagen response. These results provide the in vivo data
which show a role for IL-15 in inflammatory arthritis and suggest that
antagonists to this cytokine could be of therapeutic benefit. Wider
application to other chronic inflammatory conditions in which IL-15
expression has been localized should also be considered.
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Acknowledgments |
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, Dr. G. Feng for advice on
Western blotting, and Mr. P. Kerr for histologic
preparations. We also thank Dr. D. Boumpas for helpful
discussions. |
Footnotes |
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2 These authors contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Y. Liew, Department of Immunology, University of Glasgow, Glasgow G11 6NT, U.K. E-mail address:
4 Abbreviations used in this paper: RA, rheumatoid arthritis; mIL, murine IL; CIA, collagen-induced arthritis; sIL-15R, soluble fragment of IL-15R; HSA, human serum albumin.
Received for publication October 31, 1997. Accepted for publication January 28, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production in rheumatoid arthritis. Nat. Med. 3:189.[Medline]
, but not interleukin-10: possible relevance to pathophysiology of rheumatoid arthritis. Eur. J. Immunol. 27:624.[Medline]
) receptors in type C chronic liver disease. Clin. Exp. Immunol. 109:458.[Medline]
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M.-E. Miranda-Carus, A. Balsa, M. Benito-Miguel, C. Perez de Ayala, and E. Martin-Mola IL-15 and the Initiation of Cell Contact-Dependent Synovial Fibroblast-T Lymphocyte Cross-Talk in Rheumatoid Arthritis: Effect of Methotrexate J. Immunol., July 15, 2004; 173(2): 1463 - 1476. [Abstract] [Full Text] [PDF]
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 F Y Liew, X-Q Wei, and I B McInnes Role of interleukin 18 in rheumatoid arthritis Ann Rheum Dis, November 1, 2003; 62(90002): ii48 - 50. [Full Text] [PDF]
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I B McInnes, J A Gracie, M Harnett, W Harnett, and F Y Liew New strategies to control inflammatory synovitis: interleukin 15 and beyond Ann Rheum Dis, November 1, 2003; 62(90002): ii51 - 54. [Full Text] [PDF]
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F Y Liew and I B McInnes Role of interleukin 15 and interleukin 18 in inflammatory response Ann Rheum Dis, November 1, 2002; 61(90002): ii100 - 102. [Abstract] [Full Text] [PDF]
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K. B. Nguyen, T. P. Salazar-Mather, M. Y. Dalod, J. B. Van Deusen, X.-q. Wei, F. Y. Liew, M. A. Caligiuri, J. E. Durbin, and C. A. Biron Coordinated and Distinct Roles for IFN-{alpha}{beta}, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection J. Immunol., October 15, 2002; 169(8): 4279 - 4287. [Abstract] [Full Text] [PDF]
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M. Kurowska, W. Rudnicka, E. Kontny, I. Janicka, M. Chorazy, J. Kowalczewski, M. Ziolkowska, S. Ferrari-Lacraz, T. B. Strom, and W. Maslinski Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients Express Functional IL-15 Receptor Complex: Endogenous IL-15 in Autocrine Fashion Enhances Cell Proliferation and Expression of Bcl-xL and Bcl-2 J. Immunol., August 15, 2002; 169(4): 1760 - 1767. [Abstract] [Full Text] [PDF]
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G. Gri, C. Chiodoni, E. Gallo, A. Stoppacciaro, F. Y. Liew, and M. P. Colombo Antitumor Effect of Interleukin (IL)-12 in the Absence of Endogenous IFN-{gamma}: A Role for Intrinsic Tumor Immunogenicity and IL-15 Cancer Res., August 1, 2002; 62(15): 4390 - 4397. [Abstract] [Full Text] [PDF]
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N. Ohta, T. Hiroi, M.-N. Kweon, N. Kinoshita, M. H. Jang, T. Mashimo, J.-I. Miyazaki, and H. Kiyono IL-15-Dependent Activation-Induced Cell Death-Resistant Th1 Type CD8{alpha}{beta}+NK1.1+ T Cells for the Development of Small Intestinal Inflammation J. Immunol., July 1, 2002; 169(1): 460 - 468. [Abstract] [Full Text] [PDF]
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I. A. Khan, M. Moretto, X.-q. Wei, M. Williams, J. D. Schwartzman, and F. Y. Liew Treatment with Soluble Interleukin-15R{alpha} Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response J. Exp. Med., June 3, 2002; 195(11): 1463 - 1470. [Abstract] [Full Text] [PDF]
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F. Mattei, G. Schiavoni, F. Belardelli, and D. F. Tough IL-15 Is Expressed by Dendritic Cells in Response to Type I IFN, Double-Stranded RNA, or Lipopolysaccharide and Promotes Dendritic Cell Activation J. Immunol., August 1, 2001; 167(3): 1179 - 1187. [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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 S. Stemme Plaque T-Cell Activity : Not So Specific? Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1099 - 1101. [Full Text] [PDF]
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M. A. Houtkamp, A. C. van der Wal, O. J. de Boer, C. M. van der Loos, P. A. J. de Boer, A. F. M. Moorman, and A. E. Becker Interleukin-15 Expression in Atherosclerotic Plaques : An Alternative Pathway for T-Cell Activation in Atherosclerosis? Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1208 - 1213. [Abstract] [Full Text] [PDF]
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X.-q. Wei, M. Orchardson, J. A. Gracie, B. P. Leung, B.-m. Gao, H. Guan, W. Niedbala, G. K. Paterson, I. B. McInnes, and F. Y. Liew The Sushi Domain of Soluble IL-15 Receptor {{alpha}} Is Essential for Binding IL-15 and Inhibiting Inflammatory and Allogenic Responses In Vitro and In Vivo J. Immunol., July 1, 2001; 167(1): 277 - 282. [Abstract] [Full Text] [PDF]
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T. A. Fehniger, K. Suzuki, A. Ponnappan, J. B. VanDeusen, M. A. Cooper, S. M. Florea, A. G. Freud, M. L. Robinson, J. Durbin, and M. A. Caligiuri Fatal Leukemia in Interleukin 15 Transgenic Mice Follows Early Expansions in Natural Killer and Memory Phenotype Cd8+ T Cells J. Exp. Med., January 15, 2001; 193(2): 219 - 232. [Abstract] [Full Text] [PDF]
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X.-q. Wei, B. P. Leung, H. M. L. Arthur, I. B. McInnes, and F. Y. Liew Reduced Incidence and Severity of Collagen-Induced Arthritis in Mice Lacking IL-18 J. Immunol., January 1, 2001; 166(1): 517 - 521. [Abstract] [Full Text] [PDF]
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 T. A. Fehniger and M. A. Caligiuri Interleukin 15: biology and relevance to human disease Blood, January 1, 2001; 97(1): 14 - 32. [Full Text] [PDF]
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X. G. Smith, E. M. Bolton, H. Ruchatz, X.-q. Wei, F. Y. Liew, and J. A. Bradley Selective Blockade of IL-15 by Soluble IL-15 Receptor {alpha}-Chain Enhances Cardiac Allograft Survival J. Immunol., September 15, 2000; 165(6): 3444 - 3450. [Abstract] [Full Text] [PDF]
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K. Masuko-Hongo, M. Kurokawa, T. Kobata, K. Nishioka, and T. Kato Effect of IL15 on T cell clonality in vitro and in the synovial fluid of patients with rheumatoid arthritis Ann Rheum Dis, September 1, 2000; 59(9): 688 - 694. [Abstract] [Full Text]
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B. P. Leung, I. B. McInnes, E. Esfandiari, X.-Q. Wei, and F. Y. Liew Combined Effects of IL-12 and IL-18 on the Induction of Collagen-Induced Arthritis J. Immunol., June 15, 2000; 164(12): 6495 - 6502. [Abstract] [Full Text] [PDF]
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Z. Liu, K. Geboes, S. Colpaert, G. R. D'Haens, P. Rutgeerts, and J. L. Ceuppens IL-15 Is Highly Expressed in Inflammatory Bowel Disease and Regulates Local T Cell-Dependent Cytokine Production J. Immunol., April 1, 2000; 164(7): 3608 - 3615. [Abstract] [Full Text] [PDF]
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M. Ziolkowska, A. Koc, G. Luszczykiewicz, K. Ksiezopolska-Pietrzak, E. Klimczak, H. Chwalinska-Sadowska, and W. Maslinski High Levels of IL-17 in Rheumatoid Arthritis Patients: IL-15 Triggers In Vitro IL-17 Production Via Cyclosporin A-Sensitive Mechanism J. Immunol., March 1, 2000; 164(5): 2832 - 2838. [Abstract] [Full Text] [PDF]
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T. A. Fehniger, H. Yu, M. A. Cooper, K. Suzuki, M. H. Shah, and M. A. Caligiuri Cutting Edge: IL-15 Costimulates the Generalized Shwartzman Reaction and Innate Immune IFN-{gamma} Production In Vivo J. Immunol., February 15, 2000; 164(4): 1643 - 1647. [Abstract] [Full Text] [PDF]
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H. Yamada, T. Nakamura, G. Matsuzaki, Y. Iwamoto, and K. Nomoto TCR-Independent Activation of Extrathymically Developed, Self Antigen-Specific T Cells by IL-2/IL-15 J. Immunol., February 15, 2000; 164(4): 1746 - 1752. [Abstract] [Full Text] [PDF]
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C. S. Kasyapa, C. L. Stentz, M. P. Davey, and D. W. Carr Regulation of IL-15-Stimulated TNF-{alpha} Production by Rolipram J. Immunol., September 1, 1999; 163(5): 2836 - 2843. [Abstract] [Full Text] [PDF]
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P. Estess, A. Nandi, M. Mohamadzadeh, and M. H. Siegelman Interleukin 15 Induces Endothelial Hyaluronan Expression in Vitro and Promotes Activated T Cell Extravasation through a Cd44-Dependent Pathway in Vivo J. Exp. Med., July 1, 1999; 190(1): 9 - 20. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) or 40
µg of HSA (•) starting on day 22. Mice were monitored daily for
disease progression, which was quantified as mean clinical score
(A), mean number of arthritic paws
(B), or mean paw thickness
(C). Values are mean ± SEM. At the end
of treatment (day 36), 20% of mice developed mild CIA in the
sIL-15R
