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Ann Thorac Surg 2003;75:S72-S78
© 2003 The Society of Thoracic Surgeons
a Department of Cardiovascular Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA
* Address reprint requests to Dr Taylor, Department of Cardiovascular Diseases, Cleveland Clinic Foundation, 9500 Euclid Ave, Desk F-25, Cleveland, OH 44195, USA.
e-mail: taylord2{at}ccf.org
Presented at the Heart Failure & Circulatory Support Summit, Cleveland, OH Aug 22–25, 2002.
Abstract
Survival with congestive heart failure has improved significantly over the last 20 years. However, many patients continue to progress to end-stage disease and suffer unacceptable morbidity and mortality. In the current era, survival after cardiac transplantation approaches 88% to 90% by 1 year at most centers, with more than 50% of patients surviving more than 10 years. Thus, for end-stage patients who are acceptable candidates, cardiac transplantation remains the treatment of choice. The majority of the early (<30-day) postoperative mortality relates to allograft quality and surgical issues, whereas the majority of deaths after 30 days relates to issues of "over" or "under" immunosuppression. With an early mortality rate of less than 10%, the majority of deaths occur after 30 days. Thus a "perfect" immunosuppression regimen would save more lives than a "perfect" donor heart or surgical procedure. Immunosuppression continues to improve but we are all striving for the "perfect" regimen: one free of adverse side effects with perfect graft function. Only a protocol with no chronic immunosuppressive drugs, in other words, complete allograft tolerance, will accomplish this. Many fascinating tolerance-inducing strategies are currently under development.
Despite the latest advances in the treatment of chronic heart failure, the short- and long-term mortality remains high and many patients progress to advanced, end-stage failure. It is commonly stated that the 5-year survival for patients with symptomatic heart failure is only 50%. Whereas the recent results of the COPERNICUS trial using carvedilol in patients with advanced heart failure demonstrated an encouraging 89% 1-year survival, the survival rate was already down to approximately 80% by 18 months, and longer-term data are not yet available [1]. In addition, COPERNICUS excluded patients who were inotrope dependent or in cardiogenic shock: a large group of sicker patients typically listed for transplantation. Current survival rates for cardiac transplantation approach 88% to 90% at 1 year for most U.S. transplant centers, with survival rates approaching 50% at 10 years, a marked improvement over the longer-term survival rates with conventional medical therapy alone. Thus, for those patients with advanced, end-stage heart failure who are candidates, cardiac transplantation is the only proven therapy to offer improved survival and quality of life. Regardless of the apparent statistical benefit of cardiac transplantation over medical therapy alone, an organ "half-life" of only 10 years is woefully inadequate, particularly for the young transplant recipient. At the current rates, a young adult or child would possibly have to undergo more than six transplant procedures to achieve anything close to a normal life expectancy. Certainly, in its current state, cardiac transplantation cannot be considered curative, but simply trading one quickly fatal disease for one with a slower time course.
What are the current obstacles to long-term graft function and patient survival? One can consider acute allograft rejection and chronic allograft vasculopathy (chronic rejection) as evidence for inadequate or "under" immunosuppression, and infection, malignancy, and drug-induced renal failure as evidence for excessive or "over" immunosuppression. Whereas surgical/technical complications and primary allograft dysfunction account for approximately 80% of the early mortalities (<30 days), issues related to "over/under-immunosuppression" account for 50% to 70% of mortalities after 30 days [2]. With the current 30-day mortality of less than 10%, the overwhelming majority of the posttransplant deaths occur after 30 days. Thus, the "perfect" immunosuppressive regimen would save many more lives that the "perfect" surgical technique or donor organ.
Immunosuppressive regimens have changed significantly since the first human heart transplant in 1967. The early days of azathioprine, high-dose corticosteroids, and antithymocyte globulin (ATG) gave way to the "cyclosporine era" in the early 1980s. Cyclosporine, in combination with lower doses of corticosteroids and azathioprine, became the standard cocktail in the mid-1980s and was often referred to as "triple-drug therapy." The addition of antilymphocyte preparations back into the regimen, using ATG or OKT3, became popular but failed to demonstrate superiority over "triple therapy" alone. The 1990s saw the introduction of tacrolimus as an alternative to cyclosporine in heart transplantation and the introduction of mycophenolate mofetil as an alternative to azathioprine. In recent years, we have seen the introduction of sirolimus (rapamycin) and everolimus (a derivative of rapamycin), and new humanized, monoclonal antilymphocyte preparations (namely the interleukin-2 receptor antagonists) into clinical heart transplantation. There are several new immunosuppressive agents and strategies ready to be tested in the upcoming years. So, what will be the immunosuppressive regimen for the next century? The ideal regimen regimen must, by definition, be free of significant side effects, highly effective and relatively cost-effective, a far cry from our current regimens. In fact, the only "perfect" chronic immunosuppressive drug regimen would be a no-drug regimen, that is, complete and permanent allograft acceptance without the need for ongoing immunosuppressive drugs, so-called "allograft tolerance." Tolerance is no pipe dream, as it has been demonstrated in many animal models, including primate models and on a limited basis in unique human situations. "Complete and permanent tolerance" will be the immunosuppressive regimen for the 21st Century; however, it is at least a decade, perhaps several, away from reality.
Basic transplantation immunology
Over the first 40 years of clinical transplantation, the application of immunosuppressive drugs into clinical practice has moved from the use of agents developed for other unrelated diseases in the early years to the current practice of "designer" drug development based on our basic understanding of the immunobiology of allograft rejection. A working knowledge of the basic immunobiology of allograft rejection is crucial to understanding the rationale for today’s (and tomorrow’s) immunosuppressive strategies.
It is widely held that the immune system–allograft interaction begins when a variety of immune cells, including T-lymphocytes and antigen-presenting cells (APCs), adhere to the vascular endothelium of the transplanted organ. This occurs because of the interaction of adhesion molecules on the immune cells with ligands on the endothelial cell surface as part of the initial inflammatory response. Quiescent endothelial cells are induced to express adhesion molecules by ischemia, surgical manipulation, or by cytokines, resulting in leukocyte adhesion and transmigration. Transplanted organs undergo anoxia and surgical manipulation, and consequently upregulate endothelial adhesion molecules. Thus, the adhesion molecule/ligand interaction plays a major early role in the immune response, and offers potential targets for attenuating the overall immunologic response. The major adhesion molecule–ligand pairs involved are CD2LFA3 (leukocyte function–associated antigen-3) and ICAM1 (intercellular adhesion molecule-1) and LFA1, which enhance the interaction of T-cells with both endothelium and APCs. Blockade of these interactions has been shown to attenuate immune responses in animal models.
It is generally believed that T-lymphocytes become activated against alloantigen by one of two pathways: (1) a "direct" interaction with foreign antigens presented by endothelial cells, myocytes, or passenger dendritic cells in association with donor major histocompatibility complex (MHC) proteins; and (2) "indirect" interaction with foreign peptides processed and presented by recipient APCs in association with recipient MHC proteins. This presentation of antigen leads to a series of intracellular events resulting in an "activated" T-cell, which secretes various cytokines, including interleukin-2 (IL-2). Amplification of this T-cell response occurs due to the self-expression of IL-2 receptor, occupancy by IL-2, and stimulation of T-cell proliferation. Other cytokines secreted (interferon-gamma [IFN-gamma], tumor necrosis factor-alpha [TNF-alpha], IL-4, IL-5, and IL-6) stimulate the activation and proliferation of macrophages, B-cells, and other cells involved in the inflammatory response. The immune cascade, involving helper T-cells, cytotoxic T-cells, natural killer (NK) cells, B-cells, antibodies, and complement, ultimately leads to damage of the donor endothelial cells, vascular smooth muscle cells, myocytes, and intracellular matrix, which presents clinically as acute and chronic allograft rejection.
The initial direct or indirect presentation of the alloantigen to the T-cell receptor/CD3 complex leads to activation of several tyrosine kinases, which phosphorylate and activate phospholipase C (PLC), ultimately causing a rise in intracellular calcium. Calcium, along with calmodulin, activates the serine-threonine phosphatase calcineurin. Calcineurin dephosphorylates the cytoplasmic subunit of nuclear factor of activated T-cells (NFAT-c), enabling its translocation to the nucleus, where it complexes with the nuclear subunit (NFAT-n). This complex binds to the promoter regions of various cytokine genes, especially the IL-2 promoter, upregulating transcription. IL-2, in both an autocrine and paracrine fashion, activates the proliferative pathways in the activated T-cells, as well as other immune cells. Cyclosporine and tacrolimus (formerly FK506) in complex with their cytoplasmic binding proteins, cyclophilins and FK binding proteins (FKBP), respectively, inhibit the function of calcineurin and thus downregulate expression of IL-2 and other cytokines.
Once IL-2 binds to its receptor on the T-cell, a series of intracellular events occur by activation of various cyclin kinases. These kinases are important cell cycle regulatory proteins. In order for the cell to proliferate and the immune response amplify, the activated T-cell must progress through the cell cycle. As in most dividing cells, the cell must pass from the G1 state to the synthetic (S) phase, which is dependent on nucleic acid synthesis in preparation for mitosis. Antimetabolites, like azathioprine, cyclophosphamide, and methotrexate, act by inhibiting DNA synthesis during this crucial phase of cell replication. Lymphocytes are particularly dependent on the de novo pathway of purine and pyrimidine synthesis, unlike other cells capable of rapid division, where the "salvage" pathways can contribute to a significant extent. Mycophenolate mofetil, by inhibiting a key enzyme of the de novo pathway, inosine monophosphate dehydrogenase (IMPDH), blocks the proliferative response, particularly in lymphocytes. Sirolimus (rapamycin) and everolimus (a derivative of rapamycin) act by blocking several events downstream of the IL-2 receptor. Interestingly, these drugs bind to the same binding proteins as tacrolimus (primarily FKBP-12), but rather than inhibiting calcineurin, they inhibit cytoplasmic proteins collectively termed "target of rapamycin" (TOR) proteins. These proteins are required for cell cycle progression in response to IL-2 stimulation, and hence, sirolimus and everolimus are able to block the proliferative response of T-cells after immune activation. The IL-2 receptor itself can be blocked or inactivated by monoclonal antibodies directed against specific components of the receptor complex. Two such agents, basiliximab and daclizumab, are currently in human trials and appear promising.
Another critical event in T-cell activation involves the "costimulatory" signals, which are antigen-independent pathways that significantly enhance the T-cell responses. It is currently believed that these "costimulatory" signals are necessary for full activation of the T-cell. Activation of the T-cell receptor without a costimulatory signal leads to programed cell death or anergy, rather than activation. The CD28 and CD40 molecules and their ligands are the two best-studied costimulatory signals to date. The CD28 molecule, found on T-cells, interacts with its ligand (B7 to 1 [CD80], B7 to 2 [CD86], and B7 to 3) on activated APCs. This interaction amplifies the T-cell response by a series of intracellular events that ultimately lead to increased IL-2 gene expression. A second costimulatory signal involves the interaction between CD40 on the APC with its ligand on activated T-cells, CD154. This interaction has effects on both T- and B-cells, leading to both direct activation and upregulation of the expression of B7 to 1, B7 to 2, and B7 to 3. Upregulation of B7 molecules will lead to an increased CD28/B7 signal, amplifying the immune response as noted above. In small and large animal models, blockade of these costimulatory pathways markedly attenuates the immune response to the transplanted organ.
In summary, current immunosuppressive agents and strategies attempt to: (1) prevent the initial activation of the T-cell by interferring with the T-cell receptor complex; (2) prevent activation of the costimulatory pathways by blockade of these receptors; (3) interfere with the downstream effects of TCR activation, namely IL-2 production; (4) prevent activation of the IL-2 receptor; and (5) interfere with the downstream effects of IL-2 receptor activation, namely cell cycling and proliferation.
Basic immunosuppressive regimens
Currently, the "standard" maintenance immunosuppression protocols for heart transplantation (so-called "triple therapy") include: (1) a calcineurin inhibitor (CNI) such as cyclosporine or tacrolimus; (2) an antiproliferative agent such as azathioprine (AZA), mycophenolate mofetil (MMF), or rarely cyclophosphamide; and (3) corticosteroids such as prednisone or prednisolone. Many centers also add an antilymphocyte antibody perioperatively such as ATG, OKT3, or an IL-2 receptor blocker (basiliximab or daclizumab) to create a "quadruple-drug" regimen. In the setting of pretransplant renal insufficiency, a popular protocol involves delaying the initiation of the calcineurin inhibitors for 1 to 2 weeks postoperatively to allow for recovery of renal function and using antilymphocyte antibody therapy in the interim, so-called "sequential therapy." Significant controversy remains regarding which agent within each of the first two categories is preferred, whether corticosteroids are required long-term, and the role of the antilymphocyte antibody therapies. According to the most recent data from the Registry of International Society for Heart and Lung Transplantation [2], approximately 47% of patients transplanted from 1999 to 2001 received perioperative antilymphocyte antibody therapy, approximately half of these receiving ATG, the rest divided equally between OKT3 and IL-2 antibodies. Approximately 72% of these patients were receiving cyclosporine at year 1 as their CNI, compared with 25% receiving tacrolimus. Approximately 70% of these patients were receiving mycophenolate mofetil at year 1 as their antiproliferative agent, compared with 15% receiving azathioprine, and only 3% receiving rapamycin. Eighty-two percent of patients were receiving some dose of corticosteroids at 1 year.
The calcineurin inhibitors: cyclosporine versus tacrolimus therapy
Two single-center (University of Pittsburgh [3] and University of Munich [4]) and two multicenter (US [5] and European [6]) trials have suggested at least equivalent and perhaps better antirejection properties of tacrolimus when compared with cyclosporine with significantly less hyperlipidemia, hirsuitism and hypertension associated with tacrolimus use. The incidence of renal dysfunction is similar between the two agents, and the incidence of new or worsening diabetes is only minimally higher with tacrolimus use. Likewise, the costs and need for blood level monitoring is similar between the two agents. Currently, the choice of agents seems to be dictated by institutional preference and individual patient efficacy and side effect profile.
The antiproliferatives: azathioprine versus mycophenolate mofetil therapy versus rapamycin
In a large, randomized controlled trial, MMF was compared with azathioprine in combination with cyclosporine and corticosteroids. In this study, reported by Kobashigawa and associates [7], 650 primary heart transplant recipients were randomized equally between the two study groups. Intent-to-treat analysis of all 650 randomized patients revealed no significant differences between the two study groups with regards to survival, rejection or safety variables. Because intravenous MMF was not available during the time of this study, 72 patients unable to take oral medications by the sixth day after surgery were withdrawn without ever receiving study drug, and three-fourths were placed on open-label azathioprine. These 72 patients experienced a high mortality or retransplant rate (56% by 1 year) and had more MMF assigned patients (38 vs 34). These facts, coupled with the 11% early crossover rate (primarily in one direction), significantly affected the discriminatory power of the study. When the data were analyzed for only those 578 patients receiving at least one dose of the study drug (a more clinically relevant group), the MMF group experienced an 11% (2% to 22%, 95% confidence intervals) reduction in treated rejection episodes and a 34% (1% to 56%, 95% confidence intervals) reduction in biopsy-proven rejection episodes associated with severe hemodynamic compromise. In addition, the MMF-treated group experienced less mortality during the first 12 months posttransplant (6.2% vs 11.4%, p = 0.031). Of particular interest is the observation that during the 12 months posttransplant, there were no deaths in the 19 patients in the MMF group who experienced an episode of severe hemodynamically compromising rejection, as compared with 12 deaths (32%) in the 38 such patients in the azathioprine group. The whole of these data suggest that MMF may be superior to azathioprine in preventing (and successfully treating) the more severe forms of allograft rejection. The adverse events in the two groups were similar except for more diarrhea, esophagitis, and opportunistic infections (primarily herpes virus) in the MMF group and more leukopenia in the azathioprine group.
Sirolimus (rapamycin) and its derivative, everolimus (formerly SDZ-RAD), have muddied the "antiproliferative" waters. They are potent antiproliferative agents and have made a major breakthrough in the field of coronary stenting, where the introduction of rapamycin-eluting stents has almost eliminated restenosis in stented segments. However, the introduction of these drugs into solid organ transplantation has probably led to more questions than answers. It is unclear whether these agents are best used in place of the CNI, with mycophenolate and corticosteroids (as part of a so-called, "CNI-free" protocol), or with a CNI, in the place of mycophenolate or azathioprine. The currently completed and ongoing clinical trials in renal transplantation include both of these approaches. For heart transplantation, only the latter approach has been tried. In the Everolimus Trial [8], 634 heart transplant recipients were randomized between two doses of everolimus (3.0 and 1.5 mg/d) and azathioprine (1 to 3 mg/kg/d) along with cyclosporine and corticosteroids. At 6 months, the two everolimus groups had significantly fewer efficacy failures (acute rejection 3A or higher, hemodynamically compromising rejection, death, graft loss, or lost-to-follow-up) than the azathioprine group (27% in 3-mg/d RAD group and 36.4% in the 1.5-mg/d RAD group vs 47.7% in the azathioprine group). The survival rates were not significantly different between the groups. The incidence of viral infections, primarily cytomegalovirus, was significantly lower in the two RAD groups than the AZA group, and the incidence of bacterial infections was slightly higher in the RAD groups than the AZA group. Arguably, the most exciting results of the trial involve the effect on allograft vasculopathy, measured in this trial by 12-month intravascular ultrasound (IVUS) [9]. In a subgroup of 211 patients, postoperative and 12-month IVUS images were compared. There was a significant difference in the primary IVUS endpoint (change in average maximal intimal thickness) between the azathioprine group and the two RAD groups (0.10 mm in AZA vs 0.03 mm in RAD 3 mg/d and 0.04 in RAD 1.5 mg/d). Similar differences were found in the secondary endpoints of average intimal area and volume. When allograft vasculopathy was defined as a maximal intimal thickness increase greater than or equal to 0.5 mm, 52.8% of the AZA group, 35.7% of the RAD 1.5 mg/d group, and 30.4% of the RAD 3 mg/d group developed vasculopathy at 1 year.
A similar, but smaller trial comparing sirolimus with azathioprine has reported similar findings. Keogh and associates [10, 11] randomized 136 heart transplant recipients to two doses of sirolimus (SRL 3 mg/d and SRL 5 mg/d) versus azathioprine (2.5 mg/kg/d). At 6 months, the incidence of acute rejection was significantly lower in the two SRL groups (29.4% in 3 mg/d and 36.2% in the 5 mg/d) when compared with the AZA group (61.4%). The mean maximal proximal coronary stenosis increased 41% in the AZA group as compared with only 4% in the combined SRL groups. Similarly, the maximal midvessel stenosis increased by 56% in the AZA group but decreased 5% in the combined SRL groups.
Whether these changes in IVUS-defined vasculopathy will translate into better long-term outcomes remains to be seen. However, given the good correlation between 1-year IVUS values and long-term outcome in prior studies, these results are quite encouraging. However, both of these studies compared sirolimus and everolimus with azathioprine rather than mycophenolate mofetil. The magnitude of difference in rejection rates between the groups was greater in the sirolimus/everolimus studies than the mycophenolate study [7]. Likewise, mycophenolate was not associated with a significant decrease in IVUS-defined vasculopathy at 12 months when compared with azathioprine [7].
In summary, it appears that mycophenolate mofetil has eclipsed azathioprine as the principle antiproliferative agent in heart transplantation, but expect a marked increase in the use of sirolimus and everolimus in the near future given these most recent study results.
Chronic corticosteroid therapy
The role of corticosteroids in chronic immunosuppressive protocols remains unsettled. There has never been an appropriately sized, randomized controlled trial addressing this issue; however, there is much single-center data supporting the use of corticosteroid-free maintenance protocols, at least in a substantial subgroup of patients. Few programs currently use a true corticosteroid-free protocol from the time of transplantation, but most programs attempt to wean corticosteroids completely off during the first 4 to 12 months, primarily in those patients who experience little or no acute allograft rejection. Most programs utilizing triple-drug protocols without antilymphocyte antibody induction therapy attempt to completely withdraw corticosteroid no sooner that 4 to 6 months posttransplant, whereas the programs with the earliest corticosteroid withdrawal (2 days to 2 months) use "quadruple-drug" protocols (standard triple therapy plus antilymphocyte antibody therapy). Whereas it is arguable whether patients experiencing multiple rejection episodes early after transplant should be weaned completely off corticosteroids late after transplant, it seems clear that patients who experience little or no acute allograft rejection episodes can be safely maintained without corticosteroids. Taylor and associates [12] reported outcomes in 374 patients who received antilymphocyte antibody therapy (primarily OKT3) along with cyclosporine and azathioprine and tapering doses of corticosteroid until discontinued over a 5- to 6-week period postoperatively. Early mild or moderate rejection episodes were treated with augmented corticosteroids followed by another weaning attempt. Early corticosteroid weaning was abandoned if a severe cellular rejection, vascular rejection, or more than two treated mild-moderate rejection episodes occurred. One hundred eleven (30%) patients were successfully weaned early from corticosteroids and experienced an excellent long-term survival (82%, 10-year actuarial), which is significantly better than the remaining patients (36%, 10-year actuarial). Whereas these data do not suggest that it was the lack of corticosteroids that led to the excellent survival, it seems unlikely that the addition of corticosteroids back to the regimen of these patients could have improved survival further.
Combination therapy
With prednisone, two CNIs, at least three antiproliferative agents, and at least four antilymphocyte antibodies, the number of possible combinations is quite large. In small, case control reports, just about every possible combination has been tried. However, in the larger clinical trials (including those discussed above), the combinations have included primarily: (1) cyclosporine, AZA, prednisone; (2) cyclosporine, MMF, prednisone; (3) tacrolimus, AZA, prednisone; (4) cyclosporine, everolimus, prednisone; and (5) cyclosporine, sirolimus, prednisone. Protocols 1 to 4 above have included antithymocyte antibodies OKT3 or ATG in selected patients. These combinations have proved safe and effective in heart transplantation. Several other combinations are now undergoing evaluation.
A small, single-center study from the University of Munich [4] suggests that the combination of tacrolimus, MMF, and corticosteroids may be more effective than cyclosporine, MMF, and corticosteroids ,especially when MMF dosing is adjusted to blood levels rather than administered as a fixed dose. The infection risks associated with this combination seemed acceptable. It appears that equivalent doses of MMF are associated with higher MPA levels when combined with tacrolimus as compared with cyclosporine. Preliminary evidence suggests that cyclosporine decreases the MPA level slightly by affecting intestinal absorption and enterohepatic recirculation of MPA, whereas tacrolimus has a neutral effect on MPA pharmacokinetics.
Whereas most of the current clinical investigative effort is focused on better utilizing the immunosuppressive agents we have available, there are a few new agents in animal studies and early clinical trials. None, however, seems at this stage to be "break-through" drugs. Gene therapy is a promising technique that is currently being investigated. The ability to genetically alter a donor organ could one day revolutionize organ transplantation. Attempts at "humanizing" xenografts are well underway, primarily using transgenic pig models. Genetic manipulation of these pigs to express human complement regulatory proteins has led to marked attenuation of the typical hyperacute xenograft rejection. Genetic manipulation utilizing gene transfection (both viral and nonviral) has been successfully performed in animals. A variety of genes have been targeted. Over-expression of both TGF-b1 and IL-10 has been associated with improved murine allograft survival. Likewise, over-expression of CTLA-4Ig in murine liver transplantation is associated with mononuclear infiltrates but no parenchymal damage (suggestive of local T-cell anergy). Causing apoptosis of the infiltrating allo-reactive immune cells by over-expression of Fas-ligand in the graft would seem like a potentially successful approach. However, experimental trials of this method have generally failed. The major limitation of the current transfection technology is the durability of the transfection. Unlike transgenic organs, transfected organs would require repeated treatments to maintain gene expression. Despite its limitations, gene therapy will likely play a significant role in the future of transplantation.
Allograft tolerance
Simply put, the best immunosuppressive agent is no immunosuppressive agent. Unless an immunosuppressive agent is capable of affecting only the allo-reactive immune cells, there will always be the risk of "collateral damage" or toxicity. Given the tremendous redundancy in the human immune system, it is unlikely that such a drug or combination of drugs will be developed in the near future. Thu, only "immunologic" tolerance can provide the results we strive for: indefinite allograft (or xenograft) function, otherwise normal immune function, without the risks or complications of ongoing immunosuppressive therapy. In the majority of patients, current drug regimens lead to (or allow) some degree of tolerance (as demonstrated by long-term graft function despite decreasing immunosuppressive drug requirements, and the lack of late cellular rejection). However, this tolerance is incomplete (as demonstrated by the ultimate destruction of the graft) and nondurable (as evidenced by the ability to induce acute rejection by decreasing or stopping immunosuppressive drugs or by acute viral infections). Whereas a complete discussion of tolerance is well beyond the scope of this paper (see references 13 and 14 for more detailed discussions), a few basic concepts are worth noting. Immunologic tolerance has been demonstrated in a variety of nonhuman transplant models, utilizing a variety of techniques and based on a variety of immunologic mechanisms. The more commonly invoked mechanisms of tolerance include: chimerism (both macro and micro), clonal deletion, clonal anergy, immune deviation (ie, Th1:Th2 paradigm), and suppressor and "veto" cells. Unfortunately it seems that different mechanisms (and multiple mechanisms) are operative in the different animal models and with different tolerizing techniques; thus, it is unclear which mechanism should be pursued in human heart transplantation.
In animal models, creating true chimerism leads to robust tolerance. Chimerism in simplest terms indicates the "peaceful" coexistence of large numbers of both donor and recipient cells, in general, recipient immune cells and donor allograft cells (and sometimes immune cells). Whereas allowing quite durable and complete tolerance, it generally requires lethal irradiation and salvage with allogeneic bone marrow transplantation. Given the current results with non-HLA-identical, allogeneic bone marrow transplantation, this technique has not been applied to human heart transplantation. Based on data from the University of Pittsburgh [15] demonstrating the presence of donor-derived immune cells in patients with long-term graft survival (so-called micro-chimerism), several groups are performing bone marrow–augmented cardiac transplantation in an attempt to facilitate the development of this micro-chimeric state. However, it is not clear whether the donor-derived cells are actually responsible for the long-term graft acceptance or simply are present because of the lack of allo-reactivity to the donor (to both the graft and the passenger immune cells). Preliminary results from the University of Pittsburgh [16] suggest a modest improvement in rejection incidence with bone marrow augmentation in heart and lung recipients but no evidence of true tolerance. Attempts at clonal deletion or clonal anergy are arguably the most promising techniques. As discussed in the immunobiology paragraph above, it has been demonstrated that T-lymphocytes require at least two major signals from the APC to become activated: (1) the T-cell receptor/MHC-antigen interaction (often called signal 1); and (2) a costimulatory signal involving CD28 on the T-cell and its ligands B7.1/B7.2 (CD80/CD86) (often called signal 2). In addition, the interaction between CD154 (CD40 ligand) on the T-cell and its receptor CD40 on the APC is facilitated by signal 1, which then facilitates signal 2. It has been demonstrated in animal models that activation of signal 1 without signal 2 can cause anergy or apoptosis of the T-cell. Interference with signal 2 by administration of antibodies directed at the CD28 or a related receptor, CTLA4, while allowing signal 1 to proceed has successfully induced tolerance in animal models. In one of the most promising animal study to date, Kirk and associates [17] treated MHC-mismatched rhesus monkeys undergoing renal transplantation with antibodies against CTLA4 (human CTLA4-Ig) and CD40 ligand (5C8) briefly after transplant without other immunosuppressive drugs. Long-term graft survival without ongoing immunosuppression was demonstrated in several animals. However, this clinical tolerance was not durable, as evidenced by late acute rejection episodes in several animals that, interestingly, responded to repeat treatment with these antibodies. In addition, apparently tolerant animals retained normal third-party reactivity as well as donor-reactivity in mixed lymphocyte culture despite the lack of acute rejection. This relatively simple and well-tolerated protocol holds promise for clinical transplantation, and human renal transplant trials utilizing this approach are currently under consideration.
A number of other methods have been successful in rodent models, including donor-specific transfusions, therapy with peptides of MHC class I and II, intrathymic injection of donor antigen, monoclonal antibodies against a variety of receptors (anti-CD4, anti-CD45, anti-LFA, anti-ICAM1, anti-MHC class I and II antibodies), and increasing Fas ligand expression in the allograft to cause apoptosis of the infiltrating T-cells.
Unfortunately, because memory T-cells are quite difficult to tolerize as compared with naive T-cells, tolerizing strategies may not be effective in posttransplant patients already experiencing acute allograft rejection, and potential recipients with HLA-sensitization.
It is important to note that many of the proposed tolerance mechanisms require a competent immune system. In fact, in some models, tolerance can be broken by the administration of immunosuppressive agents! Thus, our current immunosuppressive regimens, in addition to preventing acute allograft rejection, may also be preventing the development of tolerance. However, it will be quite difficult to attempt a tolerizing strategy in human heart transplant that includes no long-term immunosuppressive therapy, given the severe consequences of failure. Because of this reality, tolerizing strategies of the (near) future will likely include some degree of underlying immunosuppression. Thus, the current "tolerance" protocols in development typically include chronic low-level immunosuppression.
Predictions for the 21st century
Given the great strides occurring in immunosuppressive drug development and application, I predict that tolerizing protocols will be successfully applied to clinical heart transplantation within the next 10 to 15 years. For those rare "tolerance failures" and for xenografts, I predict that regimens utilizing low doses of multiple "designer-drugs" with nonoverlapping toxicities will, nonetheless, allow long-term graft survival.
References
This article has been cited by other articles:
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  L. U. Nwakanma, A. S. Shah, J. V. Conte, and W. A. Baumgartner Heart Transplantation Card. Surg. Adult, January 1, 2008; 3(2008): 1539 - 1578. [Full Text]
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 A. Morgun, N. Shulzhenko, A. Perez-Diez, R. V.Z. Diniz, G. F. Sanson, D. R. Almeida, P. Matzinger, and M. Gerbase-DeLima Molecular Profiling Improves Diagnoses of Rejection and Infection in Transplanted Organs Circ. Res., June 23, 2006; 98(12): e74 - e83. [Abstract] [Full Text] [PDF]
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 A. Lembcke, S. Dushe, S. Sonntag, C. Kloeters, C. N. H. Enzweiler, T. H. Wiese, B. Hamm, F.-X. Kleber, and W. F. Konertz Changes in right ventricular dimensions and performance after passive cardiac containment Ann. Thorac. Surg., September 1, 2004; 78(3): 900 - 905. [Abstract] [Full Text] [PDF]
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