- Email: [email protected]
Clinical update: immunosuppression minimisation
Comment
Clinical update: immunosuppression minimisation For decades, the main principle of immunosuppression in transplantation has been based on the use of combination treatment. The aim of this strategy is to target distinct mechanisms of the immune response to control organ rejection and maintain long-term graft function, to minimise overall immunosuppression to avoid infections and malignancy, and to prevent drug-specific toxic effects. The introduction of the calcineurin inhibitor, ciclosporin, for clinical use in kidney transplantation in the early 1980s, resulted in two major achievements: first, substantial lowering of acute rejection rates and improvement in short-term graft survival; and second, expansion of solid-organ transplantation procedures to include the liver, pancreas, heart, and lung. Until 1995, transplant specialists were limited in their abilities to devise rational combination immunosuppression strategies, and most patients were maintained on triple treatment with ciclosporin, azathioprine, and steroids. Ciclosporin was the only immunosuppressant ever approved that improved graft survival, but this benefit was limited to short-term 1-year survival data. One of the main toxic effects of ciclosporin is renal dysfunction, including an acute functional drop in glomerular filtration rate, chronic structural changes of vasculopathy, and progressive fibrosis, which itself might contribute to the development of chronic allograft nephropathy—the main cause of chronic attrition of renal allografts over time.1 The study of immunosuppressive drugs and the endpoints of such studies have generally focused on acute rejection rates 6 months to 1 year after transplantation, and little attention has been paid to late endpoints, such as graft function, survival of the graft or patient, and novel endpoints and biomarkers of graft dysfunction. Between 1995 and 1999, several new immunosuppressive drugs were introduced for clinical use in organ transplantation (table). These drugs included new formulations of ciclosporin, tacrolimus (another calcineurin inhibitor), mycophenolate mofetil (purine synthesis inhibitor), sirolimus (a target of rapamycin [TOR] inhibitor), and antibodies to the interleukin-2 receptor.2 These drugs and antibodies were approved because they decreased acute organ rejection, and not because they improved graft survival. 1676
The rationale was that acute rejection was perhaps the single most important risk factor for the development of chronic allograft dysfunction, and therefore, the prevention of acute organ rejection should theoretically improve long-term outcome. Even before the introduction of new immunosuppressive drugs in 1995, projected half-life analysis showed significant improvement in long-term survival of renal allografts in recipients who had never had a rejection episode.3 Anticipating that the prevention of acute rejection should translate into even better long-term outcome, transplant doctors started devising therapeutic strategies to minimise immunosuppression.4 The rationale was that new immunosuppressant combinations with fewer and lower doses of drugs (or both) could be effective, yet less toxic. Initial trials mainly assessed safety (ie, low rates of acute rejection) and preservation or improvement of renal function. Such trials investigating minimisation of immunosuppression started spreading in the mid-1990s and continue to be started now. This effort to minimise immunosuppression in transplant recipients is affected by the aim to decrease the risk of premature cardiovascular disease, post-transplant infections, metabolic complications (diabetes and dyslipidaemia), and malignancy—although very few trials have addressed these issues specifically. Therefore, an assessment of the outcomes of these studies is now warranted.5 Importantly, although trials of immunosuppression minimisation are increasing in number, most strategies do not necessarily involve decreasing the number or doses (or both) of immunosuppressive drugs; few randomised trials have been done that actually minimise immunosuppression. Also, these trials do not have standardised endpoints, and few are initiated Treatment type
Examples
Calcineurin inhibitors
Ciclosporin (various formulations), tacrolimus
Corticosteroids
Prednisone, methylprednisone
Antiproliferative agents
Azathioprine, mycophenolate mofetil, enteric-coated mycophenolic acid, sirolimus
T-cell-depleting antibodies
OKT3, polyclonal antilymphocyte or antithymocyte antibodies, campath-1H
Anti-CD25 antibodies
Basiliximab, daclizumab
Table: Components of active immunosuppressive regimens
www.thelancet.com Vol 369 May 19, 2007
Comment
by investigators, instead, most have been started by the pharmaceutical industry. Most trials involve only one centre, relatively small numbers of patients, and usually exclude recipients who are deemed to be at high immunological risk (ie, previously sensitised recipients). Additionally, these trials tend to involve replacing one immunosuppressive treatment with another and, therefore, are useful to trial initiators. We believe that a strategy should be described as a minimisation treatment only when it truly involves the use of fewer or lower doses (or both) of initial or maintenance doses (or both) of immunosuppressive treatments. While transplant specialists were initially enthusiastic about the idea of immunosuppression minimisation, their excitement soon abated when actual half-life analysis of registry data showed that long-term outcome was not significantly changed—a finding that applies even after the introduction of the newer immunosuppressants.6 Therefore one important conclusion is that the prevention of acute rejection alone does not necessarily translate into better longterm survival. The reasons for this disappointing observation are unknown, but possible explanations include changing demographics of donors and recipients (ie, older age), the minimising of immunosuppressive treatments that were initially effective, acute rejection that remains, and subclinical pathological rejection. These possible explanations are functionally important. Emergence of new infections that might affect renal transplant function (ie, polyoma nephropathy) and later immunological and non-immunological processes are distinct and need different types of treatment. One example in support of the possibility of later immunological and non-immunological processes is the increased recognition of the detrimental effects of humoral-alloimmune responses on transplant outcome.7 Therefore immunosuppression minimisation might contribute, but is not necessarily the only factor leading to the lack of improvement in long-term transplant outcomes. Trials that completely avoid calcineurin inhibitors and use instead TOR inhibitors have had mixed results in terms of acute rejection, and the effect on long-term outcome remains unknown.8 Strategies to withdraw calcineurin inhibitors and maintain recipients on TOR inhibitors, or mycophenolate mofetil and steroids, www.thelancet.com Vol 369 May 19, 2007
had better success in improving renal function and histology in one study,9 and better long-term graft survival in another study.10 However, in that study, the initial immunosuppression regimen with full doses of ciclosporin and sirolimus tended to be more nephrotoxic. Additionally, others trials cast doubt on whether avoidance or minimisation of calcineurin inhibitors results in better renal allograft function and histological appearance, and that there might be differences between the two widely used calcineurin inhibitors, ciclosporin and tacrolimus. The use of a biological agent (LEA29Y; Bristol-Myers Squibb, New York City, NY, USA) to block CD28-B7-T-cell co-stimulation and replace calcineurin inhibitors showed promising results in short-term analyses.11,12 Pivotal phase III trials and conversion trials are underway. Steroid avoidance or early withdrawal (within 3 months of transplantation) is being applied widely, and seems to be more successful than late withdrawal (after 3 months), although the optimum induction and maintenance immunosuppression protocol and long-term results are unknown.13 Also, a few investigators have attempted even more drastic strategies by use of T-cell-depleting strategies alone or with monotherapy with a single immunosuppressant.14–16 The results are mixed at best; some showed increased incidence of acute rejection and emergence of humoral vascular rejection that tends to be resistant to immunosuppression, while others showed some promise at least in the short term. The growing interest in immunosuppressionminimisation protocols with conflicting results could add to the uncertainty faced by those involved in transplantations when choosing the best immunosuppressant combinations.17 This difficulty is compounded by the global variations in choice of regimens. These issues should be taken into account when designing novel protocols to test in well-designed trials with standardised endpoints, including biomarkers to measure outcomes. The main challenge in the development of novel immunosuppressive protocols in transplantation remains the lack of predictable assays to measure immunosuppression beyond pharmacological monitoring—a process that does not provide an assessment of the status of the immune response. Graft dysfunction is usually detected after much immunological damage; findings from allograft biopsies might not be predictive of clinical events 1677
Comment
Panel: Candidate assays as biomarkers of allograft rejection or tolerance Graft morphology and immunohistology Humoral immune responses (HLA and non-HLA antibodies) Direct and indirect T-cell-alloreactivity assays Trans-vivo delayed-type hypersensitivity assay T-cell-cytokine analysis Anergy, apoptosis, or regulatory T-cell assays Expression profiling (intragraft and in periphery—eg, blood and urine) Gene polymorphisms Gene chip, microarrays Proteomics Metabolomics
or the immune response; and biopsies are rarely done in clinical trials. Neither graft dysfunction nor biopsy findings allow tailoring or individualisation of immunosuppression. Therefore useful biomarkers to measure and monitor immunosuppression are needed to provide a clinical blueprint for drug adjustments to optimise or minimise immunosuppression.18 Future clinical trials need to be accompanied by extensive analyses of graft function, histology, assays to measure cellular and humoral immune responses, and assessment of the molecular phenotype of the alloimmune response (panel). Such experimental assays should be tested in well-designed prospective clinical trials, provide high sensitivity and specificity, and predict response to specific interventions. Whether such assays will allow individualisation, as opposed to merely narrowing down recipients to smaller aggregate groups, remains to be seen. Only then can transplantation doctors develop rational strategies to optimise transplant outcome, while minimising overall immunosuppression and the specific toxic effects of individual immunosuppressive treatments. Furthermore, induction and maintenance of immunological tolerance in human transplant recipients—already being tested in pilot clinical trials under the auspices of the Immune Tolerance Network—will become a widely applicable clinical reality only when informative, reproducible, and predictable tolerance assays are developed.19,20
1678
Mohamed H Sayegh, *Giuseppe Remuzzi Mario Negri Institute for Pharmacological Research, Negri Bergamo Laboratories, 24125 Bergamo, Italy (GR); and Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, MA, USA (MS) [email protected] We thank Bruce Kaplan for the critique and helpful suggestions for the text. We declare that we have no conflict of interest. 1 2 3
4 5 6
7 8
9
10
11 12
13 14
15 16
17
18 19 20
Sayegh MH, Carpenter CB. Transplantation 50 years later—progress, challenges, and promises. N Engl J Med 2004; 351: 2761–66. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351: 2715–29. 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: 605–12. Vincenti F. Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003; 14: 1940–48. Curtis JJ, Kaplan B. Transplant immunosuppressive drug trials on trial. Am J Transplant 2004; 4: 671–72. 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: 378–83. Terasaki PI, Cai J. Humoral theory of transplantation: further evidence. Curr Opin Immunol 2005; 17: 541–45. Harmon W, Meyers K, Ingelfinger J, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol 2006; 17: 1735–45. 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: 953–61. Kreis H, Oberbauer E, Campistol JM, et al. Long-term benefits with sirolimus based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 2004; 15: 809–17. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353: 770–81. Sayegh MH, Chandraker A. Does belatacept provide equivalent suppression of acute renal transplant rejection to cyclosporine? Nat Clin Pract Nephrol 2006; 2: 134–35. Hricik DE. Steroid-free immunosuppression in kidney transplantation: an editorial review. Am J Transplant 2002; 2: 19–24. 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: 120–29. Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003; 361: 1502–10. Barth RN, Janus CA, Lillesand CA, et al. Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation. Transpl Int 2006; 19: 885–92. Ekberg H, Grinyo J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR study. Am J Transplant 2007; 7: 560–70. Strom TB. Rejection—more than the eye can see. N Engl J Med 2005; 353: 2394–96. Salama AD, Remuzzi G, Harmon WE, Sayegh MH. Challenges to achieving clinical transplantation tolerance. J Clin Invest 2001; 108: 943–48. Najafian N, Albin MJ, Newell KA. How can we measure immunologic tolerance in humans? J Am Soc Nephrol 2006; 17: 2652–63.
www.thelancet.com Vol 369 May 19, 2007
Clinical update: immunosuppression minimisation For decades, the main principle of immunosuppression in transplantation has been based on the use of combination treatment. The aim of this strategy is to target distinct mechanisms of the immune response to control organ rejection and maintain long-term graft function, to minimise overall immunosuppression to avoid infections and malignancy, and to prevent drug-specific toxic effects. The introduction of the calcineurin inhibitor, ciclosporin, for clinical use in kidney transplantation in the early 1980s, resulted in two major achievements: first, substantial lowering of acute rejection rates and improvement in short-term graft survival; and second, expansion of solid-organ transplantation procedures to include the liver, pancreas, heart, and lung. Until 1995, transplant specialists were limited in their abilities to devise rational combination immunosuppression strategies, and most patients were maintained on triple treatment with ciclosporin, azathioprine, and steroids. Ciclosporin was the only immunosuppressant ever approved that improved graft survival, but this benefit was limited to short-term 1-year survival data. One of the main toxic effects of ciclosporin is renal dysfunction, including an acute functional drop in glomerular filtration rate, chronic structural changes of vasculopathy, and progressive fibrosis, which itself might contribute to the development of chronic allograft nephropathy—the main cause of chronic attrition of renal allografts over time.1 The study of immunosuppressive drugs and the endpoints of such studies have generally focused on acute rejection rates 6 months to 1 year after transplantation, and little attention has been paid to late endpoints, such as graft function, survival of the graft or patient, and novel endpoints and biomarkers of graft dysfunction. Between 1995 and 1999, several new immunosuppressive drugs were introduced for clinical use in organ transplantation (table). These drugs included new formulations of ciclosporin, tacrolimus (another calcineurin inhibitor), mycophenolate mofetil (purine synthesis inhibitor), sirolimus (a target of rapamycin [TOR] inhibitor), and antibodies to the interleukin-2 receptor.2 These drugs and antibodies were approved because they decreased acute organ rejection, and not because they improved graft survival. 1676
The rationale was that acute rejection was perhaps the single most important risk factor for the development of chronic allograft dysfunction, and therefore, the prevention of acute organ rejection should theoretically improve long-term outcome. Even before the introduction of new immunosuppressive drugs in 1995, projected half-life analysis showed significant improvement in long-term survival of renal allografts in recipients who had never had a rejection episode.3 Anticipating that the prevention of acute rejection should translate into even better long-term outcome, transplant doctors started devising therapeutic strategies to minimise immunosuppression.4 The rationale was that new immunosuppressant combinations with fewer and lower doses of drugs (or both) could be effective, yet less toxic. Initial trials mainly assessed safety (ie, low rates of acute rejection) and preservation or improvement of renal function. Such trials investigating minimisation of immunosuppression started spreading in the mid-1990s and continue to be started now. This effort to minimise immunosuppression in transplant recipients is affected by the aim to decrease the risk of premature cardiovascular disease, post-transplant infections, metabolic complications (diabetes and dyslipidaemia), and malignancy—although very few trials have addressed these issues specifically. Therefore, an assessment of the outcomes of these studies is now warranted.5 Importantly, although trials of immunosuppression minimisation are increasing in number, most strategies do not necessarily involve decreasing the number or doses (or both) of immunosuppressive drugs; few randomised trials have been done that actually minimise immunosuppression. Also, these trials do not have standardised endpoints, and few are initiated Treatment type
Examples
Calcineurin inhibitors
Ciclosporin (various formulations), tacrolimus
Corticosteroids
Prednisone, methylprednisone
Antiproliferative agents
Azathioprine, mycophenolate mofetil, enteric-coated mycophenolic acid, sirolimus
T-cell-depleting antibodies
OKT3, polyclonal antilymphocyte or antithymocyte antibodies, campath-1H
Anti-CD25 antibodies
Basiliximab, daclizumab
Table: Components of active immunosuppressive regimens
www.thelancet.com Vol 369 May 19, 2007
Comment
by investigators, instead, most have been started by the pharmaceutical industry. Most trials involve only one centre, relatively small numbers of patients, and usually exclude recipients who are deemed to be at high immunological risk (ie, previously sensitised recipients). Additionally, these trials tend to involve replacing one immunosuppressive treatment with another and, therefore, are useful to trial initiators. We believe that a strategy should be described as a minimisation treatment only when it truly involves the use of fewer or lower doses (or both) of initial or maintenance doses (or both) of immunosuppressive treatments. While transplant specialists were initially enthusiastic about the idea of immunosuppression minimisation, their excitement soon abated when actual half-life analysis of registry data showed that long-term outcome was not significantly changed—a finding that applies even after the introduction of the newer immunosuppressants.6 Therefore one important conclusion is that the prevention of acute rejection alone does not necessarily translate into better longterm survival. The reasons for this disappointing observation are unknown, but possible explanations include changing demographics of donors and recipients (ie, older age), the minimising of immunosuppressive treatments that were initially effective, acute rejection that remains, and subclinical pathological rejection. These possible explanations are functionally important. Emergence of new infections that might affect renal transplant function (ie, polyoma nephropathy) and later immunological and non-immunological processes are distinct and need different types of treatment. One example in support of the possibility of later immunological and non-immunological processes is the increased recognition of the detrimental effects of humoral-alloimmune responses on transplant outcome.7 Therefore immunosuppression minimisation might contribute, but is not necessarily the only factor leading to the lack of improvement in long-term transplant outcomes. Trials that completely avoid calcineurin inhibitors and use instead TOR inhibitors have had mixed results in terms of acute rejection, and the effect on long-term outcome remains unknown.8 Strategies to withdraw calcineurin inhibitors and maintain recipients on TOR inhibitors, or mycophenolate mofetil and steroids, www.thelancet.com Vol 369 May 19, 2007
had better success in improving renal function and histology in one study,9 and better long-term graft survival in another study.10 However, in that study, the initial immunosuppression regimen with full doses of ciclosporin and sirolimus tended to be more nephrotoxic. Additionally, others trials cast doubt on whether avoidance or minimisation of calcineurin inhibitors results in better renal allograft function and histological appearance, and that there might be differences between the two widely used calcineurin inhibitors, ciclosporin and tacrolimus. The use of a biological agent (LEA29Y; Bristol-Myers Squibb, New York City, NY, USA) to block CD28-B7-T-cell co-stimulation and replace calcineurin inhibitors showed promising results in short-term analyses.11,12 Pivotal phase III trials and conversion trials are underway. Steroid avoidance or early withdrawal (within 3 months of transplantation) is being applied widely, and seems to be more successful than late withdrawal (after 3 months), although the optimum induction and maintenance immunosuppression protocol and long-term results are unknown.13 Also, a few investigators have attempted even more drastic strategies by use of T-cell-depleting strategies alone or with monotherapy with a single immunosuppressant.14–16 The results are mixed at best; some showed increased incidence of acute rejection and emergence of humoral vascular rejection that tends to be resistant to immunosuppression, while others showed some promise at least in the short term. The growing interest in immunosuppressionminimisation protocols with conflicting results could add to the uncertainty faced by those involved in transplantations when choosing the best immunosuppressant combinations.17 This difficulty is compounded by the global variations in choice of regimens. These issues should be taken into account when designing novel protocols to test in well-designed trials with standardised endpoints, including biomarkers to measure outcomes. The main challenge in the development of novel immunosuppressive protocols in transplantation remains the lack of predictable assays to measure immunosuppression beyond pharmacological monitoring—a process that does not provide an assessment of the status of the immune response. Graft dysfunction is usually detected after much immunological damage; findings from allograft biopsies might not be predictive of clinical events 1677
Comment
Panel: Candidate assays as biomarkers of allograft rejection or tolerance Graft morphology and immunohistology Humoral immune responses (HLA and non-HLA antibodies) Direct and indirect T-cell-alloreactivity assays Trans-vivo delayed-type hypersensitivity assay T-cell-cytokine analysis Anergy, apoptosis, or regulatory T-cell assays Expression profiling (intragraft and in periphery—eg, blood and urine) Gene polymorphisms Gene chip, microarrays Proteomics Metabolomics
or the immune response; and biopsies are rarely done in clinical trials. Neither graft dysfunction nor biopsy findings allow tailoring or individualisation of immunosuppression. Therefore useful biomarkers to measure and monitor immunosuppression are needed to provide a clinical blueprint for drug adjustments to optimise or minimise immunosuppression.18 Future clinical trials need to be accompanied by extensive analyses of graft function, histology, assays to measure cellular and humoral immune responses, and assessment of the molecular phenotype of the alloimmune response (panel). Such experimental assays should be tested in well-designed prospective clinical trials, provide high sensitivity and specificity, and predict response to specific interventions. Whether such assays will allow individualisation, as opposed to merely narrowing down recipients to smaller aggregate groups, remains to be seen. Only then can transplantation doctors develop rational strategies to optimise transplant outcome, while minimising overall immunosuppression and the specific toxic effects of individual immunosuppressive treatments. Furthermore, induction and maintenance of immunological tolerance in human transplant recipients—already being tested in pilot clinical trials under the auspices of the Immune Tolerance Network—will become a widely applicable clinical reality only when informative, reproducible, and predictable tolerance assays are developed.19,20
1678
Mohamed H Sayegh, *Giuseppe Remuzzi Mario Negri Institute for Pharmacological Research, Negri Bergamo Laboratories, 24125 Bergamo, Italy (GR); and Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, MA, USA (MS) [email protected] We thank Bruce Kaplan for the critique and helpful suggestions for the text. We declare that we have no conflict of interest. 1 2 3
4 5 6
7 8
9
10
11 12
13 14
15 16
17
18 19 20
Sayegh MH, Carpenter CB. Transplantation 50 years later—progress, challenges, and promises. N Engl J Med 2004; 351: 2761–66. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351: 2715–29. 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: 605–12. Vincenti F. Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003; 14: 1940–48. Curtis JJ, Kaplan B. Transplant immunosuppressive drug trials on trial. Am J Transplant 2004; 4: 671–72. 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: 378–83. Terasaki PI, Cai J. Humoral theory of transplantation: further evidence. Curr Opin Immunol 2005; 17: 541–45. Harmon W, Meyers K, Ingelfinger J, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol 2006; 17: 1735–45. 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: 953–61. Kreis H, Oberbauer E, Campistol JM, et al. Long-term benefits with sirolimus based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 2004; 15: 809–17. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353: 770–81. Sayegh MH, Chandraker A. Does belatacept provide equivalent suppression of acute renal transplant rejection to cyclosporine? Nat Clin Pract Nephrol 2006; 2: 134–35. Hricik DE. Steroid-free immunosuppression in kidney transplantation: an editorial review. Am J Transplant 2002; 2: 19–24. 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: 120–29. Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003; 361: 1502–10. Barth RN, Janus CA, Lillesand CA, et al. Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation. Transpl Int 2006; 19: 885–92. Ekberg H, Grinyo J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR study. Am J Transplant 2007; 7: 560–70. Strom TB. Rejection—more than the eye can see. N Engl J Med 2005; 353: 2394–96. Salama AD, Remuzzi G, Harmon WE, Sayegh MH. Challenges to achieving clinical transplantation tolerance. J Clin Invest 2001; 108: 943–48. Najafian N, Albin MJ, Newell KA. How can we measure immunologic tolerance in humans? J Am Soc Nephrol 2006; 17: 2652–63.
www.thelancet.com Vol 369 May 19, 2007