Ann Thorac Surg 1997;64:1019-1025
© 1997 The Society of Thoracic Surgeons
Original Article: Cardiovascular
Cardiac Allograft Vasculopathy Is Abrogated by Anti-CD8 Monoclonal Antibody Therapy
James S. Allan, MD,
Joseph K. Choo, MD,
Liana Vesga, BS,
J. Scott Arn, BS,
Michael R. Pins, MD,
David H. Sachs, MD,
Joren C. Madsen, MD
Cardiac Surgical Unit and Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
 |
Abstract
|
|---|
Background. Cardiac allograft vasculopathy, a diffuse and accelerated form of arteriosclerosis, is a major cause of graft loss or heart transplant recipient death after the first transplant year. This study examined the effects of depleting host CD8+ T lymphocytes on the development of cardiac allograft vasculopathy in miniature swine.
Methods. Cardiac allografts were heterotopically transplanted across a major histocompatibility complex class I barrier in partially inbred miniature swine and monitored for rejection by serial biopsies, electrocardiograms, and echocardiograms. Four control animals received cyclosporine on postoperative days 0 to 11. Another four miniswine were given 14.5 mg/kg of 76-2-11 (a mouse anti-swine CD8 monoclonal antibody) on postoperative day 0, in addition to a 12-day course of cyclosporine. Host CD8+ T cells and circulating 76-2-11 monoclonal antibodies were monitored by flow cytometry.
Results. As compared with cyclosporine-treated control animals, swine receiving 76-2-11 demonstrated near-complete depletion of peripheral CD8+ T cells by postoperative day 2, which persisted for 14 to 18 days. Mean allograft survival of the antibody-treated group and the control group was not statistically different (33 days versus 39 days, respectively) and both groups demonstrated severe interstitial rejection at necropsy. Control animals demonstrated florid intimal thickening of large and small arteries at necropsy. However, swine treated with 76-2-11 showed no intimal proliferation.
Conclusions. Depletion of host CD8+ T cells prevents or delays the development of intimal proliferation in miniature swine. CD8+ lymphocytes play an important role in the early development of cardiac allograft vasculopathy in large animals.
|
Introduction
|
|---|
See also page 1025.
Dramatic progress has been made in cardiac transplantation during the past 25 years with 1-year survival increasing from 22% in 1969 to more than 80% in 1995 [1]. However, the successful prevention of acute allograft rejection with cyclosporine (CyA) and other immunosuppressants has uncovered the more perplexing problem of chronic rejection. In long-term cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis termed cardiac allograft vasculopathy (CAV), for which there is no effective therapy [2]. The intimal proliferation associated with CAV is evident by the first posttransplantation year [3] and progresses, in a variable fashion, to vessel occlusion, myocardial infarction, and ultimately, graft failure [4]. Indeed, CAV is a major cause of mortality in long-term heart allograft recipients [5].
The diffuse and relatively rapid progression of the vascular lesions in transplant recipients, along with the sparing of native vessels and the lack of association with conventional risk factors for coronary arteriosclerosis, has led many investigators to hypothesize that CAV is an immunologically mediated disease [6]. This hypothesis is supported by experimental rodent studies showing that vasculopathy does not develop in syngeneic or isogeneic grafts [7] and that both T-cell mediated immune responses [7] and alloantibody formation [8] participate in the pathogenesis of the vascular lesions.
Using a partially inbred herd of miniature swine, whose major histocompatibility complex (MHC) loci have been defined through selective breeding [9], our group has developed and validated a large animal model of CAV [10]. Because transplantation across defined MHC incompatibilities can be performed reproducibly in our partially inbred miniature swine, we have been able to analyze the immunogenetics of CAV in a preclinical model. Selective transplantation across major or minor histoincompatibilities revealed that the development of florid CAV was critically dependent on crossing a class I MHC barrier at the time of transplantation (manuscript submitted). These vascular lesions reproduced with fidelity those lesions observed in long-term human cardiac allografts [11]. The striking relationship between MHC class I antigen disparities and the development of vasculopathy in miniature swine suggested that the CD8+ subpopulation of T lymphocytes, which recognize foreign antigen in association with MHC class I molecules, may play an important role in the early pathogenesis of CAV. In this study, we examined the effects of early depletion of host CD8+ T lymphocytes on the development of CAV in miniature swine.
|
Material and Methods
|
|---|
Animals
A selective breeding program has been used during the past 25 years to develop and maintain a herd of miniature swine with defined MHC loci (termed SLA for swine leukocyte antigen) [9]. At present, swine of three homozygous MHC haplotypes, SLAa, SLAc, and SLAd, are maintained. In addition, swine bearing four intra-MHC recombinant haplotypes, SLAg, SLAh, SLAj, and SLAk, have been derived by spontaneous recombination events during the breeding of heterozygotes [12]. Genotyping has been controlled by strict pedigree breeding and confirmed by microcytotoxicity testing using allospecific antisera.
A total of 16 swine (8 recipients, 8 donors) were used to perform eight two-haplotype, MHC class I mismatched heterotopic heart transplants. The strain combinations used were either SLAj into SLAc or SLAg into SLAd. As shown in Table 1
, there were no significant differences between the control and treatment groups with respect to recipient age (p = 0.27), recipient weight (p = 0.26), donor age (p = 0.96), and donor weight (p = 0.91). All animal care and procedures were 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 Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985).
|
Heterotopic Cardiac Transplantation
|
|---|
Heterotopic cardiac transplantation was performed by methods described previously [10]. In brief, general anesthesia (halothane 1%, N2O 1%, and O2) was achieved, and a permanent indwelling central venous catheter was placed through jugular cut-down for long-term vascular access. The recipient's infrarenal aorta and inferior vena cava were isolated through either a transabdominal or retroperitoneal approach. After systemic heparinization (3 mg/kg) and administration of cold (4°C) cardioplegia (Plegisol; Abbott Laboratories, North Chicago, IL), the donor heart was harvested and the donor cavae ligated. An atrial septal defect was created, and the mitral valve was defunctionalized to minimize left ventricular atrophy and intracavitary thrombus formation. The recipient was then heparinized (3 mg/kg), and an end-to-side donor pulmonary artery to recipient inferior vena cava anastomosis was performed with continuous 6-0 polypropylene sutures (Prolene; Ethicon, Inc, Somerville, NJ). The donor ascending aorta was anastomosed to recipient abdominal aorta in a similar manner. The average (± standard deviation) total ischemic time was 82.5 ± 12.5 minutes. There was no significant difference in ischemic time between the control and antibody-treated groups (82.5 ± 12.5 versus 76.8 ± 14.3, respectively; p = 0.22). After removal of the aortic cross-clamp, most of the donor hearts spontaneously reverted to normal sinus rhythm. Several hearts required low-energy (10 to 20 J) internal defibrillation. Iridium-tipped ventricular electrodes (model 6500; Medtronic, Inc, Secaucus, NJ) were implanted before closure for long-term electrocardiographic monitoring.
Graft function was followed daily by direct transabdominal palpation, electrocardiography (EK/5A, Burdick Corp, Milton, WI), surface echocardiography (Sonos 1500; Hewlett-Packard, Andover, MA), or a combination of these. Allograft rejection was defined by either a lack of ventricular impulse on palpation, an R wave amplitude less than 3 mm on the electrocardiogram, or the loss of ventricular contraction on surface echocardiography. When rejection occurred, the allograft was promptly explanted and preserved for pathologic evaluation.
|
Immunosuppression
|
|---|
All recipients received intravenous CyA (10 to 20 mg • kg-1 • day-1) from postoperative day 0 to 11. Cyclosporine dosage was adjusted daily to maintain cyclosporine levels between 500 and 1,000 ng/mL as determined by fluorescence polarization immunoassay. Cyclosporine was generously provided by Sandoz Pharmaceuticals (Hanover, NJ).
In addition to the 12-day course of CyA, four recipients received a single intravenous dose (14.5 mg/kg) of the anti-CD8 monoclonal antibody 76-2-11 on the day of operation (postoperative day [POD] 0). 76-2-11 is an IgG2a mouse anti-swine monoclonal antibody (MAb) with known in vitro and in vivo activity against porcine CD8+ T cells [13–15]. It was administered either as microfiltered ascites (swine 12091) or as a protein A Sepharose column-purified preparation from ascites (swines 12279, 12309, 12285) reconstituted to the original volume. Before intravenous administration, the MAb was diluted 1:10 in Hank's balanced salt solution. Antibody-treated animals were administered single doses of diphenhydramine, cimetidine, and hydrocortisone (1 mg/kg) at the time of operation to attenuate the allergic response sometimes exhibited with infusion of the antibody. Control animals were treated in an identical fashion.
|
Flow Cytometry
|
|---|
The depletion of the CD8+ lymphocyte population after administration of 76-2-11 was documented by daily flow cytometric analyses of recipient peripheral blood lymphocytes (PBL). Briefly, flow cytometry was performed by suspending 1 x 106 PBLs in a staining buffer (0.1% bovine serum albumin and 0.1% sodium azide in Hank's balanced saline solution). All cells were then incubated for 5 minutes at 4°C with purified swine immunoglobulin G to block nonspecific binding. Cells were then stained selectively with 76-2-11 (anti-CD8 MAb), 74-12-4 (anti-CD4 MAb) [15], MSA4 (anti-CD2 MAb) [16], 898H-6-15 (anti-CD3 MAb) (T. Lorf, unpublished results), 36-7-5 (anti-H-2Kk MAb, negative control) [17], or 2.27.3a (anti-SLA class I MAb, positive control) [18] as either fluorescein isothiocyanate (FITC) conjugated or unconjugated MAbs. Cells incubated with unconjugated MAbs required counterstaining with the FITC-conjugated polyclonal goat-anti-mouse (GAM-FITC) antibody (Boerhinger-Mannheim) as the second-stage reagent. The percentage of CD8+ lymphocytes which remained coated with 76-2-11 after in vivo MAb treatment was determined by staining recipient PBLs with GAM-FITC alone. The persistence of circulating 76-2-11 in the recipient's serum was determined by incubating naive PBLs with recipient sera, then adding GAM-FITC as the second-stage reagent. A minimum of 104 cells were analyzed on logarithmic amplification for magnitude of green fluorescence using a FACScan (Becton-Dickinson, Sunnyvale, CA) flow cytometer. Dead cells were excluded by propidium iodide uptake, as shown by red fluorescence. Data were analyzed using WinList v. 3.0 (Verity Software House, Inc, Topsham, ME) software.
|
Histology
|
|---|
Heart tissue obtained at autopsy was fixed in 10% formalin and subsequently embedded in paraffin. Tissue sections were obtained at 1-cm intervals from the base to the apex, along the course of the left anterior descending artery and posterior descending artery, to examine vessels ranging in size from large epicardial arteries to small arterioles. Tissue was stained with both hematoxylin/eosin and van Gieson's elastic stain. Histologic findings were scored by blinded observers with the use of light microscopy to determine the severity of both vasculopathy and interstitial rejection. The degree of intimal proliferation was graded using the classification of Lurie and colleagues [19] (Table 2). The mean vascular score reflected the average grade of all arteries in the specimen exhibiting vascular lesions. The degree of interstitial rejection was similarly scored using a modification of the International Society for Heart and Lung Transplantation system [2] (Table 3).
|
Statistical Analysis
|
|---|
Comparisons of animal characteristics, ischemic times, and survival times were made using unpaired, two-tailed, two-sample, heteroscedastic t tests. Comparisons of mean interstitial and mean vascular scores were made using non-parametric Mann-Whitney U tests.
|
Results
|
|---|
Effects of Anti-CD8 MAb Treatment on Target Cells
Each animal treated with a single dose of 76-2-11 exhibited near complete depletion of peripheral CD8+ T lymphocytes by POD 2 (Fig 1). Furthermore, depletion of the CD8+ T-cell subset persisted up until 14 to 18 days after transplantation (Fig 1). The efficacy of 76-2-11 in depleting target cells was evident in both direct (76-2-11-FITC) and indirect (76-2-11 and GAM-FITC) flow cytometric assays. The persistence of CD8+ T cell depletion for more than 2 weeks after a single dose of MAb suggested that target cell depletion did occur. However, the possibility of surface antigen modulation was not formally ruled out.
View larger version (20K):
[in this window]
[in a new window]
|
Fig 1. . Target cell depletion by the anti-CD8 monoclonal antibody 76-2-11. The percentage of total peripheral blood lymphocytes (PBL) staining positively for the CD8 surface antigen is plotted with respect to experimental day for all antibody-treated recipients (square = 12091; circle = 12285; star = 12309; diamond = 12279). These data were derived from single-stage flow cytometric analysis using fluorescein isothiocyanate-conjugated 76-2-11. Monoclonal antibody was administrated on day 0.
|
|
Immediately after the administration of antibody (POD 0), a population of peripheral antibody-coated CD8+ lymphocytes was documented by staining host PBL with GAM-FITC alone. The antibody-coated CD8+ T cells disappeared 2 to 4 days after MAb administration (data not shown).
Analysis of sera from antibody-treated recipients revealed that free circulating MAb persisted in hosts until PODs 14 to 18 (Fig 2). Thus, clearing of residual antibody in the host coincided with the return of peripheral CD8+ T-cells (Fig 2).
View larger version (17K):
[in this window]
[in a new window]
|
Fig 2. . Persistence of circulating monoclonal antibody in pig 12091 after a single administration of 76-2-11 on day 0. The percentage of naive peripheral blood lymphocytes (PBL) reactive with serum from pig 12091 is plotted with respect to experimental day (solid line). These data were derived from a two-stage flow cytometric analysis using sera from pig 12091 at a 1:100 dilution (first stage) and goat-anti-mouse-fluorescein isothiocyanate (second stage). For comparison, the percentage of total peripheral blood lymphocytes from pig 12091 staining positively for CD8 with respect to experimental day (dashed line) has been superimposed. Similar results were obtained for each of the 76-2-11-treated recipients.
|
|
|
Effects of Host CD8+ T Cell Depletion on Allograft Survival
|
|---|
There was no significant difference in mean (± standard deviation) allograft survival between CyA-treated recipients given anti-CD8 MAb and control animals treated with CyA alone (32.8 ± 5.0 days versus 39.3 ± 8.1 days, respectively; p = 0.23). At the time of necropsy, all eight allografts exhibited severe interstitial rejection (Table 4). Of note, all heart grafts survived up until or beyond POD 28. This represents the time by which CAV had become histologically apparent in previous recipients treated with CyA alone and transplanted with MHC class I-mismatched cardiac allografts (unpublished results).
View this table:
[in this window]
[in a new window]
|
Table 4. . Effects of Anti-CD8 Monoclonal Antibody Therapy on Survival and Cardiac Allograft Vasculopathy in Major Histocompatibility Class I Mismatched Cardiac Allografts
|
|
|
Effects of Host CD8+ T Cell Depletion on CAV
|
|---|
Histologic analysis of autopsy specimens revealed that all class I mismatched allografts in recipients treated with CyA alone developed significant coronary intimal proliferation with an average mean vascular score of 2.75 (Table 3
). The characteristics of the pathologic changes in these arterial lesions reproduced with fidelity those observed in human heart transplant recipients undergoing chronic rejection [11]. The vascular lesions exhibited proliferation of spindle cells and matrix in the intima of arteries and arterioles, which resulted in significant lumenal stenosis. More advanced lesions demonstrated deposition of lipid and progressive intimal fibrosis that, in many cases, occluded the lumens of both large and small arteries (Fig 3).
View larger version (135K):
[in this window]
[in a new window]
|
Fig 3. . Coronary artery histology from control swine treated with cyclosporine alone. (A) Arteriole from pig 12049 stained with van Gieson's elastin stain (x250 before 48% reduction) and (B) arteriole from pig 11065 stained with van Gieson's elastin stain (x300 before 48% reduction) show intimal thickening due to the deposition of extracellular matrix and the proliferation of spindle cells resulting in luminal occlusion.
|
|
In marked contrast, the 4 recipients of class I mismatched hearts treated with anti-CD8 MAb showed no evidence of intimal thickening with an average mean vascular score of 0.75 (Table 3). The difference in mean vascular scores between the control group and the antibody treated-group was significant (p < 0.05). Coronary vessels exhibited either no lesions, or they exhibited intimal or adventitial mononuclear cell infiltrates suggestive of an early intimitis or adventitiitis (Fig 4). Unlike recipients treated with CyA alone, coronary arteries from antibody-treated recipients showed no evidence of an intimal spindle cell proliferation or the accumulation of extracellular matrix products or lipid within the intima (see Fig 4).
View larger version (124K):
[in this window]
[in a new window]
|
Fig 4. . Coronary artery histology from swine treated with cyclosporine and anti-CD8 monoclonal antibody. (A) Arteriole from pig 12285 stained with hematoxylin and eosin (x200 before 48% reduction) and (B) arteriole from pig 12279 stained with hematoxylin and eosin (x350 before 48% reduction) show a mild to moderate mononuclear endothelialitis without intimal proliferation.
|
|
|
Comment
|
|---|
We know from our previous immunogenetic studies in partially inbred miniature swine that the most florid vascular lesions develop in cardiac allografts transplanted across a class I histocompatibility barrier (unpublished results). This finding suggested that CD8+ T lymphocytes, which recognize foreign antigen in the context of MHC class I antigens, could play an important role in the early pathogenesis of CAV. To test this hypothesis, recipients bearing class I-disparate allografts were treated with the anti-CD8 MAb 76-2-11, which effectively depleted host CD8+ T cells for up to 18 days after transplantation. The sustained nature of target cell depletion may be explained by the high levels of excess MAb circulating during 2 weeks after MAb administration (Fig 2). Although unlikely, it is possible that antigen modulation could account for some of the effectiveness of 76-2-11. Even so, prolonged modulation of the CD8 antigen from the cell surface would be functionally similar to actual clearance of the target cell population.
Two principal observations can be made in comparing the antibody-treated group and control group in Table 4. The first is that early depletion of host CD8+ T cells had no significant effect on allograft survival. Indeed, at the time of clinical allograft rejection, both antibody-treated and control allografts had histologic evidence of severe interstitial rejection, which included multifocal myocyte necrosis and hemorrhage (see Figs 3, 4). These findings are consistent with mouse studies that showed that anti-CD8 MAb treatment has no beneficial effect on the first-set rejection of H-2 disparate cardiac allografts [20].
The major finding from this study is that the early depletion of host CD8+ lymphocytes abrogated the development of CAV in MHC class I mismatched allografts. Instead of developing the exuberant intimal thickening observed in recipients treated with CyA alone, allografts removed from the anti-CD8 MAb-treated recipients exhibited only a mononuclear cell intimitis and/or adventitiitis, without significant intimal proliferation (Table 4). Thus, early treatment with MAb directed against CD8+ T cells seemed to prevent the development of intimal proliferation, which is the sine qua non of CAV. Alternatively, anti-CD8 MAb therapy may simply be delaying the maturation of early vascular lesions. Colvin and colleagues [11] have recently defined the histologic progression of the vascular lesions of CAV. They describe three characteristic stages common to all transplant arteriopathy. The earliest lesions (stage 1) consist of a mononuclear intimitis. Over time, these lesions progress to frank intimal thickening (stage 2) and, ultimately, to intimal fibrosis with luminal obliteration (stage 3). To distinguish whether anti-CD8 MAb therapy actually prevents the onset of intimal proliferation or simply delays the natural maturation of the lesions, we plan to treat recipients with clinically based triple-drug therapy (CyA, azathioprine, steroids) to prolong allograft survival and observe the long-term changes in the coronary vasculature of anti-CD8 MAb-treated recipients.
Our results demonstrating the efficacy of anti-CD8 MAb therapy in preventing or delaying CAV stand in contrast to similar experiments performed in a rat heart allograft model of chronic rejection [21]. Clarke-Forbes and associates [21] treated LEW recipients of WF.1L heart grafts with the anti-CD8 MAb MRC OX8 and found that MRC OX8 had no beneficial effects on the development of CAV as compared with untreated controls. This discrepancy may be explained by the fact that swine, like humans, consitutively express MHC class II antigens on their vascular endothelium, whereas the mouse and rat do not [22].
In conclusion, the fact that anti-CD8 MAb treatment abrogated the development of CAV in miniature swine has three implications: (1) that the chronic rejection of heart allografts is an immune-driven process, (2) that the mechanisms underlying chronic rejection probably differ from those mediating acute rejection, and (3) that CD8+ T cells play an important role in the early development of CAV in large animals. Further studies will be necessary to elucidate the mechanism of this beneficial effect and potentially to use the selective depletion of CD8+ lymphocytes in the prevention of cardiac allograft vasculopathy in clinical heart transplantation.
|
Acknowledgments
|
|---|
This work was supported in part by National Institutes of Health grant RO1-HL54211 (Dr Madsen) and a grant from the The Thoracic Surgery Foundation for Research & Education (Dr Madsen). Doctor Allan is an Edward D. Churchill Research Fellow, Massachusetts General Hospital, Boston.
|
Footnotes
|
|---|
Presented at the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.
Address reprint requests to Dr Madsen, Cardiac Surgical Unit, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114 (e-mail: madsen{at}helix.mgh.harvard.edu).
|
References
|
|---|
- Hosenpud JD, Novick RJ, Bennett LE, Keck BM, Fiol B, Daily OP. The registry of the International Society for Heart and Lung Transplantation: thirteenth official report—1996. J Heart Lung Transplant 1996;15:655–74.[Medline]
- Billingham ME. Cardiac transplantation arteriosclerosis. Transplant Proc 1987;19:19–25.[Medline]
- Johnson DE, Gao S, Schroeder JS, DeCampli WM, Billingham ME. The spectrum of coronary artery pathologic findings in human cardiac allografts. J Heart Lung Transplant 1989;8:349–59.
- Gao SZ, Hunt SA, Schroeder JS, Alderman EL, Hill IR, Stinson EB. Early development of accelerated graft coronary artery disease: risk factors and course. J Am Coll Cardiol 1996;28:673–9.[Abstract]
- Gao SZ, Schroeder JS, Alderman E, et al. Prevalence of accelerated coronary artery disease in heart transplant survivors: comparison of cyclosporin and azathioprine regimens. Circulation 1989;80(Suppl 3):100–5.
- Hosenpud JD. Immune mechanisms of cardiac allograft vasculopathy: an update. Transplant Immunol 1993;1:237–49.[Medline]
- Russell PS, Chase CM, Winn HJ, Colvin RB. Coronary atherosclerosis in transplanted mouse hearts. I. Time course and immunogenetic and immunopathological considerations. Am J Pathol 1994;144:260–74.[Abstract]
- Russell PS, Chase CM, Winn HJ, Colvin RB. Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity. J Immunol 1994;152:5135–41.[Abstract]
- Sachs DH, Leight G, Cone J, Schwartz S, Stuart L, Rosenberg S. Transplantation in miniature swine. I. Fixation of the major histocompatibility complex. Transplantation 1976;22:559–67.[Medline]
- Madsen JC, Sachs DH, Fallon JT, Weissman NJ. Cardiac allograft vasculopathy in partially inbred miniature swine. J Thorac Cardiovasc Surg 1996;111:1230–9.[Abstract/Free Full Text]
- Colvin RB, Chase CM, Winn HJ, Russell PS. Chronic allograft arteriopathy: insights from experimental models. In: Orosz CG, Sedmak DD, Ferguson RM, eds. Transplant vascular sclerosis. Austin: R.G. Landes Co, 1995:7–33.
- Pennington LR, Lunney JK, Sachs DH. Transplantation in miniature swine: VIII. Recombination within the major histocompatibility complex of miniature swine. Transplantation 1981;31:66–75.[Medline]
- Suzuki T, Sundt TM III, Mixon A, Sachs DH. In vivo treatment with antiporcine T cell antibodies. Transplantation 1990;50:76–81.[Medline]
- Pescovitz MD, Lunney JK, Sachs DH. Preparation and characterization of monoclonal antibodies reactive with porcine PBL. J Immunol 1984;133:368–75.[Abstract]
- Pescovitz MD, Lunney JK, Sachs DH. Murine anti-swine T4 and T8 monoclonal antibodies: distribution and effects on proliferative and cytotoxic T cells. J Immunol 1985;134:37–44.[Abstract]
- Hammerberg C, Schurig GC. Characterization of monoclonal Ab directed against swine leukocytes. Vet Immunol Immunopathol 1986;11:107–21.[Medline]
- Ozato K, Henkart P, Jensen C, Sachs DH. Spatially distinct allodeterminants of the H-2Kk molecule as detected by monoclonal anti-H-2 antibody. J Immunol 1981;126:1780–5.[Abstract]
- Ivansoka D, Sun DC, Lunney JK. Production of monoclonal antibodies reactive with polymorphic and monomorphic determinants of SLA class I gene products. Immunogenetics 1991;33:220–3.[Medline]
- Lurie KG, Billingham ME, Jamieson SW, Harrison DC, Reitz BA. Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model. Transplantation 1981;31:41–7.[Medline]
- Madsen JC, Wood KJ, Morris PJ. Effects of anti-L3T4 and anti-Lyt 2 monoclonal antibodies on murine cardiac allograft rejection. Transplant Proc 1987;19:3991–2.[Medline]
- Clarke-Forbes RD, Zheng S, Gomersall M, Al-Saffar M, Guttmann RD. Evidence that recipient CD8+ T cell depletion does not alter development of chronic vascular rejection in a rat heart allograft model. Transplantation 1994;57:1238–46.[Medline]
- Pescovitz MD, Sachs DH, Lunney JK, Hsu SM. Localization of class II MHC antigen on porcine renal vascular endothelium. Transplantation 1984;37:627–30.[Medline]
Related Article
-
Discussion
Ann. Thorac. Surg. 1997 64: 1025.
[Extract]
[Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. Tanaka, S. Nakae, R. D. Terry, G. K. Mokhtari, F. Gunawan, L. B. Balsam, H. Kaneda, T. Kofidis, P. S. Tsao, and R. C. Robbins
Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease
Blood,
December 1, 2004;
104(12):
3789 - 3796.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. D. Poggio, M. Clemente, J. Riley, M. Roddy, N. S. Greenspan, C. Dejelo, N. Najafian, M. H. Sayegh, D. E. Hricik, and P. S. Heeger
Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy
J. Am. Soc. Nephrol.,
July 1, 2004;
15(7):
1952 - 1960.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Choy, A. Kerjner, B. W. Wong, B. M. McManus, and D. J. Granville
Perforin Mediates Endothelial Cell Death and Resultant Transplant Vascular Disease in Cardiac Allografts
Am. J. Pathol.,
July 1, 2004;
165(1):
127 - 133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Fischbein, J. Yun, H. Laks, Y. Irie, M. C. Fishbein, B. Bonavida, and A. Ardehali
Role of CD8+ lymphocytes in chronic rejection of transplanted hearts
J. Thorac. Cardiovasc. Surg.,
April 1, 2002;
123(4):
803 - 809.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Sata, Z. Luo, and K. Walsh
Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia
J. Immunol.,
June 1, 2001;
166(11):
6964 - 6971.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. S. Lee, K. Yamada, S. L. Houser, K. L. Womer, M. E. Maloney, H. S. Rose, M. H. Sayegh, and J. C. Madsen
Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy
PNAS,
March 13, 2001;
98(6):
3276 - 3281.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-F. Legare, T. Issekutz, T. D. G. Lee, and G. Hirsch
CD8+ T Lymphocytes Mediate Destruction of the Vascular Media in a Model of Chronic Rejection
Am. J. Pathol.,
September 1, 2000;
157(3):
859 - 865.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Yamada, K. Mawulawde, M. T. Menard, A. Shimizu, H. T. Aretz, J. K. Choo, K. S. Allison, J. K. Slisz, D. H. Sachs, and J. C. Madsen
MECHANISMS OF TOLERANCE INDUCTION AND PREVENTION OF CARDIAC ALLOGRAFT VASCULOPATHY IN MINIATURE SWINE: THE EFFECT OF AUGMENTATION OF DONOR ANTIGEN LOAD
J. Thorac. Cardiovasc. Surg.,
April 1, 2000;
119(4):
709 - 719.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
