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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-08-2566.
TRANSPLANTATION
From the Departments of Internal Medicine and
Pediatrics, University of Michigan Cancer Center, Ann Arbor, MI; and
the Department of Pathology, University of Florida College of Medicine,
Gainesville, FL.
Interleukin-18 (IL-18) is a unique cytokine that modulates
both TH1/TH2 responses, but its ability to
modulate diseases through induction of TH2 cytokines is
unclear. It has been shown to play an important role in allogeneic bone
marrow transplantation (BMT). Because immune responses of
allogeneic BM donors may affect acute graft-versus-host disease (GVHD),
we investigated the effect of pretreating BM transplant donors with
IL-18 on the severity of acute GVHD using a well-characterized
experimental BMT model (BALB/c Interleukin-18 (IL-18) was originally
discovered as interferon In the absence of IL-12, however, IL-18 acts somewhat differently
and can induce TH2 polarization.2,7-10 IL-18
transgenic mice produce increased amounts of both TH1 and
TH2 cytokines.11 Patients with lepromatous
leprosy, a TH2-like disease, exhibit high serum levels of
IL-18.7 Thus it is unclear whether IL-18 can modulate
certain disease processes in vivo through the induction of
TH1 cytokines only or whether its effects on
TH2 cytokines may also be important.
Acute graft-versus-host disease (GVHD) is the major toxicity of
allogeneic bone marrow transplantation (BMT). The
pathophysiology of acute GVHD is complex, and it involves donor T-cell
responses to the host alloantigens and dysregulation of inflammatory
cytokines cascades.12 The TH1 polarization of
activated T-cell subsets plays an important role in the "cytokine
storm" that characterizes several acute GVHD models, whereas a shift
to TH2 polarization of donor cells can reduce acute
GVHD.12-14 The TH1/TH2 balance as
it relates to the pathophysiology of acute GVHD is complex and
controversial. For example, administration of TH1-inducing cytokines early after BMT has been shown to paradoxically reduce the
severity of acute GVHD.15-20 The Janus kinase-signal
transducer and activator of transcription (JAK-STAT) signaling
pathways control cytokine production by T cells: STAT4 regulates
TH1 responses and STAT6 regulates TH2
responses. A recent study demonstrated that acute GVHD can occur in the
absence of either STAT4 or STAT6 signaling in donor T
cells.21 Furthermore, other studies have failed to
demonstrate a reduction in acute GVHD after direct in vivo
administration of TH2 cytokines to the
recipients.21-26
IL-18, as well as its inhibitor IL-18-binding protein, is elevated
in acute GVHD.27-30 We have previously demonstrated
that administration of IL-18 to recipient mice early after BMT
reduces the severity of acute GVHD in an IFN- Mice
BMT
Assessment of acute GVHD The degree of systemic acute GVHD was assessed by a scoring system incorporating 5 clinical parameters: weight loss, posture (hunching), activity, fur texture, and skin integrity, as published previously.35 At the time of analysis, mice from coded cages were evaluated and graded from 0 to 2 for each criterion. A clinical index was subsequently generated by summation of the 5 criteria scores (maximum index = 10). Mice that underwent transplantation were ear punched and individual scores were obtained and recorded on day 0, and weekly thereafter.IL-18 treatment Recombinant murine IL-18 was purchased from Research Diagnostic (Flanders, NJ) and reconstituted in phosphate-bufferend saline (PBS). Donor mice were injected intraperitoneally with IL-18 (1 µg/d/mouse) for 10 days from days 11 to 1 (10 injections total). Mice from the control groups
received only the diluent in a similar schedule.
Leukemia induction An EL4 leukemia model, as previously described, was used for the graft-versus-leukemia (GVL) experiments.16,36 EL4 is a subline of the B6 MHC class II / T-cell
leukemia/lymphoma EL4 (H2b), and is thus syngeneic
(H2b) to the B6 hosts and allogeneic (H2d) to
the BALB/c donors. On day 0, 2000 EL4 cells were injected into
each recipient along with syngeneic (B6) or allogeneic (BALB/c) BM and
spleen T cells. Previous studies have demonstrated that as few as 500 cells/recipient can induce fatal leukemia in the syngeneic
hosts.36 Injection of 2000 EL4 cells into animals that
cannot reject this tumor is uniformly lethal and results in massive
tumor infiltration and enlargement of various organs, particularly the
liver, spleen, and kidneys.36 Survival was monitored daily
and the cause of each death after BMT was determined by postmortem
examination. Death from EL4 was defined by enlargement of the liver and
spleen with macroscopic tumor nodules, whereas GVHD death was defined
as the absence of tumor and the presence of GVHD as determined by the
clinical scoring system described in "Assessment of acute
GVHD." Minimal residual disease was determined in surviving
animals by fluorescence-activated cell sorting (FACS) analysis
of the peripheral blood and spleen. The sensitivity of tumor detection
by this method has been previously demonstrated by mixing experiments
to be 0.2%.37
FACS analysis Fluorescein isothiocyanate (FITC)-conjugated monoclonal antibodies (MoAbs) to mouse CD3+-, Gr-1+-, CD4+-, and PE-conjugated MoAbs to B220+-, CD8+-, CD25+-, and APC-conjugated MoAbs CD45.1+ antigens were purchased from PharMingen (San Diego, CA). For determining the extent of donor T-cell number and engraftment (CD45.1+, anti-Ly5.2 MoAb) was used as host cell specific marker. The procedure was performed as described previously.34 Briefly, cells were first incubated with MoAb 2.4G2 for 15 minutes at 4°C and then with the relevant FITC-conjugated MoAb for 30 minutes at 4°C. Finally, cells were washed twice with PBS/0.2% bovine serum albumin and fixed with PBS/1% paraformaldehyde. Then 3-color flow cytometry was performed by using EPICS Elite ESP cell sorter (Beckman-Coulter, Miami, FL) and on FACS Vantage SE cell sorter (Becton Dickinson, San Jose, CA).Mixed lymphocyte cultures All culture media and incubation conditions have been previously described.38,39 Briefly, for secondary mixed lymphocyte reaction (MLR) cultures, T cells were isolated from IL-18 or diluent-treated BALB/c mice by negative selection (CD11b, MHC II) with magnetic beads and
cultured with radiated B6 Ly5.2 splenocytes. After 96 hours, donor T
cells were removed from cultures, layered over Ficoll, and adjusted for
CD3+ cell number and then restimulated with irradiated B6
Ly5.2 peritoneal cells. Supernatants were collected after 48 hours
proliferation was determined by incubation of cells with
3H-thymidine for an additional 24 hours. For post-BMT cell
culture analyses, splenocytes were removed from the animals 7 days
after transplantation and 3 to 4 spleens were combined from each group. These cells were then layered over Ficoll-Paque (Pharmacia LKB Biotechnology, Piscataway, NJ) and centrifuged at 800g for
15 minutes. Cells were then collected from the interface and washed twice before suspension in supplemented 10% fetal calf serum
(FCS)/Dulbecco modified Eagle medium. The cells were
normalized for donor T cells (CD45.1 and
CD3+) and were plated in 96-well flat-bottomed
plates (Falcon Labware, Lincoln Park, NJ) at a concentration of
2 × 105 T cells
(CD45.1CD3+)/well with 2 × 105
irradiated (2000 rad) splenocytes harvested from naive B6 (allogeneic) animals. At 48 hours, supernatants were collected for cytokine analysis
and the cultures were pulsed with 3H-thymidine (1 µCi/well [0.037 MBq]) and proliferation was determined 20 hours later on a 1205 Betaplate reader (Wallac, Turku, Finland).
51Cr release assay The cytotoxic function of T cells was analyzed by performing 51Cr release assay as described previously.37,39 Briefly, 2 × 106 allogeneic EL4 (H-2b) and syngeneic P815 (H2d) tumor targets were labeled with 100 µCi (3.7 MBq) of 51Cr sodium salt (NEN Life Sciences Products, Frederick, CO) for 2 hours. After washing 3 times, labeled targets were resuspended in 10% FCS RPMI and plated at 104 cells per well in U-bottom plates (Corning-Costar, Cambridge, MA). Recipient mice were killed on day 14 after BMT and the spleens were harvested. Splenocyte preparations were normalized for CD8+ cells and were added to quadruplicate wells at varying effector (CD8+)-to-target ratios and incubated for 5 hours. Maximal and background release was determined by the addition of Triton-X (Sigma Chemical, St Louis, MO) or media alone to targets, respectively. 51Cr activity in supernatants taken 5 hours later was determined in an autogamma counter (Packard Instrument, Meriden, CT), and lysis was expressed as a percentage of maximum: percentage of specific lysis = 100 × ([sample count background count]/[maximum count background
count]).
Cytokine enzyme-linked immunosorbent assay (ELISA) Antibodies were purchased from R&D Systems and PharMingen; assays were performed according to the manufacturer's protocol. Briefly, samples were diluted 1:5 to 1:10 and TNF- ,
IFN- , or IL-4 was captured by the specific primary
MoAb and detected by horseradish peroxidase (TNF-) or
biotin-labeled (IFN- or IL-4) secondary MoAbs. Plates were read at
450 nm using a microplate reader (Model 3550; Bio-Rad Labs, Hercules,
CA). Recombinant murine TNF- (rmTNF-), mIFN-, and
mIL-4 (PharMingen) were used as standards for ELISAs. All the samples
and standards were run in duplicate.
Serum lipopolysacchride (LPS) estimation The Limulus Amebocyte Lysate (LAL) assay (Bio Whittaker, Walkersville, MD) was performed according to the manufacturer's protocol to determine the endotoxin (LPS) concentration in serum. Briefly, serum samples were collected and analyzed using pyrogen-free materials, diluted 10% (vol/vol) in LAL reagent water, and heated to 70°C for 5 minutes to minimize nonspecific inhibition. Samples were then incubated with equal volumes of LAL for 10 minutes at 37°C and developed with equal volumes of substrate solution for 6 minutes. The absorbance of the assay plate was read at 405 nm using the same microplate reader used in cytokine assays. Samples and standards were run in duplicate and the lower limit of detection was 0.15 U/mL. All units expressed are relative to the US reference standard EC-6.Histology Formalin-preserved liver and small and large bowel were embedded in paraffin, cut into 5-µm-thick sections, and stained with hematoxylin and eosin for histologic examination. Slides were coded without reference to prior treatment and examined in a blinded fashion by a pathologist (C.L.). A semiquantitative scoring system, as described previously, was used to assess the following abnormalities known to be associated with GVHD.38 Specifically, 7 parameters each were scored for small bowel (villous blunting, crypt regeneration, crypt epithelial cell apoptosis, crypt loss, luminal sloughing of cellular debris, lamina propria inflammatory cell infiltrate, and mucosal ulceration) and large bowel (crypt regeneration, crypt epithelial cell apoptosis, crypt loss, surface colonocyte vacuolization, surface colonocyte attenuation, lamina propria inflammatory cell infiltrate, and mucosal ulceration), and 10 parameters for liver (portal tract expansion by an inflammatory cell infiltrate, lymphocytic infiltrate of bile ducts, bile duct epithelial cell apoptosis, bile duct epithelial cell sloughing, vascular endothelialitis, parenchymal apoptosis, parenchymal microabscesses, parenchymal mitotic figures, hepatocellular cholestasis, and hepatocellular steatosis).The scoring system denoted 0 as normal; 0.5 as focal and rare; 1.0 as focal and mild; 2.0 as diffuse and mild; 3.0 as diffuse and moderate; and 4.0 as diffuse and severe. Scores were added to provide a total score for each specimen. After scoring the codes were broken and data compiled.Statistical analysis The Mann-Whitney U test was used for the statistical analysis of cytokine data, LPS levels, clinical scores, weight loss, and histology, whereas the Wilcoxon rank test was used to analyze survival data. A P value less than .05 was considered statistically significant.
IL-18 treatment of donors reduces GVHD mortality and morbidity after allogeneic BMT We first studied the effect of IL-18 administration to BM transplant donors in terms of morbidity and mortality from acute GVHD following allogeneic BMT. We used a well-characterized mouse model of acute GVHD directed against both MHC and minor histocompatibility antigens, BALB/c (H-2d) B6 (H-2b). Donor
BALB/c mice were pretreated intraperitoneally with either 1 µg/mouse
of rmIL-18 or diluent for 10 days, a dose that has previously been
shown to be nontoxic and to induce TH2
polarization.7 Recipient B6 mice were conditioned with
1300 cGy TBI and received transplants of TCD BM and splenic T
cells from either IL-18 or diluent pretreated syngeneic (B6) or
allogeneic (BALB/c) donors as described in "Materials and methods."
As shown in Figure 1A, animals that
received allogeneic T cells from IL-18 pretreated donors showed a
significantly better survival after BMT compared with controls (80% vs
0%; P < .001). Clinical GVHD was quantified with a
clinical scoring system ("Materials and methods"), and was also
less severe in animals receiving allogeneic BM transplants from
IL-18-treated donors (Figure 1B; P < .05). As expected,
the clinical scores of syngeneic animals gradually returned to baseline over this time. All BM transplant recipients displayed complete donor
hematopoietic chimerism as determined by FACS analysis (data not
shown). Longer follow-up of the BM transplant recipients from IL-18-treated donors demonstrated 40% survival with clinical signs of
GVHD beyond day 100. Thus, pretreatment of donors with IL-18 reduced
and delayed the morbidity and attenuated mortality from acute GVHD.
Similar GVHD benefit was also observed in a different donor-recipient
BMT model (B6 (H2b)B6D2F1 (H2b/d)) ruling
out strain-dependent artifact (Figure 1C; P < .001). Furthermore, donor treatment with a higher dose of IL-18 for a shorter
duration (5 µg/mouse/d for 7 days) also demonstrated a similar
reduction in acute GVHD mortality (50-day survival, 75% vs 0%;
P < .01).
We next evaluated the effect of IL-18 administration on splenic-cell
number and phenotype of donor mice. IL-18 increased the total number of
splenocytes and the percent of Gr-1+ cells, but did not
significantly alter the ratios of the CD4+,
CD8+, and B220+ cells (Table
1). IL-18 administration also did not
change splenic T-cell function as measured by several responses, such
as proliferation, IFN-
Pretreatment of donors with IL-18 reduces GVHD target organ damage We next evaluated the effect of IL-18 pretreatment of donors on 2 principal target organs of acute GVHD, the GI tract (small bowel and colon) and liver. Samples were taken from animals (n = 4/group) on day 7 after transplantation and scored in a coded fashion as described in "Materials and methods." Recipients of allogeneic BM transplants from IL-18-treated donors demonstrated significantly less damage than controls in the liver (Figure 2A-C) and the GI tract (Figure 2D-F).Serum levels of LPS and TNF-
Effects of IL-18 treatment of donors on T-cell function after BMT Induction of GVHD fundamentally depends on the donor T-cell response to host alloantigens.41 We previously demonstrated that administration of IL-18 to recipient mice early in BMT reduced acute GVHD by attenuating donor T-cell expansion.20 We next evaluated the effects of IL-18 treatment of donors by measuring T-cell proliferation in the spleen after BMT. Pretreatment of donors with IL-18 did not significantly alter donor T-cell expansion in the recipient spleens in the first 2 weeks after BMT (Figure 3C).We further evaluated the effects of IL-18 administration on cytokine
secretion of donor T cells after BMT. IL-18 can promote either
TH1 or TH2 polarization depending on the
context.2,7-10 Donor splenic T cells were harvested from
BM transplant recipients 7 days after transplantation and used as
responders in MLRs with host stimulator cells. IL-18-treated donor T
cells secreted significantly less IFN-
We next examined the effects of IL-18 pretreatment on cytolytic activity of donor cells to host antigens after BMT. Splenocytes harvested on day 14 after BMT from B6 recipients of both IL-18-treated and control donor cells (H-2d) showed strong lytic activity against host-type EL-4 (H-2b) targets (Figure 4D). Significant lysis of syngeneic, P815 (H-2d), targets was not observed, confirming allospecific cytotoxic activity. Thus IL-18 treatment of donors, in contrast to the posttransplantation MLR findings, did not alter the allospecific cytotoxic T-lymphocyte (CTL) response of donor cells after BMT. STAT6 signaling in donor T cells is required for attenuation of GVHD by IL-18 We hypothesized that reduction of acute GVHD observed after IL-18 treatment of donors was mediated through the T-cell component of the donor inoculum. To test this hypothesis we first performed in vivo mixing experiments. TCD BM from control-treated allogeneic donors was mixed with purified CD4+ (purity > 90%) cells from either IL-18- or control-treated mice. As shown in Figure 5A, recipients of CD4+ cells from IL-18-treated donors demonstrated a significantly improved survival compared with the controls (70% vs 0%; P < .01).
Because pretreatment of donors with IL-18 resulted in a decrease in
IFN- In order to confirm these surprising results and to elucidate the
molecular mechanism of the effect of IL-18 on donor T-cell polarization
and GVHD protection, we used donor mice that lacked STAT4 and
that had impaired TH1 responses.44 IL-18
treatment of BALB/c STAT4-deficient donor mice reduced GVHD in B6
recipients, confirming that STAT4 is not required for the protective
effect of IL-18 (P < .02; Figure 5C). Taken together
these 2 separate experimental models confirm each other and show that
the alteration in TH1 response as determined by secretion
of IFN- Pretreatment of wild-type donors with IL-18 also enhanced secretion of
IL-4 by donor T cells after BMT (Figure 4), and Yoshimoto et
al7 have recently demonstrated that STAT6 is critical for IL-18-mediated TH2 polarization. Therefore we next
determined whether STAT6 signaling, which is critical to
TH2 responses, is important for the protective effect of
IL-18 on GVHD.44 We injected IL-18 or the diluent into
BALB/c STAT6
Administration of IL-18 to donors preserves GVL activity after allogeneic BMT Maintenance of donor cytotoxic responses to host antigens (Figure 4D) suggested that treatment of donors with IL-18 might preserve GVL activity even though it decreased acute GVHD. To test this hypothesis, we added 2000 EL-4 (T-cell leukemia/lymphoma) cells (H-2b CD45.2+) to the BM inoculum injected into each mouse on the day of BMT. In vivo EL4 behaves like leukemia, resulting in massive infiltration and enlargement of various organs, such as the liver, spleen, and kidneys, and an injection of as few as 500 cells is uniformly fatal.45 Injection of 2000 EL-4 cells with the BM transplant inoculum caused 100% mortality in syngeneic B6 hosts by day +28 with evidence of tumor infiltrating into liver and spleen (Figure 7 and data not shown). Identically treated recipients of IL-18-treated allogeneic BM transplant donors showed 70% survival compared with 10% in controls (P < .01; Figure 7). Necropsy performed on all animals (either on the day of death or at the end of the observation period) showed no residual tumor by macroscopic examination of liver, spleen, and kidneys or by FACS analysis of the spleens (data not shown). Taken together, these data confirm that allogeneic BM transplants from IL-18-treated donors reduce acute GVHD severity while preserving a GVL effect.
Since its initial discovery in the sera of mice treated with Propionibacterium acnes and LPS, IL-18 has been shown to play a critical role in the immune modulation of several disease and biologic processes by inducing TH1 secretion.1,2 Yet mice deficient in IL-18 can eventually develop TH1 cells,46,47 and exogenous administration of IL-18 to naive mice can induce TH2 polarization.7,8 Recent studies have also revealed that although IL-18R expression is up-regulated in the presence of TH1 cytokines, naive T cells express low levels of IL-18R, and when cultured with IL-18 they produce TH2 cytokines.2,48 Furthermore IL-18 induces basophils and mast cells to produce IL-4 and IL-138 and also increases serum immunoglobulin E (IgE) levels in a dose-dependent manner.7,49 Although the reason for TH2 cytokine induction by IL-18 under some circumstances remains unexplained, this phenomenon is dependent on STAT6.7 More interestingly, IL-18 transgenic mice secrete higher than normal amounts of both TH1 and TH2 cytokines.11 Thus IL-18 has the remarkable capacity to induce TH2 cytokine secretion in addition to TH1 cytokines, depending on the immunologic and stimulatory context.2 The ability of IL-18 to modulate various diseases by inducing
TH1 cytokine production has been amply
demonstrated,2 but its significance in modulating disease
processes as a TH2-inducing cytokine is unclear. We made
the surprising observation that pretreatment of allogeneic donors with
IL-18 was associated with TH2 polarization of donor cells
and attenuated acute GVHD severity and mortality. Given that GVHD in
this system is mediated predominantly by CD4+ T
cells,18 mixing experiments of control-treated TCD BM and purified CD4+ cells from IL-18-treated donor mice
demonstrate that the effects of IL-18 on GVHD reduction are secondary
to its immunomodulatory effects on donor T cells rather than accessory
cells. Even though STAT6-independent TH2 induction
has been reported,50,51 our data demonstrate that
signaling via STAT6 is necessary for acute GVHD protection associated
with TH2 polarization induced by IL-18. Allogeneic BM
transplants from STAT4-deficient donors (which have increased
propensity toward TH2 polarization) or IL-4-deficient donors (which have increased propensity toward TH1
polarization) can cause, albeit delayed, mortality from GVHD compared
with STAT6-deficient or wild-type donors.21,25
Administration of IL-18 retained its protective effect against acute
GVHD mortality when given to the donors deficient in IFN- We have previously demonstrated that administration of IL-18 to BM
transplant hosts early after transplantation attenuates acute GVHD by
enhancing Fas-dependent apoptosis of donor T cells and that
donor-derived IFN- The role of TH1/TH2 polarization as it relates
to acute GVHD is controversial. Although the "cytokine storm"
amplified by the TH1 phenotype correlates with the
development of acute GVHD,12-14 early TH1
polarization of donor T cells by administration of cytokines, such as
IFN- The toxicity of GVHD is difficult to separate from the benefits of GVL
effect, the physiology of which is complex and likely involves multiple
antitumor mechanisms, including both cellular and inflammatory
effectors.60-62 Donor cytotoxic functions are critical to
the preservation of GVL effects after allogeneic BMT.63 IL-18 administration to donors did not change antihost cytotoxic responses in vitro despite TH2 polarization and preserved
GVL effects in vivo in this model as shown by improved leukemia-free survival after BMT. The induction of GVHD in this murine model is
mediated predominantly by CD4+ T cells,18
while GVL against EL-4, an MHC II In summary, our data demonstrate a novel role for IL-18 in reducing the
severity of acute GVHD via STAT6, independent of donor-derived IFN-
K.R.C. is a scholar of the National Marrow Donor Program (NMDP) Amy Strelzer-Manasevit Scholarship Program and a Fellow of the Robert Wood Johnson Minority Medical Faculty Development Program. J.L.M.F. is a Distinguished Clinical Scientist of the Doris Duke Foundation.
Submitted August 20, 2002; accepted October 30, 2002.
Prepublished online as Blood First Edition Paper, November 14, 2002; DOI 10.1182/blood-2002-08-2566.
Supported by National Institutes of Health (NIH) grant CA 49542 (J.L.M.F.), and a Young Investigator Award by the American Society of Clinical Oncology (P.R.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: James L. M. Ferrara, 6410 CCGC, University of Michigan Cancer Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0942; e-mail: ferrara{at}umich.edu.
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D. Hashimoto, S. Asakura, S. Miyake, T. Yamamura, L. Van Kaer, C. Liu, M. Tanimoto, and T. Teshima Stimulation of Host NKT Cells by Synthetic Glycolipid Regulates Acute Graft-versus-Host Disease by Inducing Th2 Polarization of Donor T Cells J. Immunol., January 1, 2005; 174(1): 551 - 556. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, n = 10) or diluent-treated (
, n = 10)
BALB/c donors, as in "Materials and methods." Syngeneic recipients
(
, n = 5) received similar transplants of cells from B6 donors.
Data from 1 of 2 similar experiments is shown. (A) Percent survival
after BMT (
, n = 4) allogeneic donors and of syngeneic donors
(
, n = 4) are shown (C) (*P < .05; control [
and 
). Error bars represent standard
error.
