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(Circulation. 1995;91:386-392.)
© 1995 American Heart Association, Inc.
Articles |
Experimental Graft Coronary Artery Disease in a Murine Heterotopic Cardiac Transplant Model
From the Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Correspondence to Akira Matsumori, MD, Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto, 606 Japan.
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Abstract |
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Background The development of immunosuppressive therapy has brought about a remarkable decrease in the risk of acute cardiac allograft rejection; however, the major cause of patient death or retransplantation after the first postoperative year is coronary artery disease (CAD) in the graft. The pathogenesis and management of CAD are still not clearly established.
Methods and Results To make an animal model of CAD, we performed primary vascularized heterotopic cardiac transplantation using mice. Inbred strains, sharing major histocompatibility antigens but differing in minor antigens, were selected. DBA/2 mice (H-2d) served as donors and B10.D2 mice (H-2d) as recipients. Viability of the cardiac grafts was assessed by abdominal palpation. Eight of twelve cardiac allografts (67%) survived for 10 weeks after operation without any immunosuppressive therapy. Allografts rejected within 4 weeks showed acute rejection histologically, whereas allografts surviving more than 4 weeks displayed intimal hyperplasia in the coronary arteries, together with interstitial and perivascular fibrosis. The severity of intimal thickening in the graft coronary artery was then assessed by point counting. In allografts surviving for 70 days, intima comprised approximately 42% of the graft arterial wall, whereas in DBA/2 and B10.D2 syngeneic grafts, it comprised approximately 13%. A significant difference in percentage was observed between the intima area of allografts and that of syngrafts (P<.01, ANOVA). Long-term oral administration of cyclosporine at a dose of 40 mg/kg per day decreased the intima area to 34% (P<.05 versus nontreated allografts, ANOVA); however, this dose did not affect the incidence of arterial lesions.
Conclusions The histopathological features of DBA/2 allografts surviving for 10 weeks in B10.D2 recipient mice mimicked those in human CAD. Using this animal model, the beneficial effect of low-dose cyclosporine therapy on CAD was demonstrated, although this effect seemed to be limited. This DBA/2-B10.D2 mouse heterotopic cardiac transplant model provides valuable results for future studies of the disease.
Key Words: coronary disease • transplantation • rejection
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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With the rapid development of immunosuppressive therapy, the prevention and management of acute rejection have improved remarkably in cardiac transplant patients. At present, however, obstructive graft coronary artery disease (CAD) has emerged as a leading cause of late graft failure.1 2 Gao et al3 4 reported that there was a 34.5% incidence of CAD in the first year, 59% the second year, and 91% at 5 years after transplantation. There are several characteristic features that distinguish this disease from the usual coronary atherosclerosis.2 5 For instance, CAD progresses rapidly over a period of several months to a few years, whereas lesions of the common coronary atherosclerosis grow slowly over a period of many years. Histologically, CAD usually shows concentric narrowing of the arterial lumen with the involvement of both epicardial and smaller intramuscular arteries in a diffuse distribution; however, ordinary atherosclerosis is associated with eccentric luminal narrowing of epicardial arteries in a focal distribution. In addition, CAD selectively involves the arteries of the engrafted organ, with no effect on the recipient's own native vessels. The pathogenesis of CAD has not been clearly established, although recent research has suggested that it is due to chronic rejection of the graft after immunosuppressive therapy.6 7 8 In animal experiments using dogs, rabbits, and rats, the occurrence of similar vascular lesions has been reported under long-term treatment with immunosuppressive drugs.9 10 11 12 In the present study, the attempt was made to define a mouse model of CAD that requires no immunosuppression, using strains that share major histocompatibility antigens (MHC antigens) but differ from each other in multiple minor antigens.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals
Adult male DBA/2 (H-2d) and B10.D2 (H-2d) mice, 7 to 9 weeks old, were obtained from the Shizuoka (Japan) Agricultural Cooperation Association. These mice were housed in stainless steel cages with controlled light/dark cycles and provided with food and water ad libitum.
Transplantation
DBA/2 mice served as donors and B10.D2 mice
as recipients. These
two strains are compatible with each other in MHC antigens but differ
in minor histocompatible antigens (non-MHC antigens). DBA/2 and B10.D2
syngrafts were used as controls. Heterotopic cardiac transplantation
was performed using a modification of the method described by Corry et
al.13 In brief, donors and recipients were anesthetized
with 4% chloral hydrate at 0.01 mL/g body wt ip before surgery. Donor
hearts were perfused with chilled, heparinized saline via the inferior
vena cava and harvested after ligation of the vena cava and pulmonary
veins. The aorta and pulmonary artery of donor hearts were anastomosed
to the abdominal aorta and inferior vena cava of recipients using a
microsurgical technique. Ischemic time was routinely 45 to 60 minutes,
with a success rate of approximately 80%. Technical failures within
the first 72 hours were excluded from the experiment. The viability of
the cardiac allograft was assessed by daily abdominal palpation and
confirmed by ECGs. The day of rejection was defined as the day of
cessation of heartbeat.
Histopathological Examination
Mice were killed on the day of
rejection or, if their grafts
continued beating without rejection, 70 days after transplantation.
Allografts were sectioned transversely at the maximal circumference of
the ventricle and fixed in 10% formalin. The graft tissues were
embedded in paraffin and then stained with hematoxylin and eosin,
Masson's trichrome, and elastic van Gieson. Histological findings were
scored under light microscopy to determine the severity of rejection
and the degree of arterial intimal thickening, using modified scoring
methods described previously.11 14 Grading systems
are
summarized in Tables 1
and 2.
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Morphometry of Neointima
In a previous report, the intimal
cross-sectional areas of
medium- to large-sized graft coronary arteries were estimated by point
counting.15 Using an eyepiece grid with 100 points, the
number of points lying over the intima or media was counted and the
areas of the respective parts were calculated by a formula of
0.01xnumber of pointsxgrid area. Intima area (%) was defined as
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Treatment With Cyclosporine
To investigate the effect of
cyclosporine (CyA) on the graft
arterial lesion, long-term oral CyA administration was performed using
this animal model. CyA in a cremophor vehicle (Sandoz) was diluted in
olive oil, and 0.12 mL was administered to each mouse. The treatment
was carried out at a dose of 40 mg/kg per day, starting on the day of
transplant and continuing for 70 days. This dose seems to be much
higher than the dose used in humans; however, on the basis of body
surface area, a given dose in mice is comparable to a dose that is
about 12 times lower in humans.16 Thus, a dose of 40 mg/kg
per day in mice is equivalent to a dose of 3.3 mg/kg per day in humans,
which is within the range of long-term maintenance
doses.17
Statistical Analysis
The Mann-Whitney U test was
used to compare the
allograft survival time or the histological grading scores, since these
data were nonparametrically distributed. Morphometrical results for the
intima area (%) were compared using one-way ANOVA. Data are expressed
as mean±SD.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Graft Survival
The percent survival of DBA/2 transplanted hearts in B10.D2 recipient mice is shown in Fig 1
. In this MHC-compatible
combination, 8 of 12 cardiac allografts (67%) survived for 70 days
after transplant without any immunosuppressive treatment. In the
recipients treated with CyA at 40 mg/kg per day, 10 of 12 allografts
(83%) survived for 70 days. Although CyA appeared to enhance the
allograft survival at this dose, it was not statistically significant.
This may be partly due to the fact that the long-term allograft
survival rate in the nontreated mice was considerably high. Fig
2 shows serial ECGs of a nontreated cardiac allograft
that survived for 70 days. ECGs were taken 1 week, 4 weeks, and 10
weeks after transplantation. QRS complexes of the graft are indicated
by arrows.
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Histopathological Findings
The pathological features of
cardiac allografts rejected within 4
weeks included interstitial edema, hemorrhage, myocardial necrosis, and
severe mononuclear cell infiltration with diffuse fibrosis, suggesting
acute rejection. In these grafts, coronary arteries showed marked
mononuclear cell accumulation in the intima with occasional occlusion
of the lumen (Fig 3A). The grafts that survived longer
than 4 weeks displayed mild to moderate cellular infiltration and
interstitial fibrosis with concentric intimal thickening (Fig
3B).
Similar lesions were observed in the CyA-treated allografts surviving
for 70 days; however, the severity of fibrosis and intimal thickening
seemed less prominent than in the nontreated allografts (Fig
3C). DBA/2
syngrafts (Fig 3D) or B10.D2 syngrafts (Fig 3E)
harvested on day 70
after transplant showed only slight perivascular fibrosis and trace
cellular infiltration with minimal intimal thickening. Table 3
summarizes the results of histological grading based
on the nontreated allografts surviving for more than 4 weeks, since
arterial lesions similar to human graft arteriosclerosis were observed
in the long-term surviving allografts. Fig 4 shows
representative photographs of each grade of intimal thickening
in graft coronary arteries. The data in Table 4 are
histological scores based on the CyA-treated allografts compared with
those on the nontreated allografts. According to these data, the
severity of graft arterial lesion was diminished by low-dose CyA
treatment (P<.05 by the Mann-Whitney U test);
however, the incidence of diseased arteries was not significantly
affected by the treatment.
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Morphometric Examination
Intimal thickening in cardiac grafts
surviving for 70 days was
confirmed by point counting (Fig 5). Intima of coronary
arteries in the nontreated allografts comprised 42.2±4.6%
(mean±SD,
n=8) of the arterial wall, whereas that of the DBA/2 or B10.D2
syngrafts comprised 13.1±2.3% (n=7) or 12.9±1.7%
(n=8). There was a
significant difference in percentage between the intima area of the
nontreated allografts and that of the DBA/2 or B10.D2 syngrafts
(P<.01 by ANOVA); however, no significant difference was
noted between the two kinds of syngrafts. Percent intima area of the
CyA-treated allografts was 33.5±7.6% (n=10), which was
significantly
lower than that of the nontreated allografts (P<.05 by
ANOVA).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present study, a mouse model of CAD was developed using a method of primary vascularized heterotopic cardiac transplantation. The arterial lesions developed in this DBA/2-B10.D2 model seem to have similarities with human CAD and to vessel lesions described in previous animal experiments.2 9 10 11 Intimal thickening of the affected graft coronary arteries in this model showed concentric narrowing of the lumen in a patchy distribution; however, no typical atheromatous plaque was observed. Assessment of graft arterial lesion by scoring was done by combining small, medium, and large vessels as described in a previous study,11 since no apparent differences were noted in the incidence and severity of vessel disease among arteries of different sizes. However, because of the difficulty in handling small vessels, morphometrical analysis by point counting was performed using medium- to large-sized arteries. Other histological features accompanying the arterial lesion included perivascular and interstitial fibrosis with mild to moderate mononuclear cell infiltration.
As shown in Table 3
, there was no apparent correlation
between the
severity of rejection and the degree of vessel disease. The endothelium
appeared intact in every section of the diseased artery under a light
microscope, suggesting that the thickened intima consisted mainly of
subendothelial cells. This observation was in accordance with previous
immunohistochemical studies showing that cells comprising the
neointima were mainly smooth muscle cells, macrophages, and
T-lymphocytes.2 15 18 19 The
pathogenetic roles of these
cells in CAD have been reviewed.20 There is a general
consensus that chronic repetitive arterial injuries by immunological
mechanisms induce local inflammation, followed by the release of
various cytokines and growth factors from activated T cells and
macrophages, and then smooth muscle cell proliferation occurs. This
hypothesis resembles the "response-to-injury" theory explaining
the pathogenesis of ordinary native atherosclerosis.21
Salomon et al18 reported increased endothelial class II
MHC antigen expression in human CAD and hypothesized that persistent
T-cell stimulation by class II MHC-positive endothelium might initiate
local inflammation. Recent studies have focused on the pathogenetic
roles of a variety of mediator molecules of
inflammation.22 23 Gregory et al15
demonstrated that long-term surviving rat allograft vessels had diffuse
expressions of mRNAs for platelet-derived growth factor-
(PDGF-),
basic fibroblast growth factor (bFGF), transforming growth factor-ß
(TGF-ß), interleukin-1 (IL-1), interleukin-2 (IL-2), and
interferon-
(IFN-). Such growth factors and cytokines as PDGF,
bFGF, IL-1, and tumor necrosis factor have been shown to stimulate
smooth muscle cell proliferation and are regarded as important factors
in the pathogenesis of both hyperplastic neointima and
common atherosclerotic
plaque.21 24 25 26 27
In addition, the role of thrombus in the progression of CAD has been discussed by several researchers. Hunt et al28 demonstrated that human heart transplant recipients had increased levels of fibrinogen, factor VII, and von Willebrand factor antigen and speculated that a prothrombotic state in recipients might induce fibrin deposition in the graft arterial lesion. Wissler et al29 reported that the native human advanced concentric atherosclerosis was much more prone to thrombosis with higher circulating immune complex concentration in the sera than the more usual eccentric atheroma. These researchers hypothesized that the immune complex might play a role in provoking endothelial injury and initiating the atherosclerotic process, which includes formation of thrombus, in both the pathogeneses of advanced atherosclerosis and transplant-related arteritis. An increase in the incidence of anti-MHC antibodies and soluble donor antigens, observed in the sera of human recipients who had chronically rejected cardiac allografts, may support this hypothesis.30 At present, thrombus seems to be regarded as a secondary factor that accompanies immunological arterial injury and exaggerates CAD.
Although there have been numerous immunobiological findings concerning CAD, as mentioned above, the actual pathogenesis still remains poorly understood. To further investigate the pathogenesis and management of CAD, a more reliable animal model must be defined. There have been a number of animal models of the disease proposed using dogs, rabbits, and rats; however, most of these required treatment with immunosuppressive drugs to prevent acute rejection.9 10 11 12 Because immunosuppressive drugs have been known to be associated with the acceleration of atherosclerosis,31 32 the development of an animal model that requires no immunosuppression would be preferable. Cramer et al14 succeeded in producing arterial lesions similar to CAD without immunosuppression by using inbred rat strains that were MHC compatible but non–MHC incompatible with each other. Adams et al33 defined another rat cardiac transplant model using MHC-compatible Lewis and F-344 strains; however, 70% of the total allografts were rejected within 10 weeks when no immunosuppression was used. To define a more favorable animal model, we attempted to use inbred mice, since there is a wider variety of commercially available strains of mice than of rats. As previous rat models have shown difficulty in getting long-term surviving allografts across MHC barriers without immunosuppression, a combination of MHC-compatible strains was selected for the models in this study. In this mouse model, donor DBA/2 and recipient B10.D2 mice shared identical class I and class II MHC alloantigens and differed in multiple non-MHC antigens.34 An advantage of this mouse model is that the rate of allograft survival reached 67% at posttransplant day 70 without any immunosuppressive treatment, demonstrating its usefulness for researching the pathogenetic process of CAD under a drug-free condition. The efficacy of various new drugs might be assessed more clearly using this model, since vascular toxicity of such a drug as cyclosporine or prednisolone at their initial high induction doses can be avoided. This advantage, on the other hand, seems to make it possible to assess the net effect of conventional immunosuppressive drugs at low maintenance doses without influences of high initial induction doses.
In the present study, the effect of low-dose CyA maintenance therapy on the graft arterial lesion was investigated, since CAD has been known to emerge as a major problem during the posttransplant maintenance period. The results showed that the therapy decreased the severity of the graft arterial lesion; however, it did not affect the incidence of the disease. These results may suggest that long-term CyA therapy at a low maintenance dose is itself not an aggravating factor in CAD; rather, it is partially effective in delaying the speed at which CAD evolves. However, to develop better management of CAD, further study, including various combination therapies, should be performed using this mouse model.
Recently, Russell et al35 reported new mouse models of CAD using B10.A-B10.BR, bm12-C57BL/6, and 129-C57BL/6 combinations. They succeeded in producing similar graft arterial lesions as rat models; however, in their models, interrelation of the arterial lesion with other pathological features, for instance, fibrosis or cellular infiltration, appeared to be somewhat obscure compared with this model. This interrelation should be discussed more clearly in their article, since allograft arteritis, presenting mononuclear cell accumulation in the intima with endothelial disruption, has been known to be associated with acute rejection rather than chronic rejection.33
Conclusions
A new mouse model of CAD was defined, which holds
promise for the
future studies of the disease.
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Acknowledgments |
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This work was supported by a research grant from the Ministry of Health and Welfare of Japan and a grant-in-aid for general scientific research from the Ministry of Education, Science, and Culture of Japan. We would like to thank J. Shelby and H. Kikuchi for technical instructions regarding the murine cardiac transplant procedure.
Received January 21, 1994; accepted August 22, 1994.
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