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Cardiac allograft pathology in rhesus monkeys.

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Cardiac Allograft Pathology in Rhesus Monkeys
C. F. HOLLANDER
Institute f o r Experimental Gerontology T N O , Rijswijk-ZH,
T h e Netherlands
ABSTRACT
Orthotopic, allogeneic heart transplantations were performed in
26 randomly selected rhesus monkeys to study the effect of immunosuppressive
treatment on survival and cardiac morphology. The histological picture of the
acute and chronically rejected hearts was similar to that described for acute
and chronic cardiac allograft rejection in man. As seems to be the case in man,
an obliterative arteritis of the coronary arteries appears to be the limiting factor
in cardiac allograft survival in the rhesus monkey. Immunosuppressive treatment
with either Imuran and ALS or Imuran, ALS, and Prednisone could not prevent
the occurrence of obliterative arteritis of the coronary arteries. Contrary to the
observation in man, no atherosclerotic changes were found in the affected parts
of the coronary arteries or in the non-diseased parts.
Orthotopic, allogeneic heart transplantations were performed in 26 randomly
selected rhesus monkeys of about 3 kg to
study the effect of immunosuppressive
treatment on survival and cardiac morphology. In this study special attention was
given to lesions of the coronary arteries because in m a n obliterative arteritis seems
to emerge as the limiting factor in cardiac
allograft survival (Bieber et al., '70;
Kennedy et al., '71).
MATERIALS AND METHODS
The well-known superficial immersion
cooling technique without extracorporeal
circulation was adapted for these transplantations. Grafting of the heart was performed at a n esophageal temperature of
24°C. The circulation was arrested for
about 30 minutes. The interarterial septum, the right and left atrium, the pulmonary artery, and the aorta were joined
by continuous suture.
The following experimental groups were
established :
Group 1. Five animals receiving no immunosuppressive treatment.
Group 2. Eleven animals treated postoperatively with Imuran i.m., 4 mg/kg/
day for 36 days, combined with antilymphocyte serum (ALS) s . ~ . 2
, ml/kg/
day for 60 days.
Group 3 . Ten animals treated post-operatively with: ALS as in group 2; Imuran
AM. 3.
PHYS.
ANTHROP., 38: 431-434.
i m . , 4 mg/kg/day for 28 days, followed by
1 mg/kg/day until death; and from day
20, Prednisone i.m., 2 mg/kg/day, also
until death.
A complete autopsy was performed on
all animals, which were either killed when
moribund or were found dead. At the time
of autopsy, nearly all monkeys showed
gross morphological signs of severe myocardial insufficiency. Tissues submitted
for histological examination were fixed in
10% buffered formalin, embedded in paraffin, and routinely stained with Hematoxylin-phloxin-saffron. Special stains were
made when necessary.
RESULTS
The mean survival time of the five
monkeys receiving n o immunosupressive
treatment (Group 1 ) was 13.2 days with a
range of 6 to 27 days. At autopsy, the
hearts of these animals were dark red,
edematous, and enlarged. Histological examination showed severe congestion of
small vessels in the myocardium with
platelet thrombi and focal rupture of
the wall. Extensive hemorrhages and degeneration of myocardial muscle fibers
were seen. Focal signs of arteritis were
seen only in the longest survivors and were
restricted to the main branches of the
coronary artery. They consisted of endothelial swelling, slight intimal proliferation, infiltration with poly- and mononu431
432
C. F. HOLLANDER
clear cells, and fibrinoid material adhering
closely to the internal elastic membrane.
The mean survival time of the 11 animals treated w i t h Imuran and ALS (Group
2) was 44.9 days with a range of 11 to
128 days. At the time of autopsy, the
hearts were also enlarged, of firm consistency, and with fibrinous pericarditis or
its fibrous residue and a mottled brownyellow myocardium. Microscopic examination showed a focal or more diffuse infiltration of the myocardium with lymphoblasts,
small lymphocytes, plasmacells, and a n
occasional polynuclear granulocyte. The
myocardial fibers showed myccytolysis and
small areas of myocardial necrosis. In
some cases scar tissue and minute hemorrhages were also observed.
In all animals surviving beyond day 14,
the main branches of the coronary arteries
showed severe focal, obliterative arteritis.
The microscopic picture ranged from a n
active arteritis to sections of arteries in
which the lumen was nearly totally
occluded by fibrous tissue, which had also
destroyed and replaced the vessel wall and
exhibited a scar-like appearance. In case
of active arteritis, extensive intimal proliferation was seen. This was characterized
by infiltration of all wall layers with predominantly mononuclear cells and destruction of the internal and external elastic
membranes. Pictures intermediate between
more active arteritis and almost totally
occluded vessels in which the wall was replaced by fibrous tissue were frequently observed. In some instances, the internal
elastic membrane was found to be intact in
parts of arteries in which the wall layers
were replaced by fibrous, scar-like tissue.
No explanation can be given for this observation. Small, intramural branches of
the coronary arteries were affected only in
the longest survivors. In a few animals,
eosinophilic granulocytes were observed in
the infiltrate of the coronary artery wall.
In these animals arterial lesions of
arteries elsewhere in the body as well as
lesions in the kidney were observed that
were consistent with the picture of serum
sickness. In these cases serum sickness
was thought to be induced by the non-purified ALS which was used. In no instances
were atheroslerotic changes found in the
affected or intact parts of the coronary
arteries.
The mean survival time of the ten animals treated with Imuran, ALS and
Prednisone (Group 3 ) , not greatly different
from the animals of Group 2, was 45.1
days and ranged from ten to 104 days.
Microscopic examination of the hearts
showed a picture identical to that of animals treated with Imuran and ALS alone.
DISCUSSION AND CONCLUSIONS
The lesions observed in acute and chronically rejected hearts in the rhesus monkey are similar to those described for acute
and chronically rejected hearts in man
(Bieber et al., '70; Knieriem et al., '71;
Milam et al., '70; Stinson et al., '69) and
dogs (Kosek et al., '68; Wegmann, '70).
As seems to be the case in man, a n obliterative arteritis of the coronary arteries appears to be the limiting factor in cardiac
allografts survival in the rhesus monkey.
A survey of the histological changes observed in the present series is shown in
table 1. No influence of the immunosuppressive treatment regimens on the occurrence of obliterative arteritis has been observed. Further studies therefore seem
necessary in order to devise a n immunosuppressive treatment regimen that will effectively prevent obliterative arteritis of the
coronary arteries. Such studies may also
be of benefit for other solid organ grafts,
including the kidney in man (Kennedy
et al., '71).
Up to the present time, no atherosclerotic lesions have been observed in rhesus
monkeys kept under standard conditions in
the Primate Center TNO, not even in a
few approximately 15 year old animals.
Failure to observe atherosclerotic changes
similar to those often found in man in the
affected parts of the coronary arteries in
rhesus monkeys receiving a cardiac transplant may indicate that in the case of man
the underlying metabolic state of the recipient is of importance (Kosek et al., '71).
ACKNOWLEDGMENTS
These studies were performed in collaboration with H. Snijders, J. Vincent,
H. J. Stol, Z. Aytug, and H. F. L. Brom,
Department of Thoracic Surgery, Univer-
433
CARDIAC ALLOGRAFT PATHOLOGY IN MONKEYS
TABLE 1
Orthotopic-homologous heart transplantation in 26 rhesus monfieys
Postoperative
treatment
None
None
None
None
None
Morphology
Parenchymatous rejection
Survival
in days
Capillary lesions Cellular infiltrate
hemorrhage
muscle degenerations
6
6
7
20
27
+ Imuran
+ Imuran
+ Imuran
+ Imuran
+ Imuran
+ Imuran
+ Imuran
+ Imuran
+ Imuran
+ Imuran
+ Imuran
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS + Im + Pred.
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
+
-
Arterial
rejection
Arteritis
-
11
12
14
15
16
4s
56
60
61
76
128
10
12
15
20
36
46
61
65
82
104
-, nolesion.
+, clearcut lesion.
2 , minimal lesion.
sity of Leyden, and D. W. van Bekkum,
H. Balner, R. L. Marquet, and G. A.
Heystek, Radiobiological Institute TNO,
Rij swijk-ZH.
LITERATURE CITED
Bieber, C. P., E. B. Stinson, N. E. Shumway,
R. Payne and J. Kosek 1970 Cardiac transplantation i n man. VII. Cardiac allograft
pathology. Circulation, 41 : 753-772.
Kennedy, Jr., L. J., and I. L. Weissman 1971
Dual origin of intimal cells in cardiac-allograft arterioscelerosis. N. Engl. J. Med., 285:
884-887.
Knieriem, H. J., H. Meessen and H. D. Schulte
1971 Morphologische Befunde bei Herztransplantationen. Klin. Wschz., 49: 837-852.
f
+-
-
-
-
f
++
+
+
+
+
&
ALS, Antilymphocyte serum.
Im, Imuran.
Pred, Prednisone.
Kosek, J. C., E. J. Hurley and R. R. Lower
1968 Histopathology of orthotopic canine
cardiac homografts. Lab. Invest., 19: 97-112.
Kosek, J. C., C. P. Bieber and R. R. Lower 1971
Heart graft arteriosclerosis. Transplant. Proc.,
3: 512-514.
Milam, J . D., F. H. Shipkey, Jr., C. J. Lind, Jr.,
J. J. Nora, R. D. Leachman, D. G. Rochelle,
R. D. Bloodwell, G . L. Hallman and D. A. Cooley
1970 Morphologic findings in human cardiac
allografts. Circulation, 41 : 519-535.
Stinson, E. B., E. Dong, Jr., C. P. Bieber, R. L.
Popp and N. E. Shumway 1969 Cardiac
transplantation in man. 11. Immunosuppressive
therapy. J. Thorac Cardiovasc. Surg., 58:
326-337.
Wegmann, W. 1970 Pathologische Anatomie
der Herztransplantation. Experimenteller Teil.
Bull. schweiz. Akad. med. Wiss., 26: 197-205.
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