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The Importance of Bringing Transplantation Tolerance to the Clinic

2021; Wolters Kluwer; Volume: 105; Issue: 5 Linguagem: Inglês

10.1097/tp.0000000000003532

1534-6080

A. Benedict Cosimi, Nancy L. Ascher, Jean C. Emond, Dixon B. Kaufman, Joren C. Madsen, Joshua Miller, Anthony P. Monaco, Robert A. Montgomery, Kenneth A. Newell, Alberto Sánchez‐Fueyo, Minnie Sarwal, John D. Scandling, Samuel Strober, Satoru Todo, Matthew R. Weir, David H. Sachs,

Organ Donation and Transplantation

NECESSITY OF CLINICAL TOLERANCE PROTOCOLS IN ORGAN TRANSPLANTATION Since its clinical inception in 1954, organ transplantation has saved lives of many thousands of patients who were dying because of the failure of a single organ. As such, it is clear that transplantation has had enormous clinical success. However, it is likewise clear, both to transplant patients and to their physicians, that the life-long requirement for drug treatment to prevent transplant rejection causes complications that do not permit recipients of organ transplants to live a normal life. These side effects can be especially troubling in pediatric recipients, where drug-related complications do not infrequently lead to noncompliance and subsequent graft failure.1 Many of these patients live with a chronic condition and must deal with problems caused by the very medications that are required to maintain the organs that have saved their lives. Transplant tolerance, on the other hand, which has occasionally been observed in patients who stopped taking their medications2-5 and which has recently been achieved intentionally in renal transplant recipients,6,7 allows the recipients of these life-saving transplants to be restored to a normal life. All authors have witnessed, first-hand, both the rapid development of this life-saving technology and the ravages of chronic immunosuppression and have shared the excitement of seeing the promise of tolerance successfully brought to the clinic. This white article has been developed in anticipation that the documentation of the successes of tolerance versus the limitations of current immunosuppressive therapy will persuade regulatory authorities to approve the drugs and protocols required for tolerance induction. DEFINITION OF TOLERANCE Transplantation tolerance is probably best defined as the specific absence of a destructive immunologic response to a transplanted organ or tissue without ongoing exogenous immunosuppression.8 This state may be mediated by (1) deletional tolerance, or the absence of an immune response due to "deletion" of immune cells capable of reacting with the relevant antigens; or by (2) regulatory tolerance, or the presence of a nondestructive or "regulatory" immune response, which downregulates the effector response, which would otherwise lead to rejection. In both cases, this tolerance is "specific," affecting only the response to the transplant, as opposed to the nonspecific loss of immune responses brought about by immunosuppressive drugs. RELATIONSHIP OF ALLOGENEIC TOLERANCE WITH SELF-TOLERANCE Both of these mechanisms (ie, deletional and regulatory) which have been pursued to induce transplantation tolerance across allogeneic barriers are present in the normal immune system, presumably to prevent autoimmunity. Deletional tolerance occurs predominantly in the thymus, where developing T cells are taught not to react with self through a process called "negative selection," thus avoiding autoimmunity. The process of "mixed chimerism," which has been used effectively to induce tolerance in animals and most recently in human transplant recipients, involves establishing a mixture of host and donor hematopoietic cells in the peripheral blood.9 These cells can enter the thymus and cause negative selection of both host and donor reactive T cells so that the recipient becomes tolerant not only to self-antigens but also to antigens of the donor. T cells required for other purposes, such as fighting microbial disease, are not affected, leaving the recipient specifically tolerant to the donor. Regulatory tolerance is likewise thought to be present in the normal immune system to prevent autoimmunity, which in this case is caused by T cells that have escaped negative selection in the thymus. Peripheral downregulation of these potentially self-reactive cells is brought about by regulatory T cells (Treg), initially discovered when their removal in animal models was shown to cause autoimmune disease.10 Treg that control alloreactivity following a transplant have been shown to be induced by both costimulatory blockade11 and mixed chimerism.9 Even when mixed chimerism is transient, host-derived Treg have been shown to maintain tolerance of transplanted tissues after donor cells have disappeared from the circulation.12 Thus, both mechanisms of tolerance used by the immune system to prevent autoimmunity have also been used experimentally and clinically to induce tolerance of organ transplants. MEANS FOR AVOIDING REJECTION HLA-Matching There are 3 main ways to avoid rejection of a transplanted allogeneic organ. The first is through matching, a situation in which recipient and donor share the antigens, which otherwise would cause rejection. The only full match for humans is between identical twins, which was indeed the basis of the first successful allogeneic kidney transplant.13 In this case, no immunosuppressive drugs are required because there is no destructive immune response that needs to be suppressed. For clinical purposes, this approach is, of course, rarely relevant. The next best match exists between HLA-identical siblings. Because the HLA antigens, which are the major stimulus for rejection, are carried on a single chromosome, 1 out of 4 siblings of a patient requiring a transplant would be expected to share the same HLA antigens inherited from their parents. HLA-matched transplants, nevertheless, still require exogenous immunosuppression due to the existence of numerous minor transplantation antigens.14 Although the intensity of immunosuppression required is sometimes less and the results of transplantation are moderately better than they are for transplants between HLA-mismatched donor-recipient pairs,15 the majority of even these patients currently remain on life-long immunosuppressive medications. Thus, although matching is theoretically an effective way of eliminating rejection, its clinical applicability has remained severely limited, at best to identical twins and rarely to a recipient of an HLA-identical donor organ. Essentially, all other transplant recipients currently require life-long maintenance immunosuppression. Chemical Immunosuppression The second methodology for preventing rejection is the use of immunosuppressive drugs, which suppress the immune response nonspecifically, thus allowing the transplant to survive despite differences in HLA and minor antigens between the recipient and the donor. These drugs have indeed been essential to the success of transplantation as a field and have been responsible for saving many thousands of lives that would otherwise have been lost due to failure of a vital organ. Over the past several decades, pharmaceutical companies have strived to develop immunosuppressive drugs that inhibit the rejection response to a greater extent than they inhibit the response to infectious diseases. Nevertheless, as described in more detail below, all available immunosuppressive drugs increase susceptibility to infection and have side effects that often cause severe morbidity. Transplant-specific Tolerance Allogeneic tolerance was first discovered as an experiment of nature by Owen, who was studying the origin of unusual blood groups in cattle. Owen16 reported in 1945 that certain fraternal cattle twins, called freemartin cattle, which were born from a common placenta, exhibited a mixture of blood types from both animals later in life. Subsequently, Medawar recognized that these findings implied the persistence of donor cells in a recipient without immunosuppression—a phenomenon he and his colleagues called immunologic tolerance.17 They were able to reproduce this phenomenon in the laboratory by injecting allogeneic cells into fetal or into neonatal mice during the first 24 hours of life. Many of these mice appeared to live normal lives but were capable of accepting skin grafts from the donor strain later in life. While these studies proved that the induction of tolerance could lead to successful transplantation without immunosuppression, this phenomenon did not have great clinical significance as described because one does not know that at the time of birth, who will eventually become a patient requiring an organ transplant, nor the appropriate donor. Therefore, since that time, numerous investigators have attempted to induce such immunologic tolerance in adult recipients. Many means for inducing transplant tolerance have been described in mice. However, among these, only the establishment of mixed hematopoietic chimerism has been successfully translated from mice to large animals, to nonhuman primates, and most recently to renal transplant patients.9 THE LIMITATIONS OF IMMUNOSUPPRESSION Despite improvement in short-term survival of organ transplant recipients over the past 3 decades, toxicity of life-long immunosuppressive drug administration results in significantly increased morbidity and mortality.18,19 Not surprisingly, infection is the major cause of rehospitalization during the early posttransplant period. However, even after 1 year, infections in the immunosuppressed patient remain a major issue requiring meticulous monitoring.20 Additionally, every transplant physician is aware of the common development of malignancies in allograft recipients where the overall risk of cancer after 20 years of immunosuppression exceeds 40% in contrast to approximately 10% cumulative risk in nonsuppressed individuals. Moreover, currently used immunosuppressive agents are associated with well-documented risks of accelerated atherosclerosis, including hypertension, dyslipidemia, and hyperglycemia. Not surprisingly, therefore, cardiovascular events develop in 20% of renal recipients by 15 years and in as many as 50% of cardiac recipients.21 Additional side effects include de novo diabetes in 30%, which remains permanent in 15% of immunosuppressed individuals,22,23 nephrotoxicity which is almost universal, and neurotoxicity.24 Unfortunately, despite these toxicities that accompany the potent immunomodulatory effects of current therapeutic protocols, chronic rejection is not consistently prevented. In the renal allograft, chronic, repetitive endothelial cell injury, predominantly in the glomerulus, causes tissue lesions, which are referred to as transplant glomerulopathy (TG).25 TG is caused by humoral or cellular immune responses,26,27 infection,28,29 and calcineurin-inhibitor toxicity30 and has been reported to occur in 20% of patients over 5 years posttransplant.31 Over 50% of patients diagnosed with TG suffer from either graft loss or substantial (>50%) reduction of glomerular filtration rate over 36 months postdiagnosis, and there are currently no specific treatments proven to work for this important predictor of graft loss.32 Because of these morbidities and rejection, 10-year graft survival of deceased donor kidney transplantation remains around 50% and for HLA-mismatched living donor kidneys, only 60%,33 although over 80% of the surviving allografts show significant nephropathy on protocol biopsies by 10 years.34 Death with a functioning graft accounts for at least half of the graft losses, primarily due to the ravages of chronic immunosuppression.35 Induction of allograft tolerance has been considered the probable solution for many of these limitations associated with long-term immunosuppression as well as the best approach to reduce the risk of chronic rejection. THE PROMISE OF TOLERANCE Another major cause of late graft loss is nonadherence by recipients who discontinue immunosuppressive medication because of the costs and adverse effects noted above.36 A review of 38 studies of long-term survival in renal recipients revealed noncompliance rates that ranged between 28% and 52%.37,38 In a prospective multicenter study including 313 patients undergoing renal transplantation, 64% of graft failure was attributed to antibody-mediated or mixed rejection, of which nonadherence was recorded in 47%.39 Because few ( 15 years has been achieved in recipients of living-donor, HLA 1-haplotype–mismatched kidney transplants.8 In the initial study, conventional immunosuppression was successfully discontinued in 7 of 10 recipients for 5 or more years. Three of 7 patients required reinstitution of maintenance immunosuppression at 5, 7, and 8 years because of recurrent disease or chronic rejection. An important limitation of the initial study was the development of a cytokine-like response including acute kidney injury in 9 of 10 individuals. This syndrome has previously been described in bone marrow transplant recipients,46,47 in which the renal dysfunction was always self-limited and never posed a major clinical concern. However, those patients generally had normal kidneys, as opposed to the patients in the MGH tolerance study, who had just undergone a renal transplant. Even in the case of these transplant recipients, the phenomenon appeared to be self-limited, with renal function returning to baseline in all but 1 patient who developed tacrolimus nephrotoxicity, probably due to misinterpretation of the renal dysfunction as rejection.48,49 A modification of the preoperative regimen that is currently under study may eliminate this complication. TABLE 1. - Published clinical trials of tolerance induction45 Study site Approach Organ Subjects I.S. d/c'd Years Off I.S. Massachusetts General Hospital, Boston DBM/transient chimerism Kidney HLA mismatched 10 7 6–17 Stanford University, Palo Alto CD34+ cells/durable chimerism Kidney HLA matched 29 21 1–10 HLA mismatched 27 0 NA Northwestern University, Chicago CD34+ and facilitator cells/durable chimerism Kidney HLA mismatched 37 26 2.5–10 Samsung Medical Center, Seoul DBM/transient chimerism Kidney HLA mismatched 8 4 1.5–5 "One" Study, International Reg cell infusions Kidney HLA mismatched 60 0 NA Hokkaido University, Sapporo, Japan Treg infusion Liver 10 7 6–8 DBM, donor bone marrow; Treg, regulatory T cell; NA, not available. At Stanford University, a conditioning regimen based upon total lymphoid irradiation and CD34+ cell infusions has been used to induce mixed chimerism.50-52 Conventional immunosuppression has been successfully withdrawn from approximately 75% of HLA-matched recipients receiving this treatment. No HLA-mismatched recipients have yet been reported to have undergone successful immunosuppression withdrawal on this protocol. A clinical trial at Northwestern University has also included CD34+ stem cell infusions, but with the addition of "facilitator cells."53,54 The effort has been to achieve durable hematopoietic chimerism and has resulted in successful withdrawal of immunosuppression in >2 of 3 HLA-mismatched renal recipients, although graft-versus-host disease was reported in 2 of 37 patients, 1 of whom died. A trial at the Samsung Medical Center in Seoul, South Korea, similar in design to that being carried out at MGH, has permitted withdrawal of all immunosuppression in 4 of 8 treated patients, but with a relatively short follow-up.55 The "One" Study, testing the effect of administering Treg to kidney transplant recipients, is included in Table 1 for completeness, but because drug withdrawal has not yet been included as an endpoint, it cannot really be considered as a tolerance trial. Experience in all of these trials has emphasized that more careful selection of patients for tolerance induction, such as excluding presensitized individuals and those with a high likelihood of recurrent native disease, will undoubtedly provide even higher rates of successful immunosuppression withdrawal. Also included in Table 1 is a single reported trial of tolerance induction (versus simple drug withdrawal) in liver transplant recipients that has been undertaken in Japan. Ten adult liver transplant recipients were treated with conventional immunosuppression plus ex vivo expanded donor-specific Treg. Successful withdrawal of all immunosuppression was accomplished in 7 of the 10 liver–Treg recipients for 2 years or more.56 DRUG MINIMIZATION AS AN ALTERNATIVE MEANS OF OVERCOMING THE CURRENT LIMITATIONS OF IMMUNOSUPPRESSION To decrease the side effects and morbidity of current immunosuppressive therapy, many transplant centers have attempted "drug minimization," that is, to systematically decrease the number or dosage of drugs administered, in the hope that lower blood levels can be achieved that will still prevent rejection with less undesirable side effects. Although there have been claims of success with this approach, the evidence supporting this conclusion is limited. Sawinski et al57 have recently reviewed the results from 88 randomized controlled trials attempting to assess the impact of drug minimization on patient and allograft survival following kidney transplantation, as well as on the incidence of acute rejection and renal allograft function. Although some trends toward an advantage of drug minimization versus standard immunosuppression were seen, there was great variability between the results of different studies for most of the parameters compared. The scatter of results favoring drug minimization versus those favoring standard immunosuppression made it difficult to accept any firm conclusion with regard to the benefit of drug minimization. With regard to decreasing the number of drugs used, according to the Scientific Registry of Transplant Recipients (data request May 25, 2018), about 66% of kidney transplant recipients were maintained on 3 immunosuppressive drugs 1 year after transplant, about 26% percent were on 2 drugs, and <2% were on 1 drug. Thus, minimization to 1 drug is relatively rare in SOC patients. SUMMARY Except for recipients of identical twin allografts, life-long immunosuppression is required following transplantation. As currently practiced, this situation leaves much to be desired, with respect both to complications caused by the drugs used and to the efficacy with which rejection is prevented. Although still in its infancy with respect to clinical applications, the induction of tolerance already appears to have major advantages over this current SOC. To date, patients in whom tolerance has been induced successfully have been restored to a normal life, enjoying freedom from the complications of immunosuppression and transplant function as good or better than can be obtained with SOC. Madariaga et al recently compared a large series of "quality of life" parameters for patients who had achieved long-term renal allograft survival through a tolerance induction protocol versus comparable kidney transplant patients on conventional immunosuppression.58 Despite the small sample size, they found a significant improvement in quality of life for the tolerance cohort. The only alternative to tolerance that has been proposed for reducing the complications of current SOC has been drug minimization, the results of which have to date been disappointing. We, therefore, conclude that the successes of tolerance versus the limitations of immunosuppressive therapy provide ample reason for vigorous further pursuit of promising clinical protocols for the induction of transplantation tolerance in both adult and pediatric transplant recipients.FIGURE 1.: The 2 major mechanisms by which mixed chimerism induces transplantation tolerance: (A) negative selection in the thymus of developing host effector T cells through their interaction with donor dendritic cells in the corticomedullary junction and (B) downregulation in the periphery by Treg that are produced during positive selection of host T cells in the cortex of the thymus. HSC, hematopoietic stem cell; Treg, regulatory T cell.ACKNOWLEDGMENTS The authors thank ITB-Med for support of the preparation of this article, Ms. Rebecca Brophy for expert editorial assistance, and Dr Tatsuo Kawai for providing data for Table 1.