(Circulation. 1997;96:1605-1611.)
© 1997 American Heart Association, Inc.
Articles |
Major Histocompatibility Complex Class II Antigen Expression in Rejecting Cardiac Allografts
Detection Using In Vivo Imaging With Radiolabeled Monoclonal Antibody
From the University of Texas– Houston Medical School (A.I.M., L.L., O.H.F., J.T.W.), Texas Heart Institute/St Luke's Episcopal Hospital (B.R., P.C., F.J.C., O.H.F., J.T.W.), and Baylor College of Medicine (W.H.M.), Houston, Tex.
Correspondence to A. Iain McGhie, MD, University of Texas– Houston Medical School, Department of Internal Medicine (Cardiology Division), 6431 Fannin, Room 1.228 MSB, Houston, TX 77225. E-mail mcghie{at}heart.med.uth.tmc.edu
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Abstract |
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Background Increased expression of major histocompatibility complex class II (MHC-II) antigen occurs during cardiac allograft rejection. We tested the hypotheses that (1) radiolabeled antibody to MHC-II antigen allows detection of cardiac allograft rejection using nuclear imaging techniques and (2) uptake of radiolabeled antibody to MHC-II antigen correlates with severity of rejection.
Methods and Results Thirteen beagles with cervical cardiac allografts were studied for 64±23 days by use of myocardial biopsy and in vivo imaging. Uptake of radiolabeled (131I [n=2], 123I [n=1], or 111In [n=10]) antibody to MHC-II increased over baseline in 7 animals that developed histological evidence of progressively worsening allograft rejection (group A), from 72.2±46.1 to 176.8±102.0 counts/pixel/mCi (P<.009). In 4 beagles without progressively worsening allograft rejection (group B), uptake was unchanged during follow-up (74.4±43.8 and 60.2±37.4 counts/pixel/mCi; P=NS). In animals studied with 111In-labeled antibody, uptake increased from 102.9±23.1 at baseline to 233.2±82.7 counts/pixel/mCi at follow-up in group A animals (P=.036), with no significant change in group B (91.1±34.9 and 75.9±24.9 counts/pixel/mCi; P=NS). Uptake of 111In-labeled antibody was 107.5±35.7, 135.9±70.8, and 307.8±90.1 counts/pixel/mCi in biopsy samples showing evidence of mild, moderate, and severe rejection, respectively (P=.001). Biopsy samples showing mild, moderate, and intense MHC-II expression antibody uptake had uptakes of 92.6±36.3, 158.5±54.7, and 307.8±90.1 counts/pixel/mCi, respectively (P=.00004).
Conclusions Radiolabeled monoclonal antibodies to MHC-II antigen can detect cardiac allograft rejection in this large mammal model of cardiac allograft transplantation, and this technique may have a potential role in the detection of rejection in patients after cardiac transplantation.
Key Words: transplantation • rejection • radioisotopes • imaging • immunology
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Introduction |
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Survival after cardiac transplantation has consistently improved during the last decade, with current 1- and 5-year survival rates of 80% to 90% and 60% to 70%, respectively.1 This has led to the increasing use of cardiac transplantation in the management of patients with end-stage cardiac disease. Despite the availability of improved immunosuppressive agents, one of the most important clinical problems in the posttransplant period is detection and management of rejection. At present, detection and quantification of cardiac allograft rejection require serial endomyocardial biopsies to obtain tissue for histological analysis.2 Typically, endomyocardial biopsies are performed weekly for the first 4 to 8 weeks after transplantation and progressively reduced in frequency over the next few months to 3 to 4 biopsies per year.3 These invasive procedures are costly and prone to sampling errors.4 In addition, histological interpretation is subjective and, to a certain extent, arbitrary.
Rejection is associated with upregulation of the adhesion receptors belonging to the immunoglobulin superfamily, including the major histocompatibility complex (MHC) class II antigens.5 6 The increased expression of MHC class II antigens during rejection is seen in the graft endothelium and on infiltrating mononuclear cells. Isobe et al,7 using a murine model of cardiac transplantation, were the first to show that it was feasible to detect cardiac rejection with 111In-labeled monoclonal antibodies. One limitation of this model is that unlike larger mammals, including humans, rejection in mice is primarily provoked by MHC class I antigens, not class II antigens, and spontaneous long-term tolerance has been reported in murine graft models in the presence of class II mismatching.8 For this reason, we believed it was important to evaluate this technique further using an animal model in which the pathophysiology of graft rejection more closely paralleled that found in patients. In addition, we wanted to apply the technique of immunoscintigraphy to the serial evaluation of cardiac allografts for longer periods of time, allowing evaluation of the cardiac allograft under conditions of varying immunosuppression and degrees of rejection.
Therefore, we used a canine model of cardiac transplantation to test the hypotheses that (1) abnormal expression of MHC class II antigens can be detected noninvasively in rejecting allografts with the use of radiolabeled monoclonal antibodies and (2) detection of abnormal expression of MHC class II antigens correlates with the histological severity of rejection in cardiac allografts.
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Methods |
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Surgical Preparation
The surgical technique involved the transplantation of the cardiac allograft into the recipient's neck.9 The surgical anatomy of this nonworking cardiac allograft is illustrated schematically in Fig 1
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Thirteen conditioned beagles (weighing 10 to 15 kg each) received
heterotopic cardiac allografts from outbred puppy donors (weighing 2 to
4 kg each). Donor and recipient were premedicated with acepromazine
maleate (0.1 to 0.2 mg/kg) and oxymorphone (0.05 mg/kg).
Anesthesia was induced with intravenous
thiopental sodium (5 to 15 mg/kg) and maintained with isoflurane
(0.5% to 2.5%), which was delivered through a volume-controlled
ventilator. Muscle paralysis was provided with pancuronium (0.02 to
0.06 mg/kg IV). The donor heart was harvested through a median
sternotomy. After preliminary dissection and heparinization (5000 U),
the heart was arrested with cold potassium cardioplegic solution. After
explantation, the heart was prepared for implantation by ligation of
the pulmonary veins and inferior and superior vena
cavae. The recipients' hearts were prepared by isolating and exposing
the left common carotid artery and external jugular vein and by
creating a small cervical skin pocket. After this, a median sternotomy
and preliminary dissection were performed, followed by
intravenous heparinization. The graft was then implanted
into the recipient's neck, with the donor ascending aorta anastomosed
end to side with the recipient's common carotid artery and the donor
pulmonary artery anastomosed end to end with the recipient's
external jugular vein. After reperfusion, hearts were defibrillated and
implanted into the previously prepared cervical pocket.
Cyclosporin A was given starting 2 days before
transplantation at a dose of 20 mg/kg and was resumed on the
first postoperative day. Prednisolone (2 mg/kg) was also given 2
days before transplantation and restarted on the following day. Varying
degrees of graft rejection were obtained by gradual reductions in the
prednisolone and cyclosporine dosages using serum
cyclosporine levels and clinical indicators. All animals
used in the study received humane care in compliance with the
"Principles of Laboratory Animal Care" formulated by the National
Society for Medical Research and the Guide for the Care and Use
of Laboratory Animals prepared by the National Academy of Sciences
(NIH publication No. 85-23, revised 1985).
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Pathological Evaluation
Rejection was evaluated by serial percutaneous
transmyocardial biopsies. Two to three tissue samples were obtained at
each time point. Some were fixed in formalin and stained with
hematoxylin and eosin for microscopic evaluation and the remainder were
snap-frozen after embedding in OCT compound (Ames). After the final
image acquisition, the animals were killed and their hearts excised and
processed for subsequent histological analysis.
Representative sections of the right and left
ventricles were selected and stained with hematoxylin and eosin. Tissue
was also frozen and processed for immunohistochemistry. The degree of
cellular rejection was evaluated according to previously published
criteria using both the Texas Heart Institute (THI) and the
International Society of Heart Transplantation (ISHT)
gradations.10 11 The scoring of each section was performed
in a blinded manner by an experienced cardiac pathologist. Sections for
immunohistochemistry were cut at 5-mm intervals at -20°C in a
cryostat, transferred to slides precoated with
poly-D-lysine (Sigma Chemical Co), and fixed in cold
acetone for 10 minutes. These slides were washed twice with PBS, pH
7.4, and then immersed in a 0.1% sodium azide with 1% hydrogen
peroxide in water for 15 minutes at room temperature to neutralize
endogenous peroxidase activity. The slides were then rinsed
twice in PBS and flooded with RPMI 1640 media containing 5% horse
serum. Sections were incubated for 60 minutes with primary mouse
antibody against MHC class II antigen in a moist chamber followed by a
predetermined optimum concentration of biotinylated anti-mouse Ig,
followed by horseradish peroxidase avidin-biotin complexes (Vector
Labs). The sites of antigen/antibody reaction were detected with the
use of 3,3 diaminobenzidine (Sigma). The slides were counterstained
with Mayer's hematoxylin solution, coverslips were put on, and the
slides were then examined under the microscope. Negative control slides
were treated in an identical way except the primary monoclonal antibody
was omitted. Frozen sections of dog lymph node served as a positive
control. Findings were graded in a similar fashion to the THI grading
scale: 0 (negative) and from 1 to 10 (positive). Scoring of the
sections was performed by the same cardiac pathologists who scored the
light microscopic slides.
Immunoscintigraphy
A monoclonal antibody (TH14B; VMRD, Inc) to canine MHC class II
antigens was used. This monomorphic IgG2a monoclonal antibody, which
was obtained from mouse ascites fluid and purified by
centrifugation and filtration through a
0.22-mmol/L filter, was originally developed by Davis et
al.12 13 14 Radioiodination of intact monoclonal antibody
(0.5 to 1.0 mg) was performed with 5 to 10 mCi of either
131I (n=2; DuPont) or 123I (n=1; Nordion) by
incubation in a sterile vial coated with 1 mg Iodo-gen (Pierce Chemical
Co).15 Alternatively, when 111In chloride
(n=10) was used, a DTPA conjugation technique was used.16
Quality control assays included tests for protein-bound iodine
(trichloroacetic acid precipitation), labeling efficiency by instant
thin-layer chromatography in saline. The final
product had a labeling efficiency and protein-bound iodine that
were both >90%.
Beagles were imaged at baseline during full immunosuppression, 
2
weeks after transplantation, and at least once thereafter at the end of
the study period. On the day of percutaneous biopsy,
the animals were injected intravenously with radiolabeled
monoclonal antibody and imaged 48 hours after administration of
123I- and 111In-labeled antibodies and 72 hours
after 131I-labeled antibody. Planar images were acquired in
the anterior and left lateral projections. Each image was acquired
for 900 seconds by use of a commercially available single-headed,
rotating 
-camera equipped with the appropriate collimator with 20%
windows centered on the relevant photo peaks of the isotope used. After
acquisition of the immunoscintigraphic images, 4 to 6 mCi of
99mTc-labeled sestamibi was injected to verify the location
of native and donor hearts. Regions of interest were drawn in the left
lateral immunoscintigraphic images around the donor and native hearts.
Background regions of interest were generated for both the donor and
native hearts. For the donor heart, the background region of interest
(2 to 3 pixels wide) was drawn adjacent to the anterior wall and apex.
For the native heart, the background region of interest was drawn in
the adjacent lung. Activity in the donor and native hearts was
expressed as counts per pixel corrected for injected dose, background
activity, and decay.
Statistical Analysis
Results are expressed as mean±SD. Paired comparisons were made
by use of paired Student's t tests. ANOVA was used for
multiple comparisons between groups. A value of P<.05 was
considered statistically significant.
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Results |
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A total of 13 animals were studied. Two animals were studied by use of 131I-labeled antibody and 1 was studied with 123I-labeled antibody. The remainder were studied by use of 111In-labeled antibody because of the suboptimal quality of images obtained using radioiodinated antibodies. Two of 10 animals studied by use of 111In labeling were excluded from analysis. One animal rapidly developed clinical evidence of rejection and died suddenly before follow-up imaging could be performed. Another developed an area of regional akinesia, was found to have evidence of regional transmural infarction at autopsy, and was also excluded from analysis. In a third animal, intense activity was noted on baseline imaging without clinical or histological evidence of rejection. This activity was not present 2 weeks later. The reason for the transient increase in activity is unclear, but it may have resulted from pericardial reaction, and therefore these data were not included in the subsequent analysis.
In the remaining animals (both radioiodinated and
111In-labeled antibody), seven developed progressively
worsening cardiac allograft rejection (group A); the remaining four
animals showed no or minimal progression of allograft rejection
(Table). The animals in group A showed a
significant increase in the amount of uptake of radiolabeled antibody
to MHC class II antigen, increasing from 72.2±46.1 at baseline to
176.8±102.0 counts/pixel/mCi at the end of the study period
(P<.009). In contrast, the animals in group B showed no
significant change in uptake (74.4±43.8 and 60.2±37.4
counts/pixel/mCi, respectively; P=NS).
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Fig 2 summarizes the data obtained using
111In-labeled monoclonal antibody to MHC class II antigen.
In group A animals (n=5), the uptake increased from 102.9±23.1 at
baseline to 233.2±82.7 counts/pixel/mCi at the time of
follow-up (P=.036). In group B animals (n=3), there was no
significant change in the uptake of 111In-labeled antibody
(91.1±34.9 and 75.9±24.9 counts/pixel/mCi, respectively;
P=NS). Image quality was generally good, with rejecting
allografts being easily visualized when 111In-labeled
antibody was used (mean donor target-to-background ratio of 5.3±5.1).
The amount of activity in the region of the native heart was minimal
and often equal to or less than background activity in the adjacent
lung (Table
; Figs 3 and 4).
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, Individual data points; 
, mean
values with adjacent values. See text for further details. cts
indicates counts.
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Figs 3 and 4 show representative
111In-labeled images. Fig 3 shows uptake of labeled
antibody to MHC class II antigens at two different time intervals. The
image on the left, taken 21 days after transplantation and having a
biopsy sample showing THI grade 3 rejection, shows mild diffuse uptake.
The right-hand image was obtained 34 days after transplantation; it
reveals more intense uptake in the graft, with a corresponding biopsy
sample showing THI grade 7 changes consistent with moderate
rejection. Fig 4 shows images with corresponding biopsy samples from an
animal with moderate rejection (THI grade 7). There is diffuse uptake
of radiolabeled antibody in the donor heart, with minimal residual
blood pool activity seen in the region of the native heart. The
histological sections show marked cellular infiltration
with interstitial mononuclear cells and evidence of myocyte
degeneration, and the immunohistochemically processed section shows
fairly intense expression of MHC class II antigen occurring in the
presence of moderate rejection.
Fig 5 summarizes the relationship between
uptake of 111In-labeled monoclonal uptake and
histological severity of rejection from the
corresponding myocardial biopsy samples. Using the THI grading scale,
we graded biopsy samples as showing mild (grades 1 to 3), moderate
(grades 4 to 8), and severe (grades 9 and 10) degrees of rejection and
compared them with uptake of 111In-labeled antibody (Fig 5A). Uptake was 107.5±35.7, 135.9±70.8, and 307.8±90.1
counts/pixel/mCi in biopsy samples showing evidence of mild,
moderate, and severe rejection, respectively (P=.001).
Uptake of 111In-labeled antibody was also evaluated using
the ISHT histological gradation scale (Fig 5B). For
ISHT grades 1A, 1B, 2, 3A, 3B, and 4, uptake was 112.4±54.0,
98.8±18.9, 115.5±96.1, 134.3±56.8, 179.0±23.2, and 307.8±90.1
counts/pixel/mCi, respectively (P=.015). The
relationship between uptake of radiolabeled monoclonal antibody and
intensity of the immunohistological expression of MHC
class II antigens was closer. Uptake in biopsy samples showing mild,
moderate, and intense MHC class II antigen expression was 92.6±36.3,
158.5±54.7, and 307.8±90.1, respectively (P=.00004; Fig 5C).
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Discussion |
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Noninvasive Detection of Cardiac Rejection
Many techniques have been evaluated for noninvasively detecting rejection after cardiac transplantation. Currently, no noninvasive technique has found widespread acceptance for use in the detection of rejection in patients after cardiac transplantation. Several studies have shown that moderate to severe rejection after cardiac allograft transplantation can be detected with the use of a radiolabeled monoclonal antibody to myosin both in experimental models17 18 19 20 and in patients.21 22 These studies have shown a variable correlation between scintigraphic findings using 111In-labeled anti-myosin antibody and the histological extent of myocyte necrosis after transplantation. In patients with cardiac allografts, radiolabeled anti-myosin antibody uptake is reported to have a reasonable sensitivity (range, 80% to 95%), with a somewhat more questionable specificity (range, 33% to 80%).
MHC Class II Antigen Expression in Cardiac Rejection
The immunoglobulin superfamily of adhesion receptors, including
the MHC class II antigens, plays an important role in the
pathophysiology of allograft rejection.23 24
Immunocytochemical techniques have allowed identification of the
different types of mononuclear cells associated with rejection and
their interaction with antigens expressed on the graft. These
techniques have revealed intense expression of MHC class II antigens in
endomyocardial biopsy samples from patients with
cardiac allograft rejection.5 6
Isobe et al,7 using a murine model of cardiac transplantation, were the first to show that it was possible to detect cardiac rejection using radiolabeled antibodies to murine equivalent MHC class II antigens. However, unlike in larger mammals, rejection in mice is primarily provoked by MHC class I antigens, not class II antigens, and spontaneous long-term tolerance has been reported using a murine vascularized graft model in the presence of class II mismatching.8 In the present study, we demonstrated that the upregulation of MHC class II antigen expression that occurs during rejection can be imaged successfully in this larger mammal in which MHC class II antigens are primarily responsible for rejection, as occurs in humans. In addition, by studying animals for a period of months, we were able to show that detection of increasing uptake of radiolabeled antibody to MHC class II antigen by the cardiac allograft on follow-up imaging was associated with development of worsening rejection of the allograft.
The uptake of radiolabeled antibody to class II antigen in the cardiac
allograft correlated with the histological severity of
rejection using either the THI or ISHT gradations (Fig 5). Despite
highly statistically significant differences in antibody uptake between
these groups, there was significant overlap, particularly in the milder
degrees of rejection. Discrimination between groups appeared to be
better in the presence of more severe rejection; however, the number of
data points within groups was often small. As might have been
anticipated, the relationship between the immunoscintigraphic and
immunohistological findings was closer than with the
standard histological gradation. It has been shown
previously that the upregulation of MHC antigen typically begins before
histological evidence of rejection becomes
obvious.5 Whether this has implications for clinical
imaging is unclear; however, it may allow earlier detection of cardiac
rejection before significant myocyte necrosis occurs.
Study Limitations
The results of this study are encouraging and suggest that this
technique may have potential in the clinical arena. However, there are
several limitations to the present study. First, the main
radioisotope used in this study was 111In chloride. The
optimal time for imaging appeared to be 48 hours after administration
of the radiolabeled monoclonal antibody. At this time, the blood pool
and other background activities were minimal and allowed adequate
visualization of the graft. However, in the clinical setting, this
48-hour wait may be too long and may delay institution of therapy if
significant allograft rejection is present. Second, in this animal
model, the cardiac allograft was located in the cervical region, which
is advantageous for imaging. Imaging a cardiac allograft located within
the thorax would be more problematic, particularly because
of background activity from the liver. However, many of these
limitations could be overcome by the use of a 99mTc-labeled
peptide fragment rather than an intact antibody. The use of a peptide
fragment would result in much more rapid blood clearance, allowing
imaging within several hours rather than a few days, and the use of
99mTc would provide better imaging characteristics than
111In. Third, 1 of the animals studied demonstrated marked
uptake of labeled antibody in the absence of clinical or
histological rejection early after rejection while
receiving full immunosuppression. This was possibly due to pericardial
reaction after surgery. Although it only occurred in 1 of 11 animals,
it does raise concerns about false-positives in the presence of a local
inflammatory reaction when this technique is used. Finally, as eluded
to earlier, due to the expense of this surgical preparation, the number
of animals studied was small, which limited the statistical power of
the study, especially with regard to comparisons between individual
groups.
Conclusions
These data indicate that radiolabeled monoclonal antibodies to MHC
class II antigens can be used to detect and evaluate the severity of
cardiac allograft rejection in this large mammal model of cardiac
allograft transplantation. Our results extend previous findings in a
murine model and suggest that this technique may have a potential role
in detection of rejection in patients after cardiac transplantation,
and it therefore warrants further evaluation.
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Acknowledgments |
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This study was supported by a Grant-in-Aid (No. 93G-273) from the American Heart Association, Texas Affiliate, Inc. The authors would like to thank Edward T.H. Yeh, MD, for his help with review and criticism during the revision of this manuscript.
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Footnotes |
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Guest editor for this article was Barry L. Zaret, MD, Yale University School of Medicine, New Haven, Conn.
Received March 5, 1997; revision received April 24, 1997; accepted May 1, 1997.
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