Techniques of Immunosuppression After Cardiac Transplantation
MICHAEL D. McGOON, M.D., ROBERT P. FRANTZ, M.D., Division of Cardiovascular Diseases and Internal Medicine
Modulation of the normal immune response is the major challenge for successful organ transplantation. Cardiac allograft rejection is primarily the result of activation of T cells. Most currently used immunosuppressive agents mainly affect the T-cell-mediated limb of the immune system. Immunosuppressive strategies can be considered to have three goals: (1) prophylaxis against rejection early after cardiac transplantation, (2) long-term maintenance prophylaxis, and (3) treatment of acute rejection. The extent of immunosuppression needed varies with the time after transplantation and the rejection profile of the individual patient. The goal is to provide sufficient immunosuppression to retard rejection without causing undesirable side effects, including infection and neoplasms.
The current level of success of cardiac transplantation is critically dependent on the availability of immunosuppressive agents that effectively prevent or attenuate graft rejection. These agents must be administered carefully, and the regimen should be individualized to meet the particular requirements of each patient. Excellent detailed reviews of immunosuppression in cardiac transplantation are available; a recent review by members of the Utah Transplant Group is especially useful.' In this article, we review the fundamental mechanisms of rejection, outline the mechanisms of action of the available immunosuppressive agents, and discuss the recommended applications of these agents.
MECHANISMS OF REJECTION Because transplanted hearts are allografts in which the donor and recipient are homologous (of the same species but genetically nonidentical), the recipient's immune system can identify the donor organ as being "nonself." For such identification, the recipient recognizes proteins encoded by the major histocompatibility complex of the donor's genes, as well as other poorly understood antigens.P These proteins are collectively referred to as the human leukocyte antigens.' Macrophages respond to the presence of these foreign antigens on the donor organ. Some of the antigens are internalAddressreprintrequeststo Dr. R. P. Frantz,Divisionof Cardiovascular Diseases,Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:586-595, 1992
ized by the macrophages. Many of the internalized antigens are degraded, but some are processed and return to the macrophage surface. T cells then can recognize the processed antigen on the macrophage surface. After this recognition, the T cell binds to the macrophage, a process that stimulates release of interleukin 1 from the macrophage. As a result, T cells are activated, and rejection ensues (Fig. 1). Available clinical evidence suggests that the greater the degree of mismatching of human leukocyte antigens between the donor and recipient,the lower the survival of cardiac transplant patients'> (Fig. 2) and the greater the frequency of rejection. Therefore, prospective matching of human leukocyte antigens would be a desirable method of decreasing the probability of rejection. Unfortunately, because the ischemic time during heart transplantation must be brief, prospective matching of human leukocyte antigens between donors and recipients is generally impractical."? Hence, the prevention and treatment of rejection focus on the judicious application of various immunosuppressive agents and techniques. Because these agents influence the cellular immune response at various points in the "rejection cascade" (Fig. 1), they act synergistically and are often used concurrently for optimal prophylaxis. In addition, one agent can be added during an episode of acute rejection to provide a supplementary effect. In the absence of immunosuppression, rejection would occur in virtually all allograft recipients. 586
Mayo Clin Proc, June 1992, Vol 67
IMMUNOSUPPRESSION AFTER CARDIAC TRANSPLANTATION
Cytolysis
587
Phagocytosis
Fig. 1. Diagram showing rejection cascade and sites of action of immunosuppressive agents commonly used for cardiac transplantation. Ag = antigen; ALG = antilymphocyte globulin; ATG =antithymocyte globulin; IL = interleukin; MHC =major histocompatibility complex.
SPECIFIC IMMUNOSUPPRESSIVE REGIMENS Available immunosuppressive agents and their mechanisms of action are outlined in Table 1. No immunosuppressive agent or regimen can be considered ideal; all have side effects and potential adverse consequences, efficacy is not infallible, and, from a mechanistic perspective, none uniquely inhibits those lymphocytes activated by and directed against donor-specific alloantigens.!" Cyclosporine.-Cyclosporine, currently the mainstay of immunosuppressive therapy, was first used in cardiac transplantation in December 1980. It is an l l-amino acid polypeptide isolated from the fungus Tolypocladium inflatum. The use of cyclosporinehas positively and substantially influenced survival for recipients of cardiac transplants (Fig. 3). Despite extensive evaluation, the precise mechanism of action of cyclosporine remains uncertain. Current concepts suggest that cyclosporine passively diffuses into the cytoplasm of T cells and interferes with messenger RNA transcription involved in the production of lymphokines, including production of interleukin 2 by helper T cells.U-? Thus, the immune response is interrupted by preventing the activation and proliferation of helper and cytotoxic T cells (Table 1
and Fig. 1). Investigators have observed that, clinically, cyclosporine exerts its beneficial effect less by preventing rejection than by reducing the severity of the episodes. 1,13 When used alone, cyclosporine is considered inadequate as an immunosuppressive agent for cardiac transplantation. \ Cyclosporine apparently does not bind to the T-cell membrane or influence the early stages of the cellular immune response, such as signal reception (antigen binding to T-cell receptors), transduction, and calcium influx." Cyclosporine may be administered either intravenously or orally (in liquid or capsule form). Bioavailability seems to increase over time." The volume of distribution is large (approximately 4Iiters/kg), and the predominant site of distribution is the liver, 10 where cyclosporine is metabolized by demethylation and hydroxylation'! and excreted in the bile. Renal excretion of the parent compound and metabolites is negligible." Because the pharmacokinetic behavior of cyclosporine varies considerably, both in the same person and from patient to patient.P-'? and because the concentration of the drug in the blood usually correlates with effectiveness and toxicity, careful monitoring of drug levels is an integral part of management of patients who have undergone cardiac transplantation. The dose of cyclosporine used in cardiac
588
IMMUNOSUPPRESSION AFTER CARDIAC TRANSPLANTATION
Table I.-Available Immunosuppressive Agents or Regimens and Their Mechanisms of Action*
100 0,1 (n=19)
80
~
iii
60
en
(n=39)
Corticosteroids t
3
(n = 73) (n-33)
Azathioprinet
40
Cyclophosphamidet
20
Vincristine sulfate Cyclosporinet
0
0
Years
Fig. 2. Actuarial survival of cardiac transplant recipients based on number of human leukocyte antigen A and B loci mismatches between donor and recipient. Curves are labeled with number of mismatches (and number of patients). All curves except those depicting no or one mismatch versus two mismatches and three versus four mismatches were different to a statistically significant extent (P
MICHAEL D. McGOON, M.D., ROBERT P. FRANTZ, M.D., Division of Cardiovascular Diseases and Internal Medicine
Modulation of the normal immune response is the major challenge for successful organ transplantation. Cardiac allograft rejection is primarily the result of activation of T cells. Most currently used immunosuppressive agents mainly affect the T-cell-mediated limb of the immune system. Immunosuppressive strategies can be considered to have three goals: (1) prophylaxis against rejection early after cardiac transplantation, (2) long-term maintenance prophylaxis, and (3) treatment of acute rejection. The extent of immunosuppression needed varies with the time after transplantation and the rejection profile of the individual patient. The goal is to provide sufficient immunosuppression to retard rejection without causing undesirable side effects, including infection and neoplasms.
The current level of success of cardiac transplantation is critically dependent on the availability of immunosuppressive agents that effectively prevent or attenuate graft rejection. These agents must be administered carefully, and the regimen should be individualized to meet the particular requirements of each patient. Excellent detailed reviews of immunosuppression in cardiac transplantation are available; a recent review by members of the Utah Transplant Group is especially useful.' In this article, we review the fundamental mechanisms of rejection, outline the mechanisms of action of the available immunosuppressive agents, and discuss the recommended applications of these agents.
MECHANISMS OF REJECTION Because transplanted hearts are allografts in which the donor and recipient are homologous (of the same species but genetically nonidentical), the recipient's immune system can identify the donor organ as being "nonself." For such identification, the recipient recognizes proteins encoded by the major histocompatibility complex of the donor's genes, as well as other poorly understood antigens.P These proteins are collectively referred to as the human leukocyte antigens.' Macrophages respond to the presence of these foreign antigens on the donor organ. Some of the antigens are internalAddressreprintrequeststo Dr. R. P. Frantz,Divisionof Cardiovascular Diseases,Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:586-595, 1992
ized by the macrophages. Many of the internalized antigens are degraded, but some are processed and return to the macrophage surface. T cells then can recognize the processed antigen on the macrophage surface. After this recognition, the T cell binds to the macrophage, a process that stimulates release of interleukin 1 from the macrophage. As a result, T cells are activated, and rejection ensues (Fig. 1). Available clinical evidence suggests that the greater the degree of mismatching of human leukocyte antigens between the donor and recipient,the lower the survival of cardiac transplant patients'> (Fig. 2) and the greater the frequency of rejection. Therefore, prospective matching of human leukocyte antigens would be a desirable method of decreasing the probability of rejection. Unfortunately, because the ischemic time during heart transplantation must be brief, prospective matching of human leukocyte antigens between donors and recipients is generally impractical."? Hence, the prevention and treatment of rejection focus on the judicious application of various immunosuppressive agents and techniques. Because these agents influence the cellular immune response at various points in the "rejection cascade" (Fig. 1), they act synergistically and are often used concurrently for optimal prophylaxis. In addition, one agent can be added during an episode of acute rejection to provide a supplementary effect. In the absence of immunosuppression, rejection would occur in virtually all allograft recipients. 586
Mayo Clin Proc, June 1992, Vol 67
IMMUNOSUPPRESSION AFTER CARDIAC TRANSPLANTATION
Cytolysis
587
Phagocytosis
Fig. 1. Diagram showing rejection cascade and sites of action of immunosuppressive agents commonly used for cardiac transplantation. Ag = antigen; ALG = antilymphocyte globulin; ATG =antithymocyte globulin; IL = interleukin; MHC =major histocompatibility complex.
SPECIFIC IMMUNOSUPPRESSIVE REGIMENS Available immunosuppressive agents and their mechanisms of action are outlined in Table 1. No immunosuppressive agent or regimen can be considered ideal; all have side effects and potential adverse consequences, efficacy is not infallible, and, from a mechanistic perspective, none uniquely inhibits those lymphocytes activated by and directed against donor-specific alloantigens.!" Cyclosporine.-Cyclosporine, currently the mainstay of immunosuppressive therapy, was first used in cardiac transplantation in December 1980. It is an l l-amino acid polypeptide isolated from the fungus Tolypocladium inflatum. The use of cyclosporinehas positively and substantially influenced survival for recipients of cardiac transplants (Fig. 3). Despite extensive evaluation, the precise mechanism of action of cyclosporine remains uncertain. Current concepts suggest that cyclosporine passively diffuses into the cytoplasm of T cells and interferes with messenger RNA transcription involved in the production of lymphokines, including production of interleukin 2 by helper T cells.U-? Thus, the immune response is interrupted by preventing the activation and proliferation of helper and cytotoxic T cells (Table 1
and Fig. 1). Investigators have observed that, clinically, cyclosporine exerts its beneficial effect less by preventing rejection than by reducing the severity of the episodes. 1,13 When used alone, cyclosporine is considered inadequate as an immunosuppressive agent for cardiac transplantation. \ Cyclosporine apparently does not bind to the T-cell membrane or influence the early stages of the cellular immune response, such as signal reception (antigen binding to T-cell receptors), transduction, and calcium influx." Cyclosporine may be administered either intravenously or orally (in liquid or capsule form). Bioavailability seems to increase over time." The volume of distribution is large (approximately 4Iiters/kg), and the predominant site of distribution is the liver, 10 where cyclosporine is metabolized by demethylation and hydroxylation'! and excreted in the bile. Renal excretion of the parent compound and metabolites is negligible." Because the pharmacokinetic behavior of cyclosporine varies considerably, both in the same person and from patient to patient.P-'? and because the concentration of the drug in the blood usually correlates with effectiveness and toxicity, careful monitoring of drug levels is an integral part of management of patients who have undergone cardiac transplantation. The dose of cyclosporine used in cardiac
588
IMMUNOSUPPRESSION AFTER CARDIAC TRANSPLANTATION
Table I.-Available Immunosuppressive Agents or Regimens and Their Mechanisms of Action*
100 0,1 (n=19)
80
~
iii
60
en
(n=39)
Corticosteroids t
3
(n = 73) (n-33)
Azathioprinet
40
Cyclophosphamidet
20
Vincristine sulfate Cyclosporinet
0
0
Years
Fig. 2. Actuarial survival of cardiac transplant recipients based on number of human leukocyte antigen A and B loci mismatches between donor and recipient. Curves are labeled with number of mismatches (and number of patients). All curves except those depicting no or one mismatch versus two mismatches and three versus four mismatches were different to a statistically significant extent (P
