(Circulation. 2000;101:1034.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Attenuated Cardiac Allograft Vasculopathy in Mice With Targeted Deletion of the Transcription Factor STAT4
From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., S.G., M.E.R.); Brigham and Women’s Hospital (M.E.R.); and Harvard Medical School (M.E.R.), Boston, Mass.
Correspondence to Jörg Koglin, MD, Medizinische Klinik I, Universitätsklinikum Grosshadern, Marchioninistraße 15, 81377 Munich, Germany. E-mail joerg.koglin{at}med1.med.uni-muenchen.de
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Abstract |
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Background—To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients in our mouse cardiac transplant model of chronic rejection.
Methods and Results—At day 55 after transplantation, cardiac
grafts placed into STAT4 -/- (n=10) had reduced frequency (24±2%)
and severity (9±4%) of vascular occlusion compared with wild-type
controls (n=7, frequency 70±12% [P<0.001], severity
25±6% [P<0.05]). This decrease was associated with
reduced intragraft expression (32P RT-PCR and
immunohistochemistry) of the Th1 signature cytokines
interferon-
(P<0.001) and interleukin (IL)-2
(P<0.001). Furthermore, cardiac grafts in STAT4 -/-
had fewer infiltrating CD45+ mononuclear cells (99±27
cells/mm3 compared with 551±168 cells/mm3 in
wild-type controls [P<0.05]) and reduced expression
of P-selectin (P<0.001) and E-selectin
(P<0.01) ligand, recently shown to regulate Th1 cell
recruitment. In contrast, in grafts placed into STAT6 -/- (n=11), the
development of cardiac allograft vasculopathy (frequency 62±8%,
severity 28±6%) and Th2 cytokine profiles (IL-4, IL-10) were
comparable to those in wild-type controls.
Conclusions—Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1-specific lymphocyte recruitment, activation, and effector functions.
Key Words: lymphocytes • transplantation • immune system • cytokines • cell adhesion molecules
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Introduction |
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After solid organ transplantation, chronic rejection with the development of cardiac allograft vasculopathy is the major impediment to long-term graft survival. Experimental models have helped us to begin to understand the pathogenesis of this form of vascular occlusion. The regulation of the pathogenesis has been hypothesized as a coordinate and interactive event involving various inflammatory cell types. In addition to B lymphocytes and macrophages, T lymphocytes have been identified to play a crucial role.1 2 3 On activation, T lymphocytes differentiate into Th1 and Th2 subsets, characterized by differences in their cytokine repertoire,4 5 adhesion mechanisms,6 7 effector function profile, and character of local immune response.4 5 Transcription factors have been identified that regulate these Th1 and Th2 cell differentiation programs in a proximal manner. The signal transducer and activator of transcription (STAT) protein family includes STAT4, which controls interleukin (IL)-12–mediated Th1 differentiation.8 9 Mice with targeted deletion of STAT4 signaling show impaired differentiation of Th1 cells in response to either IL-12 or Listeria monocytogenes,8 9 whereas targeted deletion of STAT6 interrupts Th2 differentiation.10 11 12 Lymphocytes from STAT6-knockout mice have defective IL-4–mediated Th2 differentiation and proliferation.10 11 12 These mice provide the opportunity to examine the role of transcription factor pathways regulating the Th1 or Th2 pathway.
To study the impact of these transcription factor programs on graft vasculopathy, we used STAT4- and STAT6-knockout mice as recipients in our heterotopic cardiac transplant model of chronic rejection.2 13 14 We assessed the effect of recipient STAT4 or STAT6 deficiency on intragraft cytokine profiles, arteriosclerotic lesion development, Th1/Th2-specific cytoadhesion signaling, and leukocyte recruitment.
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Methods |
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Mice
As heart donors, inbred male CBA/CaJ (H-2k) mice 6 to 8 weeks old were used. As recipients, male C57BL/6Jx129Sv (H-2b) mice with targeted deletion of STAT4 (STAT4 -/-, n=10)9 or STAT6 (STAT6 -/-, n=11)11 were compared with C57BL/6Jx129Sv wild-type controls (n=7, hereafter referred to as wild-type controls). The genotype of the knockout mice was confirmed by polymerase chain reaction (PCR) using genomic mouse-tail DNA. The knockout mice were all backcrossed 6 times to C57BL/6J (F6). F2 hybrids were used as physiological wild-type controls. Because these F2 mice provide only an approximate genetic match, we had to confirm that potential differences were not due to a more dominant 129Sv influence in this group. Therefore, inbred wild-type mice on a pure C57BL/6J background (n=8, hereafter referred to as inbred controls) were used as a second comparative control group. STAT4- and STAT6-deficient mice were generously supplied by Dr James N. Ihle (St Jude Children’s Research Hospital, Memphis, Tenn). CBA/CaJ (stock No. 000654), C57BL/6Jx129 Sv (stock No. 101045), and C57BL/6J mice (stock No. 000664) were obtained from Jackson Laboratory (Bar Harbor, Me).
Heterotopic Mouse Transplant Model of Chronic Rejection
Vascularized, heterotopic abdominal transplantation of the donor
heart was performed, monitored, and harvested at day 55 as previously
described.2 13 14 15 16 Immunosuppressive therapy to prevent
acute parenchymal rejection and produce grafts undergoing chronic
rejection consisted of anti-CD4 and anti-CD8 (GK1.5 and 2.43, 2 mg IP
on days 1 to 4 and then weekly to day 28).13 14
Cytokine Expression
Relative gene transcript levels were measured by reverse
transcription (RT)-PCR from graft cDNA panels as published
previously.2 13 14 15 16 In this model, in which the small size
of allograft tissue is limiting, 32P RT-PCR
offers the advantage of studying a large number of factors in replicate
in a semiquantitative manner. PCR primers were designed with MacVector
5.0 (Oxford Molecular Scientific), and specificity of the primer
sequence was confirmed by basic local alignment search tool (BLAST)
analysis. For each individual primer pair, specific annealing
temperature and cycle number were optimized by serial annealing
studies, PCR cycle studies, and cDNA dilution studies. The logarithmic
ranges of amplification were established as previously
described17 to ensure that the amplified PCR product
reflects the original levels of transcription. Primer sequences,
sequence accession numbers, optimized annealing temperatures, and cycle
numbers are listed in the
Table
.
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Triplicate samples were amplified with AmpliTaq Gold DNA polymerase (Perkin-Elmer). [32P]dCTP (150 000 cpm per reaction) was included to quantify the amplified product. Incorporated [32P]dCTP in amplified products from dried agarose gels was measured by volume integration (Molecular Dynamics). Corrected levels of the specific transcript were derived by dividing the amplified product value by the mean value for the control gene G3PDH in the respective sample and reported as mean±SEM for all grafts in each recipient group.
To confirm the presence of cytokine gene products shown to
be regulated at the transcript level, we performed
immunostaining in frozen sections from 4
representative grafts from each recipient group as
published previously.15 The primary antibodies used were
anti–interferon (IFN)- (clone R4-6A2, 1:100, Pharmingen),
anti–IL-2 (clone S4B6, 1:100, Pharmingen), and anti–IL-10 (clone
JES5-16E3, 1:100, Pharmingen).
Morphometric Vessel Analysis
Vascular analysis was performed in paraffin sections
stained with Verhoeff’s elastin as previously
described.14 Microscopic images of all elastin-positive
vessel cross sections were used to trace the lumen and the internal
elastic lamina (NIH Image 1.6) and derive the percentage of luminal
occlusion.14 Values were calculated as the mean from all
captured vessels per heart and reported as mean±SEM for all grafts in
each recipient group.
Leukocyte Infiltration
Immunostaining for the leukocyte common antigen
CD45 (clone 30F11.1, 1:1000, 1 hour at 37°C, Pharmingen) was
performed in paraffin sections from 5 representative
grafts in each group. Microscopic images over the entire sagittal cross
section of all grafts were captured with NIH Image 1.6 (NIH). The
number of CD45-positive cells/mm2 was counted and
reported as mean±SEM for all grafts in each group.
Statistics
For comparisons between the average measurements of 2 groups,
unpaired t tests were used. For comparison between >2
groups, ANOVA and the Bonferroni-Dunn procedure were used for post hoc
testing. A probability value <0.05 was considered
significant.
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Results |
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Intragraft Cytokine Activation
Cardiac grafts placed into STAT4 -/- recipients had reduced expression of Th1 cytokines. As shown in Figure 1A
, corrected transcript levels for
IFN- (0.03±0.01 relative units [RU]) and IL-2 (0.06±0.01
RU) were significantly lower than those in grafts from wild-type
control recipients (IFN- 0.50±0.12 RU, P<0.001; IL-2
0.60±0.11 RU, P<0.001). In grafts from wild-type control
recipients, IFN- antigen typically localized within the thin
cytoplasmic rim of mononuclear cells (Figure 1B). These positive
cells were diffusely distributed throughout the perivascular spaces and
the myocardium. In contrast, grafts from STAT4 -/- had
occasional but rare IFN-–positive cells. IL-2 antigen also
localized to mononuclear cells (Figure 1C). IL-2 was expressed
in disseminated clusters of mononuclear cells throughout the entire
graft cross section. In contrast, grafts from STAT4 -/- only had far
fewer IL-2–positive mononuclear cells. The deficiency in Th1
cytokines was associated with modest but significant reductions
in the Th2 cytokines IL-4 (0.02±0.01 RU, P<0.05)
and IL-10 (0.10±0.02 RU, P<0.05).
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In contrast, grafts placed into STAT6 -/- recipients had expression
levels of Th2 cytokines comparable to those of wild-type
controls. Corrected transcript levels for IL-4 were expressed at
baseline levels in both groups (STAT6 -/- 0.09±0.02 RU, controls
0.07±0.02 RU). IL-10 transcript levels were unchanged in grafts from
STAT6 -/- (0.35±0.07 RU) compared with control recipients
(0.29±0.07 RU). The presence of the IL-10 gene product was
confirmed by immunostaining in grafts from both groups.
In both STAT6 -/- and wild-type control recipients, IL-10 antigen was
present in the thin cytoplasmic rim of mononuclear cells, which
were distributed throughout the perivascular myocardium
(data not shown). Transcript levels for the Th1 cytokines
IFN- (0.42±0.16 RU) and IL-2 (0.57±0.11 RU) were not significantly
changed.
Hence, transplantation into STAT4-deficient recipients ablated the Th1 response compared with wild-type controls, whereas STAT6-deficient recipients had a profile of signature cytokines resembling that of wild-type controls.
Graft Vasculopathy
As shown in Figure 2, grafts in
STAT4 -/- recipients had less prominent vascular thickening than
those in wild-type controls. Grafts from wild-type controls and
STAT6-deficient recipients had circumferential thickening of the
vessels with perivascular mononuclear cell infiltration. The expanded
neointima was composed of cells with features of vascular
smooth muscle cells and mononuclear cells. In marked contrast, grafts
from STAT4-deficient recipients had only a small amount of
neointimal formation, with markedly less perivascular
mononuclear cell infiltration. Because of the small amount of
neointimal formation in the majority of the vessels, the
composition of the expanded neointima was difficult to
discern.
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Quantitative analysis of all elastin-positive vessels showed that grafts placed into STAT4 -/- recipients had significant reductions in frequency (24±2% of all vessels [n=113] affected) and severity (9±4% mean luminal occlusion) of cardiac allograft vasculopathy compared with those placed into wild-type controls (70±12% of all vessels [n=56], 25±6% mean luminal occlusion). In contrast, in grafts placed into STAT6 -/- recipients, the development of cardiac allograft vasculopathy was comparable to that in wild-type controls (62±8% of all vessels affected, with a mean luminal occlusion of 28±6%). Frequency and severity of allograft vasculopathy were comparable in grafts placed into C57BL/6Jx129Sv wild-type controls and those placed into C57BL/6J inbred controls (61±10% of all vessels [n=101], 29±7% mean luminal occlusion). This clearly argues that the significant reduction in vascular occlusion in grafts from STAT4 -/- recipients can be attributed to the deletion of the transcription factors rather than potential differences in the genetic background. Taken together, STAT4, but not STAT6, plays an essential role in the development of cardiac allograft vasculopathy.
Mononuclear Cell Infiltration
Grafts in STAT4-deficient recipients had fewer infiltrating
CD45+ mononuclear cells, as shown in the
representative photographs in Figures 3A and 3C. Analysis of 410
high-power fields showed that grafts placed into STAT4 -/- recipients
had significantly lower numbers of graft-infiltrating CD45-positive
cells (99±27 cells/mm2) compared with wild-type
controls (551±168 cells/mm2, P<0.05;
Figure 3B).
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For quantification of CD4, CD8, and Mac-1 expression to estimate the contribution of CD4- and CD8-positive lymphocytes and macrophages, we elected to measure corrected transcript levels because the resolution of these cell surface markers after immunostaining of frozen sections is not sufficient to perform quantification. Grafts placed into STAT4 -/- recipients had significantly lower transcript levels for CD4 (0.24±0.04 RU) and CD8 (0.10±0.04 RU) than those placed into wild-type controls (CD4 0.85±0.12 RU, P<0.001; CD8 0.68±0.24 RU, P<0.05). There was no significant difference in corrected transcript levels for Mac-1 (STAT4 -/- 0.35±0.02 RU, wild-type controls 0.49±0.09 RU). Taken together, there is reduced mononuclear cell infiltration in grafts from STAT4-deficient recipients, which may be related, in part, to differential recruitment of CD4- and CD8-positive lymphocytes.
Cytoadhesion Pattern
Because recruitment of Th1 lymphocytes has been shown to be
regulated by P- and E-selectin cytoadhesion pathways,6 we
measured intragraft transcript levels (Figure 4). Corrected transcript levels for P-
and E-selectin, expressed by the donor-derived
endothelium, were comparable in grafts from STAT4 -/-
(P-selectin 0.37±0.02 RU, E-selectin 0.20±0.05 RU) and wild-type
control recipients (P-selectin 0.35±0.04 RU, E-selectin 0.33±0.03
RU). In contrast, transcript levels for P- and E-selectin
glycoprotein ligands (PSGL and ESGL), expressed by
recipient-derived lymphocytes, were significantly lower in grafts
placed into STAT4 -/- recipients (PSGL 0.14±0.02 RU, ESGL 0.30±0.03
RU) than in those placed into wild-type controls (PSGL 0.62±0.11 RU,
P<0.001; ESGL 0.71±0.17 RU, P<0.01). Hence,
STAT4-deficient recipients had reduced expression of
glycoprotein ligands, which are responsible for selective
tissue recruitment of Th1 cells.
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Discussion |
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Here, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. Cardiac allografts placed into immunosuppressed recipient mice with targeted deletion of STAT4 had marked reductions in frequency and severity of vascular occlusion. The decrease in intimal thickening in the STAT4-deficient microenvironment was associated with low intragraft expression of Th1 signature cytokines (IFN-
and IL-2),
reduced expression of Th1-specific cytoadhesion markers (PSGL and
ESGL), and decreased infiltration of CD45-positive cells within
the graft. Hence, when present, STAT4-mediated pathways contribute
to the alloimmune response that culminates in cardiac allograft
vasculopathy by directing Th1-specific effector functions.
STAT4-Mediated Th1 Forces Promote Cardiac Allograft
Vasculopathy
This study is the first to exploit mice with targeted deletion of
STAT4 to characterize the role of Th1 cytokine programs in
vivo. As opposed to single cytokine knockouts used in the past,
this approach offers the advantage of presumably disrupting an entire
differentiation program, resulting in deficiencies of multiple
cytokines and effector pathways. In these mice, our results
indicate that Th1-type immune activation may be an essential driving
force in the development of chronic rejection.
These findings complement previous studies showing reduced vascular
occlusion if mice with targeted deletion of the Th1 cytokine
IFN- are used as recipients in immunosuppressed models producing
chronic graft survival.13 18 However, depending on the
immunosuppressive program, recipient IFN- deficiency may also
accelerate late forms of parenchymal rejection,15 19 which
supports the argument that IFN- may be protective. For the Th2
cytokine IL-4, targeted deletion of recipient sources did not
alter survival times or development of vascular thickening in mouse
transplant models with various immunosuppressive
programs.15 16 20
Recently, migration studies have shown that Th1 cells are selectively
recruited into inflamed sites in Th1- but not in Th2-dominated disease
models by distinct cytoadhesion pathways.6 21 Only Th1
cells accumulated in sites of a delayed-type hypersensitivity reaction
of the skin or arthritic joints. Th1 cell migration was blocked by
antibodies against P- and E-selectin. Hence, STAT4-mediated pathways,
when present, might upregulate surface expression of ESGL and PSGL
(and potentially other adhesion mechanisms), thereby controlling
infiltration of activated Th1 cells. In response to alloimmune
stimulation, these graft-infiltrating cells would express Th1-type
cytokines, initiating downstream effects promoting
arteriosclerotic thickening. IFN-, for example,
has been shown to promote cardiac allograft vasculopathy through
increased expansion of vascular smooth muscle cells within the
neointima.13 Alternatively, STAT4-mediated
expression of Th1 cytokines might also amplify the
arteriosclerotic cascade by inducing expression of
ESGL and PSGL in an autocrine fashion. Studies in IFN- knockout
recipients have shown reduced expression of leukocyte adhesion
molecules associated with attenuated lesion development.18
In the present study design, we were not able to determine whether
decreased PSGL and ESGL expression causes the reduced Th1 cell
infiltration or whether it just reflects the reduction in
glycoprotein-bearing Th1 cells. At this point, the
transcriptional control of the expression of the respective
glycoprotein ligands in T cells has not yet been studied.
Future studies will help to dissect the interrelated roles of
cytokines and cytoadhesion molecules contributing to
Th1-mediated effector functions.
Cardiac Allograft Vasculopathy Develops Independently of
STAT6
Evidence that STAT6 is essential for Th2 responses has been
established in Th2-dominated disease models. Lymphocytes from
STAT6-deficient mice infected with Nippostrongylus
brasiliensis produced profoundly reduced IgE and IgG1
responses12 and failed to expel the
parasite.22 STAT6-deficient mice infected with
Schistosoma mansoni developed smaller hepatic granulomas
associated with reduced amounts of Th2
cytokines.23 Finally, STAT6-deficient mice
showed markedly reduced airway reactivity, peribronchial inflammation,
and eosinophilia in allergen-induced airway models.24 25
Hence, targeted deletion of STAT6 proved to be sufficient to disrupt
Th2 responses in these experimental model systems.
In contrast, in our model system, disruption of recipient sources of
STAT6 did not result in any phenotypic changes in the graft vasculature
or cytokine activation. As described above, IL-4 transcripts
were hard to detect in grafts placed into both wild-type and
STAT6-deficient recipients. Graft expression of IL-10, IFN-, and
IL-2 was comparable in grafts from both groups. One interpretation is
that cardiac allograft vasculopathy in chronically rejecting hearts
develops independently of STAT6-mediated signaling pathways. This would
extend previous studies in IL-4 knockout recipients showing no
differences in parenchymal and vascular outcome.15 16 20
Taken together, these findings argue against a role for Th2 forces in
promoting chronic rejection.
Conclusions
We used recipient mice with targeted gene deletion to demonstrate
a significant role for STAT4-mediated Th1 forces in the pathogenesis of
cardiac allograft vasculopathy. When present, STAT4 might promote
the development of cardiac allograft vasculopathy by directing P- and
E-selectin–mediated recruitment of activated Th1 cells into
the graft. This would result in increased inflammatory activation and
graft-specific secretion of the proarteriosclerotic
Th1 effector cytokines IFN- and IL-2. In the future, this
model system can be used to identify the downstream molecular pathways
regulated by Th1 forces that contribute to cardiac allograft
vasculopathy.
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Acknowledgments |
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This work was supported by the NIH (HL-59578). Dr Koglin was supported by grants from the Deutsche Forschungsgemeinschaft, Bonn, Germany, and from the Deutsche Transplantationsgesellschaft. We are indebted to Dr James N. Ihle (St Jude Children’s Research Hospital, Memphis, Tenn) for providing STAT4- and STAT6-knockout mice.
Received June 28, 1999; revision received August 23, 1999; accepted September 9, 1999.
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