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Tolerance protocols and cell transplantation
Tolerance Protocols and Cell Transplantation: Prospects for the Clinic R.Y. Calne
I
N SCIENCE, as in politics and economics, long-term predictions are hazardous, but the chances of a correct guess for the immediate future are reasonable. I wish to consider two recent advances that point the way to therapeutic improvement. The first recent advance is the use of powerful induction treatment and then minimal maintenance immunosuppression. I have called this “almost tolerance” or the Latin words prope tolerance. In Cambridge, we have followed up 31 cases now for 4 years. The patients, recipients of cadaveric renal allografts, were given two injections of 20 mg of the powerful lymphocyte– depleting antibody Campath 1H at the time of operation and were maintained on low-dose cyclosporine. No other immunosuppressant agents were given unless there was evidence of rejection. The results overall have been gratifying.1,2 The patients with good function in their kidneys have been delighted with the simplicity of the immunosuppressant regimen. Now, larger trials are under way and we need to determine the optimum dosage of both Campath and cyclosporine or whether an alternative maintenance immmunosuppression might be better. Second, all those interested in the treatment of diabetes were encouraged by the report in the New England Journal of Medicine in the year 2000 by the Edmonton Group.3 They succeeded in controlling type 1 diabetes in patients who had not yet developed serious complications by transplanting islets extracted from cadaveric donor pancreata using an immunosuppressive regimen that did not include steroids. The islets were injected under X-ray control into the portal vein. Currently, a number of centers are attempting to repeat the Edmonton protocol with varying degrees of success and recently there has been a successful islet transplantation in a patient who already had a renal transplant.4 It would be a considerable advance if we could treat patients who already have kidney grafts and, therefore, require immunosuppression with the relatively small addition of an injection of islets. The results of organ transplantation have improved enormously during the last 20 years. The introduction of cyclosporine into clinical practice resulted in the 1-year cadaveric kidney graft survival rate increasing from 50% to 80%. However, at 10 years, the graft survival decreased to the same as that achieved previously with aziothioprine and steroids. The causes of these long-term disappointing re-
sults were probably a combination of chronic rejection and nephrotoxicity of cyclosporine. During the intervening years, a number of new agents have been introduced and, with an understanding of their use, the 1-year graft survival has improved further, but the long-term results have changed little. There has been a tendency to increase the number and dosage of immunosuppressive agents with a further reduction of acute rejection, but also with increased toxicity. In an attempt to move away from this unfortunate progression, we adopted a proof of principle introduced by Knechtle5 of using a powerful induction antibody to eliminate T-cell activity and then maintain the patient on a much-reduced immunosuppressant regimen; we call this almost or prope tolerance. We gave the patients two doses of the unique monoclonal antibody Campath 1H and used maintenance dosage with monotherapy of cyclosporine at half the normal dose. The follow-up now of a minimum of 4 years of these recipients of cadaveric renal allografts has been encouraging. A number of centres are now attempting to determine the optimum choice of maintenance immunosuppressant drug and the minimum dose that will be effective. Also, changes in dosage and timing of the Campath are being investigated. It is likely that other induction regimens will be tried, including polyclonal anti-lymphocyte antibodies. The principle, however, would seem to be established that this has advantages over traditional highdosage regimens. As we are becoming more confident with the use of low-dose immunosuppression preceded by an induction treatment, so the potential for cell transplantation begins to look attractive. Since the beginning of organ transplantation, running in parallel has been transplantation of bone marrow. This is now extremely successful, but the requirements are identity of tissue matching and blood group. The regimen used to prepare the patient was harsh, requiring large doses of total body irradiation and drugs to destroy the whole of the recipient’s bone marrow and immune From the Department of Surgery, University of Cambridge (Addenbrooke’s Hospital), Cambridge, United Kingdom. Address reprint requests to R.Y. Calne, Department of Surgery, University of Cambridge (Addenbrooke’s Hospital), Douglas House Annexe, 18 Trumpington Rd, Cambridge, CB2 2AH UK.
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00206-9
© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
1248
Transplantation Proceedings, 35, 1248 –1249 (2003)
TOLERANCE PROTOCOLS AND CELL TRANSPLANTATION
system and replace these with the transplant. The donor’s marrow is injected intravenously and automatically homes in to the bone marrow location of the recipient, which has been depopulated. In the last few years, less severe conditioning has been developed, which is nonablative and permits coexistence of donor and recipient bone marrow in a chimaeric state. Successful bone marrow transplantation results in tolerance so that an organ graft from the same donor will be accepted without the need for any additional immunosuppressive treatment. Already both experimentally and in the clinic this nonablative bone marrow transplantation has been used to produce immunological tolerance for organ transplantation.6,7 This is an important pointer to the future, although at present the requirement is for donor and recipient to be well matched for tissue typing and blood grouping. With this background, attention is being directed to other types of cell transplantation, in particular, for the treatment of serious chronic diseases, such as diabetes and Parkinson’s disease. There is also the hope that cell transplantation will be able to cure serious rare metabolic diseases. Ideally, if the patient’s own blood stem cells could be persuaded to take on the function required, there would be no tendency for the patient’s own cells to be rejected. Another approach would be to modify stem cells, adult or embryonic. There is evidence that embryonic stem cells not only lack the ability to sensitise the recipient but also may actually cause tolerance if injected into the portal vein.8 There is hope that adult stem cells might behave similarly. Foetal cells also have been used, for example, the retinal pigment cells, which normally produce dopamine for the treatment of Parkinson’s disease.9 Diabetes type 1 and type 2 cause major morbidity and mortality throughout the world and the incidence of both types is increasing, especially type 2. Many investigators are studying the use of cell transplantation for the treatment of diabetes. For more than 2 decades, work has been in progress to try to use islets extracted from the pancreas and inject them into patients with diabetes to cure the disease. The extraction process has proved to be difficult, but gradually the procedure has improved, although it is by no means perfect. Many islets are lost in the process. There is
1249
then the problem of where to put the islets and how to prevent them from being rejected. The normal physiological drainage of insulin is first into the liver and the portal vein has proved to be the best site for injection used so far. The conventional drugs used to stop rejection are toxic to islets. Two years ago, workers in Edmonton reported successful islet transplantation using nonsteroidal immunosuppression. The early results have held up well, but the main disadvantage of this approach is that islets are required from two or even three cadaveric pancreases. Obviously, there would not be sufficient donor material to make any impact on the huge population of patients with diabetes who required treatment. Therefore, many centers are interested in alternative approaches to investigate all the possibilities mentioned above in persuading cells that do not normally produce insulin to make and release this protein in a correct physiological manner in relation to the patient’s blood sugar. An obvious goal would be to use islets taken from animals, in particular the pig. We know that porcine insulin is satisfactory in terms of its activity in humans, so islets from the pig would have all the characteristics that we need for the treatment of diabetes. Unfortunately, the immunological reaction of this discordant transplant has been very difficult to overcome, but transgenic manipulation of the pig and elimination of unwanted antigens are now giving encouragement that this xenograft reaction eventually may be soluble. REFERENCES 1. Calne RY, Friend PJ, Moffatt S, et al: Lancet 351:1701, 1998 2. Calne RY, Moffatt SD, Friend PJ, et al: Transplantion 68:1613, 1999 3. Shapiro AM, Lakey JR, Ryan EA, et al: N Engl J Med 343: 4, 2000 4. Kaufman D, Baker MS, Chen X, et al: Am J Transplant 2:674, 2002 5. Knechtle S, Vargo D, Fechner J, et al: Transplantation 63:1, 1997 6. Kuhr CS, Alken MD, Junghanss C, et al: Transplantation 73:1487, 2002 7. Spitzer TR, Delmonico F, Tolkoff-Rubin N, et al: Transplantation 68:480, 1999 8. Fandrich F, Lin X, Chai GX, et al: Nat Med 8:171, 2002 9. Watts P, et al: Presented at the XIV International Congress on Parkinson’s Disease, Helsinki, Finland, 2001
I
N SCIENCE, as in politics and economics, long-term predictions are hazardous, but the chances of a correct guess for the immediate future are reasonable. I wish to consider two recent advances that point the way to therapeutic improvement. The first recent advance is the use of powerful induction treatment and then minimal maintenance immunosuppression. I have called this “almost tolerance” or the Latin words prope tolerance. In Cambridge, we have followed up 31 cases now for 4 years. The patients, recipients of cadaveric renal allografts, were given two injections of 20 mg of the powerful lymphocyte– depleting antibody Campath 1H at the time of operation and were maintained on low-dose cyclosporine. No other immunosuppressant agents were given unless there was evidence of rejection. The results overall have been gratifying.1,2 The patients with good function in their kidneys have been delighted with the simplicity of the immunosuppressant regimen. Now, larger trials are under way and we need to determine the optimum dosage of both Campath and cyclosporine or whether an alternative maintenance immmunosuppression might be better. Second, all those interested in the treatment of diabetes were encouraged by the report in the New England Journal of Medicine in the year 2000 by the Edmonton Group.3 They succeeded in controlling type 1 diabetes in patients who had not yet developed serious complications by transplanting islets extracted from cadaveric donor pancreata using an immunosuppressive regimen that did not include steroids. The islets were injected under X-ray control into the portal vein. Currently, a number of centers are attempting to repeat the Edmonton protocol with varying degrees of success and recently there has been a successful islet transplantation in a patient who already had a renal transplant.4 It would be a considerable advance if we could treat patients who already have kidney grafts and, therefore, require immunosuppression with the relatively small addition of an injection of islets. The results of organ transplantation have improved enormously during the last 20 years. The introduction of cyclosporine into clinical practice resulted in the 1-year cadaveric kidney graft survival rate increasing from 50% to 80%. However, at 10 years, the graft survival decreased to the same as that achieved previously with aziothioprine and steroids. The causes of these long-term disappointing re-
sults were probably a combination of chronic rejection and nephrotoxicity of cyclosporine. During the intervening years, a number of new agents have been introduced and, with an understanding of their use, the 1-year graft survival has improved further, but the long-term results have changed little. There has been a tendency to increase the number and dosage of immunosuppressive agents with a further reduction of acute rejection, but also with increased toxicity. In an attempt to move away from this unfortunate progression, we adopted a proof of principle introduced by Knechtle5 of using a powerful induction antibody to eliminate T-cell activity and then maintain the patient on a much-reduced immunosuppressant regimen; we call this almost or prope tolerance. We gave the patients two doses of the unique monoclonal antibody Campath 1H and used maintenance dosage with monotherapy of cyclosporine at half the normal dose. The follow-up now of a minimum of 4 years of these recipients of cadaveric renal allografts has been encouraging. A number of centres are now attempting to determine the optimum choice of maintenance immunosuppressant drug and the minimum dose that will be effective. Also, changes in dosage and timing of the Campath are being investigated. It is likely that other induction regimens will be tried, including polyclonal anti-lymphocyte antibodies. The principle, however, would seem to be established that this has advantages over traditional highdosage regimens. As we are becoming more confident with the use of low-dose immunosuppression preceded by an induction treatment, so the potential for cell transplantation begins to look attractive. Since the beginning of organ transplantation, running in parallel has been transplantation of bone marrow. This is now extremely successful, but the requirements are identity of tissue matching and blood group. The regimen used to prepare the patient was harsh, requiring large doses of total body irradiation and drugs to destroy the whole of the recipient’s bone marrow and immune From the Department of Surgery, University of Cambridge (Addenbrooke’s Hospital), Cambridge, United Kingdom. Address reprint requests to R.Y. Calne, Department of Surgery, University of Cambridge (Addenbrooke’s Hospital), Douglas House Annexe, 18 Trumpington Rd, Cambridge, CB2 2AH UK.
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00206-9
© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
1248
Transplantation Proceedings, 35, 1248 –1249 (2003)
TOLERANCE PROTOCOLS AND CELL TRANSPLANTATION
system and replace these with the transplant. The donor’s marrow is injected intravenously and automatically homes in to the bone marrow location of the recipient, which has been depopulated. In the last few years, less severe conditioning has been developed, which is nonablative and permits coexistence of donor and recipient bone marrow in a chimaeric state. Successful bone marrow transplantation results in tolerance so that an organ graft from the same donor will be accepted without the need for any additional immunosuppressive treatment. Already both experimentally and in the clinic this nonablative bone marrow transplantation has been used to produce immunological tolerance for organ transplantation.6,7 This is an important pointer to the future, although at present the requirement is for donor and recipient to be well matched for tissue typing and blood grouping. With this background, attention is being directed to other types of cell transplantation, in particular, for the treatment of serious chronic diseases, such as diabetes and Parkinson’s disease. There is also the hope that cell transplantation will be able to cure serious rare metabolic diseases. Ideally, if the patient’s own blood stem cells could be persuaded to take on the function required, there would be no tendency for the patient’s own cells to be rejected. Another approach would be to modify stem cells, adult or embryonic. There is evidence that embryonic stem cells not only lack the ability to sensitise the recipient but also may actually cause tolerance if injected into the portal vein.8 There is hope that adult stem cells might behave similarly. Foetal cells also have been used, for example, the retinal pigment cells, which normally produce dopamine for the treatment of Parkinson’s disease.9 Diabetes type 1 and type 2 cause major morbidity and mortality throughout the world and the incidence of both types is increasing, especially type 2. Many investigators are studying the use of cell transplantation for the treatment of diabetes. For more than 2 decades, work has been in progress to try to use islets extracted from the pancreas and inject them into patients with diabetes to cure the disease. The extraction process has proved to be difficult, but gradually the procedure has improved, although it is by no means perfect. Many islets are lost in the process. There is
1249
then the problem of where to put the islets and how to prevent them from being rejected. The normal physiological drainage of insulin is first into the liver and the portal vein has proved to be the best site for injection used so far. The conventional drugs used to stop rejection are toxic to islets. Two years ago, workers in Edmonton reported successful islet transplantation using nonsteroidal immunosuppression. The early results have held up well, but the main disadvantage of this approach is that islets are required from two or even three cadaveric pancreases. Obviously, there would not be sufficient donor material to make any impact on the huge population of patients with diabetes who required treatment. Therefore, many centers are interested in alternative approaches to investigate all the possibilities mentioned above in persuading cells that do not normally produce insulin to make and release this protein in a correct physiological manner in relation to the patient’s blood sugar. An obvious goal would be to use islets taken from animals, in particular the pig. We know that porcine insulin is satisfactory in terms of its activity in humans, so islets from the pig would have all the characteristics that we need for the treatment of diabetes. Unfortunately, the immunological reaction of this discordant transplant has been very difficult to overcome, but transgenic manipulation of the pig and elimination of unwanted antigens are now giving encouragement that this xenograft reaction eventually may be soluble. REFERENCES 1. Calne RY, Friend PJ, Moffatt S, et al: Lancet 351:1701, 1998 2. Calne RY, Moffatt SD, Friend PJ, et al: Transplantion 68:1613, 1999 3. Shapiro AM, Lakey JR, Ryan EA, et al: N Engl J Med 343: 4, 2000 4. Kaufman D, Baker MS, Chen X, et al: Am J Transplant 2:674, 2002 5. Knechtle S, Vargo D, Fechner J, et al: Transplantation 63:1, 1997 6. Kuhr CS, Alken MD, Junghanss C, et al: Transplantation 73:1487, 2002 7. Spitzer TR, Delmonico F, Tolkoff-Rubin N, et al: Transplantation 68:480, 1999 8. Fandrich F, Lin X, Chai GX, et al: Nat Med 8:171, 2002 9. Watts P, et al: Presented at the XIV International Congress on Parkinson’s Disease, Helsinki, Finland, 2001