Pediatric heart transplantation: Allograft rejection

Pediatric Heart Transplantation: Allograft Rejection DANIEL BERNSTEIN, M.D. CAROL CLAYBERGER, Ph.D. DAVID BAUM, M.D. Departments of Pediatrics and Cardiothoracic Surgery Stanford University School of Medicine Stanford, California

Heart transplantation has gained widespread acceptance as a treatment modality for both cardiomyopathy and certain severe congenital heart defects in infants and children.‘“’ However, the requirement of lifelong immunosuppression implies a long exposure of the young transplantation recipient to the side effects of immunosuppressive drugs. Consequently, attention has focused increasingly on the need for improved immunosuppressive regimens and easy, reliable, noninvasive methods to recognize rejection. In the early years of heart transplantation, prophylaxis against rejection was accomplished with a combination of high-dose steroids and azathioprine. However, with only these drugs, early survival was limited by complications of rejection and infection. In 1980, the introduction of cyclosporine profoundly changed the clinical practice of heart transplantation, resulting in a 20% improvement of the l-year survival rate in adults.5 Furthermore, cyclosporine allowed for a reduction in the dose of corticosteroids administered to recipients. For many patients, this reduced the risks of the most severe complications of immunosuppression, including growth impairment, with significant implications for pediatric patients. In this context, enthuAddress correspondence to Daniel Bernstein, M.D., Department of Pediatrics, Stanford University Medical Center, 750 Welch Road, Suite 305, Palo Alto, CA 94304.

siasm was rekindled for heart transplantation in children, and Stanford University and other centers lowered the age limit for the procedure to younger and younger patients.

IMMUNOSUPPRESSION In the immediate postoperative period, immunosuppression is usually accomplished with a combination of four drugs. At Stanford, usually oral cyclosporine is given initially at 10 mg *kg-’ *day-i in older children; considerably larger dosages are used in infants. The dosage is adjusted to keep the trough serum level, as measured by radioimmunoassay techniques, between 150 and 200 ng/ml during the first several months after transplantation and between 75 and 150 ng/ml thereafter. These levels can be achieved with twice-daily doses in adolescents, but in infants and young children, three daily doses are recommended because of a shorter serum half-life at these ages.6 Several drugs can alter the pharmacokinetics of cyclosporine (Table l), and when these agents are also given, the dosage of cyclosporine must be adjusted. Azathioprine is started at 1 to 2 mg . kg-‘. day-’ once a day and the dosage is adjusted to maintain the total white blood cell count between 4000 and 5000 cells/ mmZ, although this degree of suppression is often not achieved in infants, even at a maximal dose of 3 mg* kg-l *day-‘. At Stanford and many other

Prog Pediatr Cardiol 1993; 2(4):34-41 Copyright 0 1993 by Andover Medical

Rejection

TABLE 1. Drugs that Interact with Cyclosporine Increased Cyclosporine Blood Level or Enhanced Toxicity

Decreased Cyclosporine Blood Level

Imipenem Ketoconazole or itraconazole Metoclopramide Trimethoprim/sulfamethoxazole Amphotericin Diltiazim Erythromycin

Dilantin Rifampin Barbiturates

centers, prednisone is started at 0.6 mg *kg-’ *day-l divided into two doses, although some centers use much higher doses of 3 mg . kg-l - day-’ in the immediate postoperative period.6 In some centers, corticosteroids are not used routinely to maintain immunosuppression, but are added later if rejection becomes difficult to control.6,7 At Stanford, the dose of prednisone is tapered slowly over the first 6 to 12 weeks to 0.2 mg.kg-l-day-‘. In children without evidence of significant allograft rejection, corticosteroids are tapered to an alternate-day regimen after 6 to 12 months, and then stopped if tolerated. Many transplantation centers use murine anti-human T-lymphocyte antibody (OKT3) in the early posttransplant period, although some centers do not use it in infants. OKT3 is given intravenously 0.5 to 5.0 mg/day for the first 2 weeks after transplantation. For the most part, this agent has replaced antithymocyte globulin (ATG) because it is associated with a significantly lower incidence of early rejection episodes and a lower level of toxicity.‘.’

IMMUNOLOGY OF REJECTION The immune system uses a group of cell-surface molecules, the major histocompatibility complex (MHC), to distinguish self from non-self. In humans, the MHC gene complex is located on the short arm of chromosome 6 and is designated the HLA complex. The MHC genes have been divided into four classes based on their structural similarities and function: class I genes encode the HLA-A, -B, and -C cell-surface antigens; class II genes encode the HLA-DR, -DP, and -DQ cell-surface antigens; class III genes encode some of the complement components, as well as the 21-hydroxylase enzyme and the cytokines tumor necrosis factor a and I);

35

the fourth class of genes, known as Qa and Tla in the mouse, are class I-like MHC products, which have not yet been demonstrated in the human and whose function is poorly understood. Class I and II MHC gene products are the major targets of allograft rejection. Class I antigens are composed of a highly polymorphic 45kD heavy chain, noncovalently associated with P-%-microglobulin, an invariant 12kD protein. Class II MHC molecules consist of a 35kD a-chain and a 29-kD B-chain, both of which exhibit considerable polymorphism. The three-dimensional structure of a number of human class I molecules has recently been determined by x-ray crystallography. The two external domains form parallel a-helices, which overlie a B-pleated sheet and produce a deep groove, which can bind antigenic fragments of -8 to 15 amino acids in length. Most of the variable amino acids lie in this region. Although the three-dimensional structure of class II molecules has not been fully identified, they are likely to resemble class I molecules. Class 1 molecules have been demonstrated on all cells, whereas class II expression is limited normally to B cells, activated T cells, monocytes, macrophages, and dendritic cells. However, a variety of stimuli, including cytokines such as interferon-y, can upregulate class II expression on most cells. Recognition of MHC in allograft rejection involves specific receptors. The B-cell receptor is an immunoglobulin that can recognize MHC products in the cell surface or as soluble molecules in serum. The T-cell antigen receptor is a complex of cellsurface glycoproteins composed of a heterodimer of antigen-binding peptides associated with at least four CD3 peptides. In addition, a variety of coreceptors or accessory molecules are required for efficient antigen recognition by T cells. These include the CD4 and CD8 glycoproteins, which serve as coreceptors for MHC class II and class I molecules, respectively, and the lymphocyte-functionassociated antigens. Graft rejection can be divided into a series of steps: (1) recognition and triggering of recipient immune T cells by foreign MHC molecules expressed on the endothelium of the graft, (2) extravasation of these activated cells and development of a local and systemic immune response involving CD4+ and CD8+ T cells as well as B cells, (3) infiltration of cells and induction of MHC expression on the graft, and (4) injury to the graft with necrosis.

36

Progress in Pediatric Cardiology

There are two mechanisms by which T cells destroy the allograft: (1) direct lysis by cytotoxic T lymphocytes and (2) release of soluble mediators, which can injure the graft directly or recruit and activate nonspecific cells to cause graft destruction. Antigraft antibodies are commonly formed during rejection, usually against the MHC antigens expressed on the graft. Clinically, rejection can be classified into hyperacute, acute, and chronic types. Hyperacute rejection is defined as a massive rejection occurring within minutes to hours after transplantation. Recipients with preformed donor-specific anti-class I or anti-ABO antibodies are at the highest risk, but preformed antibodies against other molecules expressed on the allograft also can cause this type of rejection. These antibodies bind to the endothelium and activate complement, resulting in severe and irreversible injury to the small and medium-sized vessels in the graft. Hyperacute rejection is uncommon because all potential donor-recipient pairs are screened before surgery for the presence of these inciting antibodies. The greatest risk for acute rejection usually occurs between 5 and 100 days after transplantation, and it is mediated largely by T cells. Although the risk of acute rejection is lower after this time, a low-level risk is always present. Cells infiltrate the graft and release cytokines, which damage the graft directly and recruit other lymphocytes into the rejection response. CDS+ cytotoxic T cells mediate direct lysis of the graft. Antibodies against donor MHC antigens sometimes can be detected in acute rejection, but their role in the rejection process is not clear. Acute rejection can be treated with agents such as corticosteroids, anti-T-cell antibodies, or total lymphoid irradiation (TLI), all of which eliminate the recipient’s lymphocytes. Chronic rejection occurs in - 40 % of adult heart transplantation recipients within 5 years after surgery. Chronic rejection, also called transplant coronary artery disease, involves obliteration of the coronary arteries by proliferation of smooth muscle in the vessel wall. The etiology of chronic rejection is unknown but it may involve an antibody response against antigens expressed on the graft.

DIAGNOSIS OF REJECTION Although cyclosporine has significantly reduced the morbidity from graft rejection, rejection re-

Coronary Artery Disease (6%) ,

STANFORD

Ooerative/Technical

,

,

Hemorrhaae

Chronic Rejection (6%) Cardiac Arrest (8%)

REGISTRY FIGURE 1. Causes of death among pediatric recipients of heart transplants. Data are compared among Stanford University and all other centers supplying information to the Registry of the International Society for Heart and Lung Transplantation.

mains one of the leading causes of death in both adult and pediatric heart transplantation recipients (Figure 1).3*10The incidence of acute graft rejection is greatest within the first 6 months after transplantation (Figure 2),4J*J2 and most pediatric patients will experience at least one episode of rejection within the 1st year after transplantation4J1Jz The clinical diagnosis of acute rejection can be difficult in pediatric patients. When present, clinical symptoms of rejection may include fatigue, fluid retention, abdominal discomfort, fever, or diaphoresis. Physical examination may reveal a new gallop rhythm or friction rub. The electrocardiogram may show reduction in voltages, atria1 or ventricu-

Rejection

01234567

12

Years Post Heart Transplant

FIGURE 2. Linearized rates of allogruft rejection in pediatric heart transplantation recipients at Stanford University.

lar arrhythmias, or atrioventricular heart block. The chest radiograph may show enlargement of the cardiac silhouette or an increase in pulmonary vascular markings. I2 Unfortunately, the addition of cyclosporine to immunosuppressive regimens has resulted in the loss of the sensitivity of these clinical and noninvasive signs of acute rejection,5,12 so that most rejection episodes in both adults and children occur without any detectable clinical symptoms.*3 Moreover, many of the symptoms that can be associated with rejection are nonspecific, such as fever and respiratory distress, and can have other causes, the most important of which is infection.6 Currently, most centers agree that endomyocardial biopsy is the only reliable method of rejection surveillance.4~6,13 Routine surveillance biopsies are combined with a schedule of clinical and noninvasive evaluations to detect covert episodes of acute rejection. However, even in patients with strong clinical or echocardiographic evidence of rejection, we believe that confirmation always should be obtained by microscopic examination of a myocardial biopsy. If a patient demonstrates evidence of hemodynamic compromise, however, we do not delay in administering an initial pulse of high-dose corticosteroids while preparations are made for biopsy. In infants and young children, right ventricular myocardial biopsy is accomplished with a flexible bioptome, introduced through a femoral vein sheath. In older children and adolescents, biopsies can be performed through femoral or internal jugular venous access. Myocardial biopsies have been performed at many centers in hundreds of pediatric

37

patients of all ages with a very low incidence of complications.‘J’ The frequency of surveillance biopsies varies by institution, patient age, and the history of rejection. In older children and adolescents, myocardial biopsies may be performed as often as weekly for the 1st month, every 2 weeks for the next 2 months, and then monthly for 6 months.i4 If the patient remains free of rejection, the frequency is reduced to a minimum of three or four biopsies per year. In infants and toddlers, surveillance biopsies usually are performed less often, and if the patient is relatively free of rejection, they may be performed as infrequently as twice yearly. Despite reliance on the endomyocardial biopsy examination as a “gold standard,” there is a small risk of sampling error, which increases if sufficient tissue is not obtained. Occasionally this can be a problem in infants and small children, where the depth of the tissue sample is limited, and this limitation should be considered in interpreting biopsy results. The lifelong use of routine screening biopsies presents several additional problems in pediatric patients. Although the development of smaller and more flexible bioptomes have reduced the risk of heart perforation in infants and children,13 problems remain because of patient inconvenience and loss of venous access from venous thrombosis and fibrous scarring. A sensitive and noninvasive method to detect early cardiac rejection is vital to the long-term success of pediatric heart transplantation. In this agegroup, echocardiography has received the most attention and evaluation as a method of recognizing rejection. But echocardiographic indices of systolic dysfunction are not useful predictors of rejection until significant myocardial damage has occurred.14 Before the use of cyclosporine, an echocardiographic increase in left ventricular mass was diagnostic of rejection. With the use of cyclosporine, however, the degree of myocardial edema associated with rejection has decreased, and this measurement is no longer sensitive or reliable.15 Doppler echocardiographic indices of diastolic left ventricular filling correlate with acute cardiac rejection in cyclosporine-treated adults.15 However, our initial experience shows that in children these indices are unreliable. Several new diagnostic modalities are being evaluated in adult recipients. These include MRI,16 fast Fourier-transformed electrocardiography,17 myocardial uptake of Technetium 99, pyro-

38

Progress in Pediatric Cardiology

TABLE 2. Standardized Endomyocardial

Biopsy Grading Systems

Grade

ISHLT System

Billingham System

0 1A 1B 2 3A 3B 4

No rejection Focal infiltration without myocyte necrosis Diffuse sparse infiltration without myocyte necrosis Single focus of aggressive infiltration with myocyte necrosis Multifocal infiltration with myocyte necrosis Diffuse inflammation with myocyte necrosis Diffuse aggressive infiltration, edema, hemorrhage, and vasculitis with myocyte necrosis

No rejection Mild rejection Mild rejection Focal moderate rejection Moderate rejection Borderline severe rejection Severe rejection

ISHLT, InternationalSociety for Heart and Lung Transplantation.

phosphate sional

and Gallium

deformation,19

against cardiac myosin2’

67,18 left ventricular torindium-labeled antibodies and monitoring of circulat-

ing lymphocyte subpopulations.21-23 None of these methods have been evaluated as yet for use in pediatric patients and, even if successful in adults, developmental differences in cardiovascular and immunologic function may make them less reliable in children. The interpretation of myocardial biopsy specimens has recently been standardized by the Heart Rejection Study Group of the International Society for Heart and Lung Transplantation (ISHLT).24 Initially, cardiac rejection was scored by Billingham et a1.24 into mild, moderate, and severe categories. However, differences between transplant centers made it difficult to compare meaningful intercenter data. The new system, adopted in 1990, is shown in Table 2 and compared with the Billingham classification. Grade 0 indicates no evidence of rejection. Grade 1A rejection is when there is focal, perivascular, or interstitial mononuclear cell infiltration with no evidence of myocyte necrosis. Grade 1B indicates a more diffuse version of lA, with no evidence of myocyte necrosis. Grade 2 rejection is associated with one sharply circumscribed focus of inflammation with myocyte damage within the focus. Grade 3A rejection represents an increased degree of perivascular and interstitial cellular infiltration associated with patches of myocyte necrosis (Figure 3). Grade 3B applies to a diffuse inflammatory process involving several pieces of biopsy tissue with aggressive infiltration, often with neutrophils and eosinophils, but usually without hemorrhage. Grade 4 rejection is associated with a florid interstitial infiltration with mononuclear cells and neutrophils, hemorrhage, and myocyte necrosis; edema and vasculitis are often present as well.

Occasionally, allograft rejection is suspected clinically but the myocardial biopsy specimen shows predominantly edema and myocyte damage with little or no cellular infiltration. In this circumstance, two causes should be considered. Myocyte damage is either from graft coronary artery disease with coronary ischemia or from humoral rejection. Because the transplanted heart is denervated, patients usually do not complain of angina pectoris, and a diagnosis of coronary ischemia must be based on clinical suspicion. When the signs of cardiac dysfunction are greater than that indicated by the histologic examination, coronary angiography should be performed to eliminate the possibility of coronary disease. With humoral rejection, the histologic findings include prominent endothelial swelling, vasculitis, and immunoglobulin and complement deposition demonstrated by immunofluorescence microscopy. 25In some of these patients, circulating cytotoxic antibodies against donor-derived HLA antigens have been detected.26

TREATMENT OF REJECTION When grade 1 (mild) rejection is diagnosed, major changes in immunosuppression usually are not indicated, although cyclosporine and azathioprine doses may be adjusted to optimize serum levels and the white blood count. A repeat biopsy usually is obtained within 2 weeks. In adults with grade 1 rejection,

21% to 43% have progression

grades of rejection,

to higher

whereas others resolve spontaneously.27 When grade 2 or 3 (moderate) or grade 4 (severe) rejection is diagnosed, treatment usually involves a supplementary course of pulsed corticosteroids. In the early posttransplant period, this involves the administration of intravenous methylprednisolone (15 mg* kg-‘*day-*) for 3 days. This

Rejection

39

FIGURE 3. Diagnosis of cardiac graft rejection by endomyocardial biopsy. This photomicrograph demonstrates grade 3A (moderate) acute rejection with focal aggregates and interstitial mononuclear cells causing myocyte necrosis (courtesy of Dr.-M. E. Billingham).

corticosteriod pulse may be given orally in patients who meet the following criteria: (1) >l year posttransplant, (2) absence of symptoms related to the rejection episode, (3) only moderate grades 2 or 3 of acute rejection (episodes of severe rejection, even if asymptomatic, should be treated intravenously in the hospital), and (4) absence of a history of multiple or previous refractory rejection episodes. For teenagers and children >50 kg, prednisone is given at 50 mg twice daily for 3 days for a total of 6 doses, and is then tapered by 5 mg/dose each day. For younger children, prednisone is given at 1 mg/kg b.i.d. for 3 days and tapered gradually over 2 weeks. The taper should stop when the dose is 50% to 100% above the prerejection dose. Cyclosporine and azathioprine doses are adjusted as required, and a repeat biopsy is performed 10 to 14 days after treatment. If the biopsy shows resolution, corticosteroids can be gradually tapered over several months to the previous dose. Persistent rejection may be treated with a second 3-day course of pulsed methylprednisolone. However, if rejection persists after a second course of corticosteroids, several additional forms of therapy are available. A repeat course of 0KT3 may be

given to patients who have not developed antibodies to the murine component of the antibody.8 0KT3 treatment has been shown to reverse episodes of resistant rejection in up to 90% of patients.= ATG (50 to 200 mg intravenously) is used by some centers when 0KT3 is either ineffective or cannot be given because of antiidiotypic antibodies.6 Methotrexate has been used with success in a few older children, administered in three doses ranging from 2.5 to 7.5 mg every 8 to 12 hours once weekly, adjusted on the basis of the white blood cell count. Methotrexate therapy of acute refractory rejection has been shown to be successful in adultsz9 Total lymphoid irradiation has been used in several children. It has a theoretical advantage of possibly producing long-term graft tolerance.30 At Stanford, four pediatric patients, 6 months to 12 years of age, with refractory rejection responded initially to TLI with resolution of their rejection episodes. Two of them have had longterm rejection prophylaxis with TLI; in the other two, the benefits have been only transient. Finally, the ultimate treatment for refractory rejection is retransplantation, which has been successful in several pediatric patients.3

40

Progress in Pediatric Cardiology

The treatment of humoral rejection is controversial. Many centers use the same initial high-dose corticosteriod regimen outlined above. Others recommend the addition of methotrexate. Several centers have used plasmapheresis to treat patients with humoral rejection. ” At Stanford, we have successfully used plasmapheresis to treat a suspected case of humoral rejection in a o-month-old infant. The development of new immunosuppressive regimens will result in improvement in posttransplant survival rates. The prophylactic use of 0KT3 has reduced early rejection episodes, and in many patients, it has allowed corticosteroids to be stopped.* However, in several studies, 0KT3 has been linked to an increased incidence of lymphoproliferative disorders.3z TLI has been used with mixed results as prophylactic therapy in adultsN Finally, monoclonal antibodies against the T-cell marker CD4 are now undergoing clinical trials in adults. In pediatric transplantation, there is an important need to improve the means of cardiovascular support for children with severe rejection. Before transplantation and during severe rejection episodes, many adults receive mechanical circulatory support ranging from the intraaortic balloon pump to use of a total artificial heart.33 We have used the intraaortic balloon pump successfully in older children with severe rejection, and an isolated left ventricular assist device has been helpful in a 3-month-old pretransplant patient.

SUMMARY The early and midterm results of pediatric heart transplantation are encouraging. The procedure has evolved from an experimental therapy to an accepted medical practice for infants and children with lethal cardiomyopathy or severe congenital heart defects. The risk of rejection, though reduced by the use of cyclosporine, continues to be a significant threat to long-term survival. Several problems of rejection have special significance in children. The requirement for lifelong immunosuppression, with longer exposure to side effects, and the difficulty of performing repeated myocardial biopsies emphasize the need for accurate noninva-

sive methods of recognizing rejection. There is interest in and controversy about the optimal timing for pediatric heart transplantation, especially in infants with complex congenital heart defects. Al-

though studies have demonstrated immunological immaturity in the newborn, it remains to be seen whether this will be translated into a real long-term clinical advantage. Although the ultimate prospects for pediatric heart transplant patients remain uncertain, improvements in rejection monitoring and treatment will surely increase the prospects for long-term survival.

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after heart transplantation in children. J Heart Transplant. 1987;6:298-302. 14. Dawkins KD, Oldershaw PI, Billingham ME, et al. Noninvasive assessment of cardiac allograft rejection. Transplant Proc. 1985;17:215-217. 15. Valantine HA, Fowler MB, Hunt SA, et al. Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection. Circulation. 1987;76:(suppl 5):86-92. 16. Kurland RJ, West J, Kelley S, et al. Magnetic resonance imaging to detect heart transplant rejection: sensitivity and specificity. Transplant Proc. 1989; 21~2537-2543. 17. Reichenspumer H, Haberl R, Angermann C, et al. New methods for noninvasive monitoring of rejection after heart transplantation. Tex Heart lnst J. 1988;15:7-11. 18. Bergsland J, Carr EA. Wright JW, et al. Uptake of myocardial imaging agents by rejected hearts. Heart Transplant. 1985;4:536-540. 19. Hansen DE, Daughters GTI, Alderman EL, Stinson EB, Baldwin JC, Miller DC. Effect of acute human cardiac allograft rejection on left ventricular systolic torsion and diastolic recoil measured by intramyocardial markers. Circulation. 1987;76:998-1008. 20. Frist W, Yasuda MD, Segall G, et al. Noninvasive detection of human cardiac transplant rejection with indium-111 antimyosin (Fab) imaging. Circulation. 1987;76(suppl 5):81-85. 21. Ertel W, Reichenspurner H, Lersch C, et al. Cytoimmunological monitoring in acute rejection and viral, bacterial or fungal infection following transplantation. Heart Transplant. 1985;4:390-394. 22, OToole CM, Maher I’, Spiegelhalter DJ, et al. ‘Rejection or infection’ predictive value of T-cell subject ratio, before and after heart transplantation. Heart Transplant. 1985;4:518-524. 23. Pelletier LC, Montplasir S, Pelletier G, et al. Lymphocyte subpopulation monitoring in cyclosporinetreated patients following heart transplantation. Ann Thorac Surg. 1988;45:11-15.

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24. Billingham M, Cary N, Hammond M, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart rejection study group. J Heart Transplant. 1990;9: 587-593. 25. Hammond E, Yowell R, Nunoda S, et al. Vascular (humoral) rejection in heart transplantation: pathologic observations and clinical implications. J Heart Transplant. 1989;8:430-443. 26. Rose E, Smith C, Petrossian G, Barr M, Reemtsma K. Humoral immune responses after cardiac transplantation: correlation with fatal rejection and graft atherosclerosis. Surgery. 1989;106:203-207. 27. Imakita M, Tazelaar HD, Billingham ME. Heart allograft rejection under varying immunosuppressive protocols as evaluated by endomyocardial biopsy. J Heart Transplant. 1986;5:279-285. 28. Costanzo-Nordin MR, Silver MA, O’Connell JB, et al. Successful reversal of acute cardiac allograft rejection with 0KT3 monoclonal antibody. Circulation. 1987;76(suppl 5):71-80. 29. Costanzo-Nordin M, Grusk B, Silver M, et al. Reversal of recalcitrant cardiac allograft rejection with methotrexate. Circulation. 1988;78:11147-57. 30. Strober S, Dhillon M, Schubert M, et al. Acquired immune tolerance to cadaveric renal allografts: a study of three patients treated with total lymphoid irradiation. N Engl J Med. 1989;321:28-33. 31. Stegmayr B, Svalander C, Persson H. Reversal of kidney transplant rejection after plasmalymphocytapheresis. Transplant Proc. 1988;20:455-456. 32. Swinnen L, Costanzo-Nordin M, Fisher S, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody 0KT3 in cardiac-transplant recipients. N Engl J Med. 1990;323:1723-1728. 33. Stames VA, Oyer PE, Portner PM, et al. Isolated left ventricular assist device as bridge to cardiac transplantation. J Thorac Cardiovasc Surg. 1988;96: 62-71.