Transplantation 50 Years Later — Progress, Challenges, and Promises
http://www.100md.com
《新英格兰医药杂志》
Historical Perspective
On December 23, 1954, a surgical team at the Peter Bent Brigham Hospital in Boston, under the direction of Joseph Murray, removed a kidney from a healthy donor and transplanted it into his identical twin, who had chronic glomerulonephritis and was being sustained on the newly modified Kolff–Brigham artificial kidney machine.1 The organ functioned immediately,2 and the recipient survived for nine years, at which time his allograft failed from recurrent glomerulonephritis. The donor has survived for 50 years. Other historical details are provided by Morris elsewhere in this issue of the Journal.3 This first organ transplantation was not an isolated event but, rather, the result of a defined goal of developing a transplantation research program, initiated in the mid-1940s by George W. Thorn, the chairman of medicine, and Francis D. Moore, the chairman of surgery, at Peter Bent Brigham.
(Figure)
The First Identical-Twin Kidney Transplantation, Performed on December 23, 1954.
Photograph courtesy of Brigham and Women's Hospital.
As more transplantations were performed between identical twins,4 approaches to suppressing the recipient's immune system were pursued so that transplantation might be extended beyond procedures involving identical twins. Although the knowledge base in immunology was still rudimentary, the antibodies specific to pathogenic bacteria were well known. Furthermore, in 1925, Emile Holman, a surgeon at Peter Bent Brigham who performed skin grafts in children with extensive burns, reported in 1924 that repeated grafts from maternal donors were rejected more rapidly than the initial grafts, which indicated donor-specific sensitization to the "proteins" of individual volunteer donors.5 The first approach to suppressing the rejection process, taken in the early 1950s, involved the use of sublethal total-body irradiation combined with cortisone. These attempts were failures, with the exception of some transplantations between nonidentical twins — first at Peter Bent Brigham6 and a few weeks later in Paris7 — which provided the impetus to search for more effective ways to prevent rejection.
Robert Schwartz and William Dameshek, hematologists at Tufts University School of Medicine, expanded this horizon in 1959, when they reported that 6-mercaptopurine (6-MP), which was already in clinical use for the treatment of acute lymphocytic leukemia, suppressed the immune response in rabbits.8,9 The Wellcome Research Laboratory then synthesized several variants of 6-MP for screening by Joseph Murray and Roy Calne in canine kidney transplantations. Only one candidate drug, azathioprine, resulted in long-term survival — and in only a small number of animals. These observations prompted a rather anxious start to the first clinical trial, in 1962, of chemical immunosuppression involving azathioprine.10 In patients in whom azathioprine was combined with a corticosteroid, one-year rates of allograft survival in the range of 40 to 50 percent were observed, an enormous improvement over the canine results. These clinical breakthroughs were ultimately recognized by awarding of Nobel Prizes to Joseph Murray (and others), for the first clinical transplantation and the first use of immunosuppression, and to George Hitchings and Gertrude Elion of the Wellcome Laboratory, for the development of drugs, including azathioprine, that affect nucleotide pathways.
Progress and Challenges
The rate of successful transplantation of kidneys from cadaveric donors and familial HLA-matched living donors slowly increased during the 1960s and early 1970s, following the introduction of azathioprine with corticosteroids. Although the initial effect was beneficial, prolonged use of corticosteroids resulted in a high mortality rate due to excessive immunosuppression. Overall mortality rates also fell as programs for long-term dialysis improved, which made it possible to discontinue immunosuppression and sustain life when grafts failed. In the early 1980s, cyclosporine was introduced, which increased the rate of one-year graft survival from 70 percent to more than 80 percent.11 Further developments in the 1980s established the clinical utility of liver, heart, and lung transplantation. More recently, improvement in pancreatic transplantation and early promise in the transplantation of isolated islets have opened up new options for patients with type 1 diabetes.12,13,14
At the end of 2002, in the United States there were 150,000 people living with functioning solid-organ allografts, up from 62,000 in 1993.15 Transplantation has had a worldwide effect; there is significant organ-transplant activity in a large number of other countries.
Chronic Allograft Dysfunction
During the past decade, as increasing numbers of more powerful immunosuppressive agents became available, the short-term (i.e., 1-year) rate of organ survival significantly improved, yet the long-term results (5-to-10-year survival) did not. Table 1 shows the rates of allograft and patient survival in the United States among patients who received transplants between 1993 and 2002.16 Table 2 provides the numbers of transplantations for each organ in relation to the size of the waiting lists for those organs.17
Table 1. Mean Rates of Graft and Patient Survival for Transplantations in the United States from 1993 through 2002.
Table 2. Transplantation According to Organ and Donor Type, 1993 through 2003.
As Table 1 shows, the survival rates for kidney grafts from living donors are superior to those for grafts from cadaveric donors at 1, 5, and 10 years, but after a decade, the rate drops to 55 percent. Transplants from HLA-identical living donors would be expected to have a survival rate of 70 to 75 percent at 10 years. The initial excitement that followed a report that long-term survival of renal allografts may be improving, especially in recipients who had never had an episode of acute rejection,18 has faded as newer data19 showed that, although the rates of acute rejection are at their lowest, the long-term risk of graft loss has not improved and may have even worsened. The reasons for chronic allograft dysfunction involve many factors that concern variable tissue injuries at the time of transplantation or during subsequent episodes of rejection. However, even in the case of grafts with good function in the early years after transplantation, progressive tissue damage and slow decrements in function — conservatively called "chronic allograft dysfunction" — may develop, most often with considerable vasculopathy.20 Accumulating evidence in animals and humans suggests that there is a consistent pattern in which low-level IgG alloantibodies are directed at HLA antigens, or in which T cells are primed to donor HLA peptides, in those organ-transplant recipients in whom progressive allograft dysfunction occurs.20,21,22,23,24 Chronic allograft dysfunction affects all transplanted organs and is the most common cause of graft loss after the first year after transplantation.20
When a transplanted kidney is rejected, the patient returns to dialysis while waiting for another transplant. The situation with liver transplants differs in that recurrent disease, such as hepatitis C, remains the most common cause of long-term graft loss.25 Since initially high levels of immunosuppression cannot be tolerated over the long term and must be tapered, it is not surprising that breakthroughs in antigen recognition and alloimmune activation can occur. A common feature of drugs used in transplantation,26 such as DNA-synthesis inhibitors, calcineurin inhibitors, and sirolimus, is their suppression of primary immune responses in naive lymphocytes; these drugs have less of an effect on the expanded clones of primed effector and memory cells.27 The in vitro culturing of lymphocytes from the peripheral blood with donor HLA peptides that are bound to the antigen-presenting cells of the recipient is a test used to identify the priming of T cells to specific HLA antigens.28,29 This test is indicative of immunization through the physiologic pathway of T-cell recognition (the "indirect pathway") (Figure 1), which leads to a switch from IgM to IgG antibodies.28,30 The "direct pathway," the main driving force in acute rejection, is an anomaly unique to transplantation in which T cells recognize intact HLA molecules on donor cells.28,29
Figure 1. Mechanisms of Chronic Allograft Dysfunction.
Factors that are both dependent on and independent of alloantigens contribute to chronic organ damage after transplantation. Classic acute rejection starts with T-cell recognition of intact donor HLA molecules (the direct pathway, unique to allotransplantation), and there is an immediate response of inflammatory factors independent of alloantigens such as cytokines, complement, and natural killer cells of the innate immune system. Patients with progressive allograft dysfunction have been shown to have low levels of T cells that are activated in response to donor allopeptides presented by their own antigen-presenting cells. This is the classic pathway for recognition of all other foreign proteins and is called the indirect pathway for transplantation. It is a necessary first step in the production of mature IgG antibodies to alloantigens. Chronic immunologic injury that is driven by T-cell recognition of alloantigens can be promoted by an innate immune-system reaction to tissue damage that is present before transplantation or is a result of the ischemic injury at the time of transplantation. This smoldering, progressive, chronic process is unresponsive to the modes of therapy that are effective against acute rejection. In addition, calcineurin inhibitors (CNI) are nephrotoxic and can contribute to progressive allograft dysfunction.
In support of the concept that the alloimmune response plays a major role in chronic rejection is the observation that chronic rejection in recipients of kidney transplants is more common in those who have acute rejection and in those who have received HLA-mismatched grafts.20 In addition, subclinical rejection, as detected by biopsy, without evidence of allograft dysfunction, may be an important contributor to chronic allograft damage.31 Nonetheless, factors independent of antigens, including fibrosis that is mediated by calcineurin inhibitors,31 do contribute to chronic graft injury (Figure 1). The identification of an effective means of preventing or intervening in chronic rejection at an early stage by targeting the factors that are both dependent and independent of alloantigens remains a challenge.20
Long-Term Need for Immunosuppression
Immunosuppressive drugs that have been introduced since 1995 have led to combination therapies that have significantly lowered the rates of acute rejection.19 Induction therapies with various antilymphocyte antibodies also reduce the rate and intensity of acute rejection and possibly prevent the onset of chronic rejection.26,32 All immunosuppressive drugs have specific side effects and additively contribute to an overall state of immunosuppression, which leads to an increased risk of infections and various specific malignant conditions.26 Such drugs probably contribute to the increased risk of cardiovascular disease, which is the most common cause of premature death in transplant recipients.33,34 Excessive total immunosuppression causes a susceptibility to infectious diseases,35 especially to DNA viruses such as cytomegalovirus, Epstein–Barr virus, and the more recently recognized polyomavirus, which causes nephropathy and renal allograft loss.36
Over the past two decades, empirical trials have led to protocols of combination therapy that reduce side effects yet maintain graft survival. A major challenge in regard to long-term immunosuppression is the need for expanded multicenter trials of various combination therapies and for the development of inexpensive and noninvasive tools to define and monitor responses along the spectrum of immunity toward, ultimately, tolerance.37 New candidates for treatment such as T-cell–depleting agents38,39,40 and T-cell blockade,28,41 all of which are used to modify the immune responses, are under study, and some transplant biologists believe that combinations of drugs without side effects will eventually be available. For example, the use of target-of-rapamycin inhibitors as a way to avoid the use of calcineurin inhibitors in recipients of kidney transplants has recently been reported to improve long-term renal function,42 decreasing the pathologic changes of chronic allograft nephropathy.43
Although a small number of grafts are not rejected after the removal of all or most of the medications used for the maintenance of immunosuppression, trials involving the deliberate withdrawal of immunosuppressive drugs according to protocol do not suggest that it is safe to do so for most patients. One reason is the lack of specific and sensitive assays that can predict the safety of drug withdrawal.44 Processes of both acute and chronic rejection can occur when therapeutic agents are reduced. Nonetheless, the induction of immunologic tolerance by intensive manipulation of recipient immunity during the very early weeks after transplantation remains the ultimate goal.44 In that regard, the National Institutes of Health Immune Tolerance Network (www.immunetolerance.org) has recently approved various pilot clinical trials designed to explore the biology of tolerance in humans; these studies should shed light on whether such a goal can be achieved.44,45
Medical Complications
Whereas infections are responsible for 11.7 percent of deaths in the recipients of primary renal transplants beyond the first year after transplantation, and malignant conditions account for 10.1 percent of such deaths, cardiovascular diseases account for 30.1 percent.46 Renal dysfunction itself is a cardiovascular risk factor before transplantation, given its association with hypertension, anemia, and lipid disorders.33 Indeed, renal function one year after transplantation is an important predictor of long-term graft survival in kidney transplantation.47 Furthermore, renal dysfunction (i.e., dysfunction of native kidneys) is being recognized as a significant clinical problem in recipients of nonrenal solid-organ allografts.48 Diabetes, which is present in 20 percent of patients who receive transplants,49 is also an important clinical problem that contributes to the risk of cardiovascular disease and hypertension. In addition, the use of calcineurin inhibitors and corticosteroids is associated with new cases of diabetes after transplantation, and the incidence has been rising in recent years.50
Organ Shortage
There is a shortage of available organs for patients on waiting lists, and the gap between supply and demand continues to grow51,52 (Table 2). The consent rate for cadaveric donors is only 50 percent. The increased willingness of living donors other than immediate family members to donate has recently led to some increase in the supply of kidneys.53 This has also allowed more patients to benefit from preemptive transplantation, which occurs before the institution of long-term dialysis,54 and thus avoids a period of potential complications. Live-donor laparoscopic nephrectomy, with its shorter recovery time, has helped to increase the willingness to donate. In addition, the use of kidneys from marginal donors — those older than 60 years of age, who were heretofore not accepted as donors because their kidneys are generally unlikely to function for more than five to eight years — is being considered. There are potential opportunities for the exchange of donors in pairs in cases in which there are incompatibilities in the blood group or HLA antibody pattern between an individual donor and recipient. Annual mortality rates among patients on waiting lists for organs from cadaveric donors are currently 6 percent for patients waiting for a kidney, 10 percent for those awaiting a liver, 12 percent for those waiting for a lung, and 14 percent for those who need a heart.55
Summary
A half-century has elapsed since the first organ transplantation, and this procedure is now accepted as the treatment of choice for end-stage organ failure. Although tremendous progress has contributed to the success of this therapy, several challenges remain if transplantation is to be widely available with minimal risks and optimal outcomes. Recent advances in the science of organ and cell transplantation provide hope that a variety of chronic diseases will ultimately be cured.
Source Information
From the Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, and Harvard Medical School, Boston.
References
Merrill JP. The artificial kidney. N Engl J Med 1952;246:17-27.
Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins. JAMA 1956;160:277-282.
Morris PJ. Transplantation -- a medical miracle of the 20th century. N Engl J Med 2004;351:2678-2680.
Murray JE, Merrill JP, Harrison JH. Kidney transplantation between seven pairs of identical twins. Ann Surg 1958;148:343-359.
Holman E. Protein sensitization in iso-skin grafting: is the latter of practical value? Surg Gynecol Obstet 1924;38:100-106.
Merrill JP, Murray JE, Harrison JH, Friedman EA, Dealy JB Jr, Dammin GJ. Successful homotransplantation of the kidney between nonidentical twins. N Engl J Med 1960;262:1251-1260.
Hamburger J, Vaysse J, Crosnier J, Auvert J, Lalanne CM, Hopper J Jr. Renal homotransplantation in man after radiation of the recipient: experience with six patients since 1959. Am J Med 1962;32:854-871.
Schwartz R, Eisner A, Dameshek W. The effect of 6-mercaptopurine on primary and secondary immune responses. J Clin Invest 1959;38:1394-1403.
Schwartz R, Dameshek W. Drug-induced immunological tolerance. Nature 1959;183:1682-1683.
Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med 1963;268:1315-1323.
Kahan BD. Cyclosporine. N Engl J Med 1989;321:1725-1738.
Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-238.
Ricordi C, Strom TB. Clinical islet transplantation: advances and immunological challenges. Nat Rev Immunol 2004;4:259-268.
Harlan DM, Rother KI. Islet transplantation as a treatment for diabetes. N Engl J Med 2004;350:2104-2104.
Organ Procurement and Transplant Network. Prevalence of people living with a functioning transplant at end of year, 1993 to 2002. In: OPTN/SRTR 2003 annual report: summary tables, transplant data 1993-2002. Table 1.15. (Accessed December 2, 2004, at http://www.ustransplant.org.)
Unadjusted graft and patient survival at 3 months, 1 year, 3 years, 5 years, and 10 years: standard errors of the survival rates. In: OPTN/SRTR 2003 annual report: summary tables, transplant data 1993-2002. Table 1.14. (Accessed December 2, 2004, at http://www.ustransplant.org.)
OPTN/SRTR 2003 annual report: summary tables, transplant data 1993-2002. Tables 1.2, 1.3, 1.8, and fast facts about transplants for 2003. (Accessed December 2, 2004, at http://www.ustransplant.org.)
Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342:605-612.
Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378-383.
Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002;346:580-590.
Vella JP, Spadafora-Ferreira M, Murphy B, et al. Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction. Transplantation 1997;64:795-800.
Ciubotariu R, Liu Z, Colovai AI, et al. Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts. J Clin Invest 1998;101:398-405.
Reznik SI, Jaramillo A, SivaSai KS, et al. Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome. Am J Transplant 2001;1:228-235.
Baker RJ, Hernandez-Fuentes MP, Brookes PA, Chaudhry AN, Cook HT, Lechler RI. Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy. J Immunol 2001;167:7199-7206.
Gane EJ, Portmann BC, Naoumov NV, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 1996;334:815-820.
Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation. Lancet 1999;353:1083-1091.
Lakkis FG, Sayegh MH. Memory T cells: a hurdle to immunologic tolerance. J Am Soc Nephrol 2003;14:2402-2410.
Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998;338:1813-1821.
Briscoe DM, Sayegh MH. A rendezvous before rejection: where do T cells meet transplant antigens? Nat Med 2002;8:220-222.
Steele DJR, Laufer TM, Smiley ST, et al. Two levels of help for B cell alloantibody production. J Exp Med 1996;183:699-703.
Nankivell BJ, Borrows RJ, Fung CL-S, O'Connell PJ, Allen RDM, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-2333.
Vincenti F. Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003;14:1940-1948.
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154-2169.
Bostom AD, Brown RS Jr, Chavers BM, et al. Prevention of post-transplant cardiovascular disease -- report and recommendations of an ad hoc group. Am J Transplant 2002;2:491-500.
Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741-1751.
Fishman JA. BK virus nephropathy -- polyomavirus adding insult to injury. N Engl J Med 2002;347:527-530.
Li B, Hartono C, Ding R, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med 2001;344:947-954.
Knechtle SJ, Pirsch JD, Fechner J Jr, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003;3:722-730.
Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation 2003;76:120-129.
Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003;361:1502-1510.
Rothstein DM, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Immunol Rev 2003;196:85-108.
Kreis H, Oberbauer R, Campistol JM, et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 2004;15:809-817.
Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 2004;4:953-961.
Salama AD, Remuzzi G, Harmon WE, Sayegh MH. Challenges to achieving clinical transplantation tolerance. J Clin Invest 2001;108:943-948.
Matthews JB, Ramos E, Bluestone JA. Clinical trials of transplant tolerance: slow but steady progress. Am J Transplant 2003;3:794-803.
Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation 2003;75:1291-1295.
Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002;62:311-318.
Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-940.
Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3:178-185.
Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 2001;59:732-737.
Neylan JF, Sayegh MH, Coffman TM, et al. The allocation of cadaver kidneys for transplantation in the United States: consensus and controversy. J Am Soc Nephrol 1999;10:2237-2243.
Ojo AO, Heinrichs D, Emond JC, et al. Organ donation and utilization in the USA. Am J Transplant 2004;4:Suppl 9:27-37.
Delmonico FL. Exchanging kidneys -- advances in living-donor transplantation. N Engl J Med 2004;350:1812-1814.
Kasiske BL, Snyder JJ, Matas AJ, Ellison MD, Gill JS, Kausz AT. Preemptive kidney transplantation: the advantage and the advantaged. J Am Soc Nephrol 2002;13:1358-1364.
Organ Procurement and Transplant Network. Reported deaths and annual death rates per 1,000 patient years at risk: waiting list, 1993 to 2002. In: OPTN/SRTR 2003 annual report: summary tables, transplant data 1993-2002. Table 1.7. (Accessed December 2, 2004, at http://www.ustransplant.org.)(Mohamed H. Sayegh, M.D., )
On December 23, 1954, a surgical team at the Peter Bent Brigham Hospital in Boston, under the direction of Joseph Murray, removed a kidney from a healthy donor and transplanted it into his identical twin, who had chronic glomerulonephritis and was being sustained on the newly modified Kolff–Brigham artificial kidney machine.1 The organ functioned immediately,2 and the recipient survived for nine years, at which time his allograft failed from recurrent glomerulonephritis. The donor has survived for 50 years. Other historical details are provided by Morris elsewhere in this issue of the Journal.3 This first organ transplantation was not an isolated event but, rather, the result of a defined goal of developing a transplantation research program, initiated in the mid-1940s by George W. Thorn, the chairman of medicine, and Francis D. Moore, the chairman of surgery, at Peter Bent Brigham.
(Figure)
The First Identical-Twin Kidney Transplantation, Performed on December 23, 1954.
Photograph courtesy of Brigham and Women's Hospital.
As more transplantations were performed between identical twins,4 approaches to suppressing the recipient's immune system were pursued so that transplantation might be extended beyond procedures involving identical twins. Although the knowledge base in immunology was still rudimentary, the antibodies specific to pathogenic bacteria were well known. Furthermore, in 1925, Emile Holman, a surgeon at Peter Bent Brigham who performed skin grafts in children with extensive burns, reported in 1924 that repeated grafts from maternal donors were rejected more rapidly than the initial grafts, which indicated donor-specific sensitization to the "proteins" of individual volunteer donors.5 The first approach to suppressing the rejection process, taken in the early 1950s, involved the use of sublethal total-body irradiation combined with cortisone. These attempts were failures, with the exception of some transplantations between nonidentical twins — first at Peter Bent Brigham6 and a few weeks later in Paris7 — which provided the impetus to search for more effective ways to prevent rejection.
Robert Schwartz and William Dameshek, hematologists at Tufts University School of Medicine, expanded this horizon in 1959, when they reported that 6-mercaptopurine (6-MP), which was already in clinical use for the treatment of acute lymphocytic leukemia, suppressed the immune response in rabbits.8,9 The Wellcome Research Laboratory then synthesized several variants of 6-MP for screening by Joseph Murray and Roy Calne in canine kidney transplantations. Only one candidate drug, azathioprine, resulted in long-term survival — and in only a small number of animals. These observations prompted a rather anxious start to the first clinical trial, in 1962, of chemical immunosuppression involving azathioprine.10 In patients in whom azathioprine was combined with a corticosteroid, one-year rates of allograft survival in the range of 40 to 50 percent were observed, an enormous improvement over the canine results. These clinical breakthroughs were ultimately recognized by awarding of Nobel Prizes to Joseph Murray (and others), for the first clinical transplantation and the first use of immunosuppression, and to George Hitchings and Gertrude Elion of the Wellcome Laboratory, for the development of drugs, including azathioprine, that affect nucleotide pathways.
Progress and Challenges
The rate of successful transplantation of kidneys from cadaveric donors and familial HLA-matched living donors slowly increased during the 1960s and early 1970s, following the introduction of azathioprine with corticosteroids. Although the initial effect was beneficial, prolonged use of corticosteroids resulted in a high mortality rate due to excessive immunosuppression. Overall mortality rates also fell as programs for long-term dialysis improved, which made it possible to discontinue immunosuppression and sustain life when grafts failed. In the early 1980s, cyclosporine was introduced, which increased the rate of one-year graft survival from 70 percent to more than 80 percent.11 Further developments in the 1980s established the clinical utility of liver, heart, and lung transplantation. More recently, improvement in pancreatic transplantation and early promise in the transplantation of isolated islets have opened up new options for patients with type 1 diabetes.12,13,14
At the end of 2002, in the United States there were 150,000 people living with functioning solid-organ allografts, up from 62,000 in 1993.15 Transplantation has had a worldwide effect; there is significant organ-transplant activity in a large number of other countries.
Chronic Allograft Dysfunction
During the past decade, as increasing numbers of more powerful immunosuppressive agents became available, the short-term (i.e., 1-year) rate of organ survival significantly improved, yet the long-term results (5-to-10-year survival) did not. Table 1 shows the rates of allograft and patient survival in the United States among patients who received transplants between 1993 and 2002.16 Table 2 provides the numbers of transplantations for each organ in relation to the size of the waiting lists for those organs.17
Table 1. Mean Rates of Graft and Patient Survival for Transplantations in the United States from 1993 through 2002.
Table 2. Transplantation According to Organ and Donor Type, 1993 through 2003.
As Table 1 shows, the survival rates for kidney grafts from living donors are superior to those for grafts from cadaveric donors at 1, 5, and 10 years, but after a decade, the rate drops to 55 percent. Transplants from HLA-identical living donors would be expected to have a survival rate of 70 to 75 percent at 10 years. The initial excitement that followed a report that long-term survival of renal allografts may be improving, especially in recipients who had never had an episode of acute rejection,18 has faded as newer data19 showed that, although the rates of acute rejection are at their lowest, the long-term risk of graft loss has not improved and may have even worsened. The reasons for chronic allograft dysfunction involve many factors that concern variable tissue injuries at the time of transplantation or during subsequent episodes of rejection. However, even in the case of grafts with good function in the early years after transplantation, progressive tissue damage and slow decrements in function — conservatively called "chronic allograft dysfunction" — may develop, most often with considerable vasculopathy.20 Accumulating evidence in animals and humans suggests that there is a consistent pattern in which low-level IgG alloantibodies are directed at HLA antigens, or in which T cells are primed to donor HLA peptides, in those organ-transplant recipients in whom progressive allograft dysfunction occurs.20,21,22,23,24 Chronic allograft dysfunction affects all transplanted organs and is the most common cause of graft loss after the first year after transplantation.20
When a transplanted kidney is rejected, the patient returns to dialysis while waiting for another transplant. The situation with liver transplants differs in that recurrent disease, such as hepatitis C, remains the most common cause of long-term graft loss.25 Since initially high levels of immunosuppression cannot be tolerated over the long term and must be tapered, it is not surprising that breakthroughs in antigen recognition and alloimmune activation can occur. A common feature of drugs used in transplantation,26 such as DNA-synthesis inhibitors, calcineurin inhibitors, and sirolimus, is their suppression of primary immune responses in naive lymphocytes; these drugs have less of an effect on the expanded clones of primed effector and memory cells.27 The in vitro culturing of lymphocytes from the peripheral blood with donor HLA peptides that are bound to the antigen-presenting cells of the recipient is a test used to identify the priming of T cells to specific HLA antigens.28,29 This test is indicative of immunization through the physiologic pathway of T-cell recognition (the "indirect pathway") (Figure 1), which leads to a switch from IgM to IgG antibodies.28,30 The "direct pathway," the main driving force in acute rejection, is an anomaly unique to transplantation in which T cells recognize intact HLA molecules on donor cells.28,29
Figure 1. Mechanisms of Chronic Allograft Dysfunction.
Factors that are both dependent on and independent of alloantigens contribute to chronic organ damage after transplantation. Classic acute rejection starts with T-cell recognition of intact donor HLA molecules (the direct pathway, unique to allotransplantation), and there is an immediate response of inflammatory factors independent of alloantigens such as cytokines, complement, and natural killer cells of the innate immune system. Patients with progressive allograft dysfunction have been shown to have low levels of T cells that are activated in response to donor allopeptides presented by their own antigen-presenting cells. This is the classic pathway for recognition of all other foreign proteins and is called the indirect pathway for transplantation. It is a necessary first step in the production of mature IgG antibodies to alloantigens. Chronic immunologic injury that is driven by T-cell recognition of alloantigens can be promoted by an innate immune-system reaction to tissue damage that is present before transplantation or is a result of the ischemic injury at the time of transplantation. This smoldering, progressive, chronic process is unresponsive to the modes of therapy that are effective against acute rejection. In addition, calcineurin inhibitors (CNI) are nephrotoxic and can contribute to progressive allograft dysfunction.
In support of the concept that the alloimmune response plays a major role in chronic rejection is the observation that chronic rejection in recipients of kidney transplants is more common in those who have acute rejection and in those who have received HLA-mismatched grafts.20 In addition, subclinical rejection, as detected by biopsy, without evidence of allograft dysfunction, may be an important contributor to chronic allograft damage.31 Nonetheless, factors independent of antigens, including fibrosis that is mediated by calcineurin inhibitors,31 do contribute to chronic graft injury (Figure 1). The identification of an effective means of preventing or intervening in chronic rejection at an early stage by targeting the factors that are both dependent and independent of alloantigens remains a challenge.20
Long-Term Need for Immunosuppression
Immunosuppressive drugs that have been introduced since 1995 have led to combination therapies that have significantly lowered the rates of acute rejection.19 Induction therapies with various antilymphocyte antibodies also reduce the rate and intensity of acute rejection and possibly prevent the onset of chronic rejection.26,32 All immunosuppressive drugs have specific side effects and additively contribute to an overall state of immunosuppression, which leads to an increased risk of infections and various specific malignant conditions.26 Such drugs probably contribute to the increased risk of cardiovascular disease, which is the most common cause of premature death in transplant recipients.33,34 Excessive total immunosuppression causes a susceptibility to infectious diseases,35 especially to DNA viruses such as cytomegalovirus, Epstein–Barr virus, and the more recently recognized polyomavirus, which causes nephropathy and renal allograft loss.36
Over the past two decades, empirical trials have led to protocols of combination therapy that reduce side effects yet maintain graft survival. A major challenge in regard to long-term immunosuppression is the need for expanded multicenter trials of various combination therapies and for the development of inexpensive and noninvasive tools to define and monitor responses along the spectrum of immunity toward, ultimately, tolerance.37 New candidates for treatment such as T-cell–depleting agents38,39,40 and T-cell blockade,28,41 all of which are used to modify the immune responses, are under study, and some transplant biologists believe that combinations of drugs without side effects will eventually be available. For example, the use of target-of-rapamycin inhibitors as a way to avoid the use of calcineurin inhibitors in recipients of kidney transplants has recently been reported to improve long-term renal function,42 decreasing the pathologic changes of chronic allograft nephropathy.43
Although a small number of grafts are not rejected after the removal of all or most of the medications used for the maintenance of immunosuppression, trials involving the deliberate withdrawal of immunosuppressive drugs according to protocol do not suggest that it is safe to do so for most patients. One reason is the lack of specific and sensitive assays that can predict the safety of drug withdrawal.44 Processes of both acute and chronic rejection can occur when therapeutic agents are reduced. Nonetheless, the induction of immunologic tolerance by intensive manipulation of recipient immunity during the very early weeks after transplantation remains the ultimate goal.44 In that regard, the National Institutes of Health Immune Tolerance Network (www.immunetolerance.org) has recently approved various pilot clinical trials designed to explore the biology of tolerance in humans; these studies should shed light on whether such a goal can be achieved.44,45
Medical Complications
Whereas infections are responsible for 11.7 percent of deaths in the recipients of primary renal transplants beyond the first year after transplantation, and malignant conditions account for 10.1 percent of such deaths, cardiovascular diseases account for 30.1 percent.46 Renal dysfunction itself is a cardiovascular risk factor before transplantation, given its association with hypertension, anemia, and lipid disorders.33 Indeed, renal function one year after transplantation is an important predictor of long-term graft survival in kidney transplantation.47 Furthermore, renal dysfunction (i.e., dysfunction of native kidneys) is being recognized as a significant clinical problem in recipients of nonrenal solid-organ allografts.48 Diabetes, which is present in 20 percent of patients who receive transplants,49 is also an important clinical problem that contributes to the risk of cardiovascular disease and hypertension. In addition, the use of calcineurin inhibitors and corticosteroids is associated with new cases of diabetes after transplantation, and the incidence has been rising in recent years.50
Organ Shortage
There is a shortage of available organs for patients on waiting lists, and the gap between supply and demand continues to grow51,52 (Table 2). The consent rate for cadaveric donors is only 50 percent. The increased willingness of living donors other than immediate family members to donate has recently led to some increase in the supply of kidneys.53 This has also allowed more patients to benefit from preemptive transplantation, which occurs before the institution of long-term dialysis,54 and thus avoids a period of potential complications. Live-donor laparoscopic nephrectomy, with its shorter recovery time, has helped to increase the willingness to donate. In addition, the use of kidneys from marginal donors — those older than 60 years of age, who were heretofore not accepted as donors because their kidneys are generally unlikely to function for more than five to eight years — is being considered. There are potential opportunities for the exchange of donors in pairs in cases in which there are incompatibilities in the blood group or HLA antibody pattern between an individual donor and recipient. Annual mortality rates among patients on waiting lists for organs from cadaveric donors are currently 6 percent for patients waiting for a kidney, 10 percent for those awaiting a liver, 12 percent for those waiting for a lung, and 14 percent for those who need a heart.55
Summary
A half-century has elapsed since the first organ transplantation, and this procedure is now accepted as the treatment of choice for end-stage organ failure. Although tremendous progress has contributed to the success of this therapy, several challenges remain if transplantation is to be widely available with minimal risks and optimal outcomes. Recent advances in the science of organ and cell transplantation provide hope that a variety of chronic diseases will ultimately be cured.
Source Information
From the Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, and Harvard Medical School, Boston.
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