Renal Transplantation for the Nephrologist: New Immunosuppressive Drugs

EDITORIAL

Renal Transplantation for the Nephrologist: New Immunosuppressive Drugs M. Roy First, MD

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N 1990 transplantation received special recognition with the awarding of the Nobel Prize in Medicine to Drs Joseph E. Murray and E. Donnall Thomas for their pioneering contributions in renal transplantation and bone marrow transplantation, respectively. The introduction in the 1980s of cyclosporine and monoclonal antibodies represented a giant therapeutic leap. The 1990s begin with a number of very promising new immunosuppressive agents on the horizon, and during the coming decade it is likely that major advances will be made in our ability to control the immune response. Many of these new immunosuppressive agents have been described in clinical and experimental studies in recent years, and it appears likely that a number of these agents will become a part of routine post-transplant immunosuppression by the turn of the century. FK-506

FK-506 is a macrolide antibiotic isolated from a soil fungus. Its immunosuppressive properties and effectiveness as an immunosuppressive agent were first described in 1987. 1,2 Like cyclosporine, the compound is lipophilic; it readily dissolves in organic solvents but is insoluble in water. 3,4 The plasma half-life of intravenous FK-506 averages 10.3 hours in dogs and 8.7 hours in humans. 5 Following intravenous administration, the highest concentration of FK-506 occurs in lung tissue with concentrations nearly eight times those of plasma. 5 After oral administration peak concentrations occur after 1 to 4 hours',Absorption of FK-506 is not dependent on the presence of bile in the gastrointestinal tract, and therefore is not affected by T-tube clamping following liver transplantation. 4-6 The drug is metabolized extensively in the liver, with less than 1% being excreted unaltered in bile and urine. The immunosuppressive effects ofFK-506 are similar to those of cyclosporine. 7,8 It binds to an immunophilin, FK-506 binding protein (FKBP), and prevents signal transduction pathways in T

lymphocytes. 7-11 The drug inhibits alloantigen and mitogen stimulation of T cell proliferation, and the production of interleukin (IL)-2, IL-3, IL-4, interferon (IFN)-,)" tumor necrosis factor (TNF), and granulocyte-macrophage colonysimulating factor (GM-CSF).3,4,7-9 FK-506 has an in vitro potency 10 to 100 times greater than cyclosporine with regard to inhibition ofthe mixed lymphocyte culture reaction, generation of cytotoxic T cells, and expression of IL-2 receptors on T cells. 3,4,7-9 1t is also substantially more potent than cyclosporine in suppressing B cell activation. 12,13 In experimental animals, FK-506 has been shown to prolong survival of skin, limb, cornea, pancreatic islets, pancreas, heart, liver, kidney, and small intestine transplants. 3,4,9,14,15 FK-506 reverses rejection of heart and kidney transplants and suppresses a variety of spontaneous and experimental autoimmune diseases in animals. 3,4,9,14 The drug has also been shown to inhibit sensitization after blood transfusion; not only does FK-506 abrogate the humoral response to class I antigens in blood transfusions, but it also enables the development of tolerance to further antigenic challenge. 16 FK-506 exhibits pharmacological antagonism with cyclosporine, even when both agents are used in low doses. 17 In clinical studies, FK-506 has been used extensively only at the University of Pittsburgh and has not been subjected to critical, randomized, prospective studies. It appears to be highly effective in conjunction with low-dose steroids as primary maintenance immunosuppression in liver transplantation. In 125 patients, with a mean follow-up of less than 1 year, patient survival was 92%, and over half of the patients experienced From the University of Cincinnati Medical Center, Cincinnati,OH. Address reprint requests to M. Roy First, MD, Professor of Internal Medicine, University of Cincinnati Medical Center, 231 Bethesda Ave, Cincinnati, OH 45267-0585 . © 1992 by the National Kidney Foundation, Inc. 0272-6386/ 92/ 1901-0002$3.00/0

American Journal of Kidney Diseases, Vol XIX, No 1 (January), 1992: pp 3-9

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no rejection episodes. 18.19 Following primary hepatic transplantation, better patient and graft survival rates, lower retransplantation rates, and lower steroid doses have been observed in FK506-treated patients compared with historical controls receiving cyclosporine. 18 ,19 In 40 liver transplant recipients with allograft dysfunction and/or complications related to cyclosporine, conversion to FK-506-based immunosuppression resulted in a clinical and/or histopathological response in over 70% of the patients. 2o FK-506 has also been shown to be effective in primary liver transplantation and in liver transplantation rescue in pediatric patients and has allowed for steroids to be discontinued in two-thirds of patients. 21 In 66 kidney transplant recipients treated with FK-506, actuarial graft survival rates were 79% in 43 primary transplants and 78% in 23 retransplanted patients with a mean follow-up of less than 1 year. 22 These results are similar to those obtained with cyclosporine. Rejection was the most frequent cause of graft loss in both groups of patients, and the histologic features were similar to those observed with cyclosporine.23 Forty percent of the FK-506-treated patients were free of antihypertensive medications, and the mean serum cholesterol and uric acid levels were 4.45 mmol/L (172 mg/dL) and 464 Mmol/L (7.8 mg/dL), respectively.22 A low incidence of hypertension, namely 15%, has also been reported in heart transplant patients treated with FK-506, as compared with the 70% incidence of hypertension in cyclosporine-treated heart transplant recipients. 24 In 25 cardiac transplant recipients treated with FK-506 and lowdose steroids, 60% never experienced a rejection episode; this was comparable to the 62% freedom from rejection in the conventional treatment consisting of rabbit antithymocyte globulin, cyclosporine, azathioprine, and high-dose steroids. 24 In addition, FK-506 was successful in reversing cardiac rejection refractory to conventional immunotherapy in five patients. 24 One third of the 30 patients in this study were weaned from steroids. Encouraging results have also beep reported with the use ofFK-506 in multiple organ transplants, cluster transplants, intractable chronic graft-versus-host disease (GVHO), small

M. ROY FIRST

intestine transplants, focal glomerulosclerosis, and psoriasis. 21 ,25 The adverse effects of FK-506 resemble those of cyclosporine and include nephrotoxicity, neurotoxicity, gastrointestinal tract complaints, the induction of diabetes, infection, and the development of lymphoproliferative diseases.2°- 3o Clearly, controlled trials comparing FK-506 with cyclosporine are needed to evaluate the future role of this very promising new immunosuppressive agent in solid organ transplantation, cellular transplants, and autoimmune disease. Many of these trials are currently in progress and the results are eagerly awaited. MIZORIBINE

Mizoribine (previously termed bredinin) is an imidazole nucleoside antibiotic that has been used in Japan for over 10 years. 31 -33 It causes inhibition of RNA and DNA synthesis in the purine biosynthetic pathway and affects both humoral and cell-mediated immune responses. Its immunosuppressive mechanism and potency is similar to that of azathioprine, but it lacks the hepatotoxicity and bone marrow suppression of the latterY-36 It has been shown to be synergistic with low-dose cyclosporine in prolonging allograft survival rates in experimental animals. 33 ,34 Impressive results have been reported with the use of mizoribine and steroids32 and mizoribine, low-dose cyclosporine, and prednisolone. 35 .36 In these studies, there has been a low graft loss rate beyond the first year; this may be a reflection of the fact that mizoribine may prevent chronic graft rejection because of its demonstrated effect on the B cell response. However, mizoribine does not appear to be a very potent immunosuppressive agent; in one study, rejection episodes occurred significantly earlier in the mizoribinetreated patients, more of the rejection episodes were steroid resistant than in the azathioprinetreated group, and a higher percentage of patients treated with mizoribine were converted to azathioprine because of acute rejection episodes than were converted from azathioprine to mizoribine. 36 Elimination of mizoribine is dependent on· renal function, and the dose needs to be adjusted during periods of renal dysfunction. 36 ,37 A major problem encountered with administration of mi-

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zoribine to canine renal allograft recipients is enterotoxicity. This has been shown to be associated with decreased renal excretion of the drug, resulting in elevated serum concentrations. 37 Elevated serum levels of mizoribine induce angionecrosis of intestinal submucosal arteries, resulting in degeneration, necrosis, and fibrosis of the mucosa. 33 ,37 This side effect has also been described in humans. 36 To avoid this complication, mizoribine should not be administered to anuric or oliguric patients. Further studies and longer follow-up data with this drug will enable clarification of its role as a useful immunosuppressive agent in the future. RS-61443

RS-61443 is the ethyl ester of the fungal antibiotic mycophenolic acid. Mycophenolic acid is a potent inhibitor of enzymes in the purine biosynthetic pathway.38-4o Mycophenolic acid is poorly absorbed following oral administration; the use of the pro-drug RS-61443 greatly improves the oral bioavailability.4,38,41 fj-Glucuronidase metabolizes RS-61443 to mycophenolic acid glucuronide, which is a potent inhibitor of inosine monophosphate dehydrogenase. Synthesis of guanosine monophosphate is inhibited, thereby preventing T and B lymphocyte proliferation, blocking antibody formation, and downregulating generation of cytotoxic T cells. 38-45 RS61443 appears to have a synergistic effect with cyclosporine and 15-deoxyspergualin. 3,42 In experimental animals, the drug has been shown to prolong skin, heart, kidney, and islet allograft survival and to inhibit the development of chronic vascular rejection in rat heart recipients. 38 ,41-45 This agent also prolongs heart allograft survival rates in highly sensitized animal recipients when combined with cyclosporine. 46 Clinical studies have recently been started with RS-61443. 45 Forty-eight renal allograft recipients have been entered in a phase I clinical ~rial. Immunosuppression consisted of quadruple induction using Minnesota antilymphocyte globulin (MALG), prednisone, cyclosporine, and RS61443, followed by maintenance immunosuppression with the latter three drugs. With a follow-up period of up to 9 months, there was only a single graft loss due to venous thrombosis. There was no evidence of nephrotoxicity or bone

marrow suppression. 45 The main side effects have been observed on the gastrointestinal tract. An additional 9 patients (7 renal, 1 renal-pancreas, 1 liver) have been entered into a pilot rescue study. All patients had biopsy-proven rejection following several courses of high-dose steroids and OKT3 therapy. In 6 of the 7 renal transplant recipients, a significant improvement in renal function occurred; one kidney was lost to rejection. In the pancreas and liver recipients, allograft rejection was reversed. 45 RS-61443 appears to be safe and well tolerated. The drug appears to show great promise both for induction and maintenance as well as for rescue therapy. Additional clinical studies using this agent should be available in the near future. RAPAMYCIN

Rapamycin is a macrolide antibiotic derived from a soil fungus that is structurally related to FK_506. 4,IO It is a lipid-soluble compound that has poor oral absorption and low bioavailability.4,47 Despite the structural similarity to FK506, rapamycin has no effect 011 the production of IL-2 but is a potent inhibitor of lymphocyte responses to cytokines such as IL-l, IL-2, IL-4, and IL-6 and is a strong inhibitor of T cell proliferation and differentiation. 4,lo,47-5o Rapamycin binds to the same immunophilin, or intracellular binding protein, as FK_506. 1O,11 Rapamycin is strongly synergistic with cyclosporine but has an antagonistic response when administered with FK_506. 4,47-51 The drug has been shown to prolong survival rates in a variety of laboratory animals for skin, heart, kidney, pancreas, and small bowel transplants. 4,47,48,52-54 In the mouse heart transplant model, rapamycin was found to be 50 times more potent than cyclosporine and 3 times more potent than FK-506. 48 Toxicity studies in rats have shown that rapamycin causes mild, focal myocardial necrosis, increased blood glucose levels, thymic involution, and little or no impairment of renal and hepatic function. 55 Vasculitis, which has been observed in dogs,4 was not observed in the rat model. Rapamycin has not yet been administered to humans. However, clinical trials are about to be instituted. The marked synergism between rapamycin and cyclosporine in experimental ani-

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mals offers an appealing approach for clinical studies. However, it will be necessary to devise means to increase the oral bioavailability before the drug can be used as part of maintenance immunosuppression. 15-DEOXYSPERGUALIN

15-Deoxyspergualin is an antitumor antibiotic from a soil Bacillus. The immunologic mechanism of action of 15-deoxyspergualin has not been well clarified. In vitro studies with this drug have shown that it suppresses macrophage function, blocks the production of IL-l, inhibits the production of oxygen-derived radicals in monocytes, decreases the expression of class II antigens on splenic macrophages, decreases cytotoxic T lymphocyte proliferation, induces long-term immunologic unresponsiveness, and inhibits antibody production. 4,56-61 15-Deoxyspergualin has also been shown to be effective in prolonging allograft survival rates and reversing allograft rejection in skin, islet, heart, liver, lung, and kidney transplant recipients and to prevent and reverse GVHD in the mouse. 4 ,56,57,59,62,63 The drug exhibits strong synergism with cyclosporine57 ,61 and FK_506. 64 Splenectomy in combination with 15deoxyspergualin has shown to prolong xenograft survival rates and to attenuate the cytotoxic antibody response. 59,65 Clinical experience with 15-deoxyspergualin comes largely from studies in Japan. When 15deoxyspergualin was used as part of induction therapy in living-related and cadaveric renal transplant recipients, the incidence of rejection in the first month appeared to be between 30% and 50%; however, most of these were reported to be mild rejections and reversed by steroid therapy.66,67 15-Deoxyspergualin has also been reported to be effective in combination with plasmapheresis and immunoabsorption in ABOincompatible kidney recipients and in recipients with high preformed antibody levels. 68 The drug has also been reported to be effective in reversing acute renal allograft rejection in 80% to 90% of cases and is particularly effective when combined with methylprednisolone. 69 ,7o There is also a single case report in which 15-deoxyspergualin was effective in reversing acute hepatic allograft rejection that had been refractory to all other forms of antirejection therapy.71 The main side effect

of 15-deoxyspergualin is bone marrow suppression. Other side effects include perioral numbness and gastrointestinal tract disturbances. 67 The published studies using this agent have been uncontrolled. Prospective, randomized studies using 15-deoxyspergualin have recently started in the United States. SKF-105685

SKF-105685 is an azaspirane with immunosuppressive activity in animal models of autoimmune disease. It is effective as a monotherapy for prolonging cardiac allograft survival rates in rats and has a synergistic effect with low-dose cyclosporine in this mode1. 72 This compound's mechanism of action appears to be the induction of nonspecific suppressor cells, similar to that induced by total lymphoid irradiation. These cells lack the surface markers characteristic of mature T cells, B cells, macrophages, or natural killer (NK) cells. 72 By the year 2000, we shall witness the emergence of a number of new potent immunosuppressive drugs for use in transplantation and autoimmune diseases. In addition, a number of new monoclonal antibodies will become available. Each of these potent immunosuppressive agents display toxic complications at full therapeutic doses. Future strategy calls for synergism between these immunosuppressive agents that may allow for dose reduction with preserved biologic effect.73 The synergistic approach uses combinations of drugs in low doses so that they potentiate each other's immunosuppressive effects and avoid the toxic effects. My prediction of the drugs most likely to enter clinical practice over the next few years is as follows: (1) RS-61443 will probably replace azathioprine as part of routine posttransplant immunosuppression and also eliminate the widespread use of mizoribine. (2) FK506 will probably play a major role in hepatic transplantation and possibly in cardiac transplant recipients; however, its nephrotoxicity may well preclude its routine use in renal transplant recipients. (3) The synergism of rapamycin and 15deoxyspergualin with cyclosporine may result in the use of either or both agents with very low doses of cyclosporine, thereby reducing the chronic nephrotoxicity of the latter drug. (4) The introduction of rapamycin, 15-deoxyspergualin, and FK-506 will result in a steroid-sparing effect,

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leading to reduced doses or elimination of steroids in the immunosuppressive regimen. (5) SKF105685 has a novel effect on the immune system;

however, this agent is in the early phases of its development and more studies are needed to evaluate its potential role in the future.

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organ transplantation under FK506. Ann Surg 212:295-307, 1990 19. Jain AB, FungJJ, Todo S, etal: Incidence and treatment of rejection episodes in primary orthotopic liver transplantation under FK 506. Transplant Proc 23:928-930, 1991 20. Fung JJ, Todo S, Tzakis A, et al: Conversion of liver allograft recipients from cyclosporine to FK 506-based immunosuppression: Benefits and pitfalls. Transplant Proc 23: 14-21, 1991 21. Tzakis AG, Fung JJ, Todo S, et al: Use ofFK 506 in pediatric patients. Transplant Proc 23:924-927, 1991 22. Shapiro R, Jordan M, Fung J, et al: Kidney transplantation under FK 506 immunosuppression. Transplant Proc 23:920-923, 1991 23. Demetris AJ, Banner B, Fung J, et al: Histopathology of human renal allograft rejection under FK506: A comparison with cyclosporine. Transplant Proc 23:944-946, 1991 24. Armitage JM, Kormos RL, Griffith BP, et al: A clinical trial of FK 506 as primary and rescue immunosuppression in cardiac transplantation. Transplant Proc 23:1149-1152, 1991 25. Starzl TE, Abu-Elmagd K, Tzakis A, et al: Selected topics on FK506, with special reference to rescue of extrahepatic whole organ grafts, transplantation of "forbidden organs," side effects, mechanisms, and practical pharmacokinetics. Transplant Proc 23:914-919, 1991 26. Shapiro R, Fung JJ, Jain AB, et al: The side effects of FK506 in humans. Transplant Proc 22:35-36, 1990 27. Kumano K, Wang G, Endo T, et al: FK 506-induced nephrotoxicity in rats. Transplant Proc 23:512-515,1991 28. McCauley J, Takaya S, Fung J, et al: The question of FK 506 nephrotoxicity after liver transplantation. Transplant Proc 23:1444-1447, 1991 29. Kusne S, Martin M, Shapiro R, et al: Early infections in kidney transplant recipients under FK 506. Transplant Proc 23:956-957, 1991 30. Carroll PB, Boschero AC, Li M-Y, et al: Effect of the immunosuppressant FK506 on glucose-induced insulin secretion from adult rat islets of Langerhans. Transplantation 51 :275-278, 1991 31. Kamata K, Okubo M, Ishigamori E, et al: Immunosuppressive effect of bred in in on cell-mediated immunity and humoral immune reactions in experimental animals. Transplantation 35:144-149, 1983 32. Tajima A, Hata M, Ohta N, et al: Brenidin treatment in clinical kidney allografting. Transplantation 38: 116-118, 1984 33. Gregory CR, Gourley 1M, Cain GR, et al: Effects of combination cyclosporine/mizoribine immunosuppression on canine renal allograft recipients. Transplantation 45:856-859, 1988 34. Hayashi R, Suzuki S, Shimatani K, et al: Synergistic effect of cyclosporine and mizoribine on graft survival in ca-

8 nine organ transplantation. Transplant Proc 22:1676-1678, 1990 35. Mita K, Akiyama N, Nagao T, et al: Advantages of mizoribine over azathioprine in combination therapy with cyclosporine for renal transplantation. Transplant Proc 22: 1679-1681,1990 36. Kokado Y, Ishibahi M, Jiang H, et al: Low-dose cyc1osporin, mizoribine and prednisolone in renal transplantation: Anew triple-drug therapy. Oin Transplant 4: 191-197, 1990 37. Gregory CR, Gourley 1M, Cain GR, et al: Mizoribine serum levels associated with enterotoxicity in the dog. Transplantation 51 :877-881 , 1991 38. Morris RE, Hoyt EG, Murphy MP, et al: Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc 22:1659-1662, 1990 39. Allison AC, Almquist SJ, Muller CD, et a1: In vitro immunosuppressive effects of mycophenolic acid and an ester pro-drug, RS-61443. Transplant Proc 23:10-14, 1991 (suppI2) 40. Eugui EM, Mirkovich A, Allison AC: Lymphocyteselective antiproliferative and immunosuppressive activity of mycophenolic acid and its morpholinoethyl ester (RS-61443) in rodents. Transplant Proc 23: 15-18, 1991 (suppl 2) 41. Platz KP, Eckhoff DE, Hullett DA, et al: Prolongation of dog renal allograft survival by RS-61443, a new, potent immunosuppressive agent. Transplant Proc 23:497-498, 1991 42. Hao L, Lafferty KJ, Allison AC, et al: RS-61443 allows islet allografting and specific tolerance in mice. Transplant Proc 22:866-879, 1990 43. Morris RE, Wang J, Blum JR, et al: Immunosuppressive effects of the morpholinoethyl ester of myco phenolic acid (RS-61443) in rat and nonhuman primate recipients of heart allografts. Transplant Proc 23: 19-25, 1991 (suppl 2) 44. Platz KP, Sollinger HW, Hullett DA, et al: RS-61443A new, potent immunosuppressive agent. Transplantation 51 : 27-31,1991 45. Sollinger HW: RS-61443: Mechanism of action, experimental and early clinical results. American Society of Transplant Surgeons, Second Postgraduate Course, Chicago, IL, June 1991 46. Knechtle SJ, Wang J, Beeskan M, et al: Effect of RS61443 in preventing rejection in sensitized recipients. Surg Forum 41:380-381 , 1990 47. Kahan BD, Chang JY, Sehgal SN: Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. Transplantation 52: 185-191 , 1991 48. Sehgal SN, Chang JY: Rapamycin: A new immunosuppressive macrolide. Transplant Immunol Letter 7: 12-14, 1990 49. Dumont FJ, Staruch MJ, Koprak SL, et al: Distinct mechanism of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol 144: 251-258, 1990 50. Kahan BD, Gibbons S, Tejpal N, etal: Synergistic effect of the rapamycin/cyclosporine combination: Median effect analysis of in vitro performances by human T lymphocytes

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in PHA, CD3 and MLR proliferative and cytotoxicity assays. Transplant Proc 23:1090-1091 , 1991 51 . Kimball PM, Kerman RH, Kahan BD: Production of synergistic but nonidentical mechanisms ofimmunosuppression by rapamycin and cyclosporine. Transplantation 51:486490, 1991 52. Morris RE, Wu J, Shorthouse R: A study of the contrasting effects of cyclosporine, FK 506, and rapamycin on the suppression of allograft rejection. Transplant Proc 22: 16381641 , 1990 53. Collier DSJ, Caine R, Thiru S, et a1: Rapamycin in experimental renal allografts in dogs and pigs. Transplant Proc 22:1674-1675,1990 54. Stepkowski SM, Chen H, Daloze P, et al: Prolongation by rapamycin of heart, kidney, pancreas, and small bowel allograft survival in rats. Transplant Proc 23:507-508, 1991 55. Whiting PH, Woo J, Adam Bl, et al: Toxicity of rapamycin-A comparative and combination study with cyclosporine at immunotherapeutic doses in the rat. Transplantation 52:203-208, 1991 56. Suzuki S, Amemiya H: 15-deoxyspergualin-A novel immunosuppressant: Experimental studies and clinical trials. Transplant Immunol Letter 7: 17-19, 1990 57. Reichenspurner H, Hildebrandt A, Human PA, et al: 15-deoxyspergualin for induction of graft nonreactivity after cardiac and renal allotransplantation in primates. Transplantation 50: 181-185, 1990 58. Waaga AM, Ulrichs K, Krzymanski M, et al: The immunosuppressive agent 15-deoxyspergualin induces tolerance and modulates MHC-antigen expression and interleukin-I production in the early phase of rat allograft responses. Transplant Proc 22:1613-1614, 1990 59. Valdivia LA, Monden M, Gotoh M, et al: Evidence that deoxyspergualin prevents sensitization and first-set cardiac xenograft rejection in rats by suppression of antibody formation. Transplantation 50: 132-136, 1990 60. Tepper MA, Petty B, Bursuker I, et al: Inhibition of antibody production by the immunosuppressive agent, 15deoxyspergualin. Transplant Proc 23:328-331, 1991 61. Yuh DD, Morris RE: 15-deoxyspergualin is a more potent and effective immunosuppressant than cyclosporine but does not effectively suppress Iymphoproliferation in vivo. Transplant Proc 23:535-539, 1991 62. Schorlemmer HU, Dickneite G, Seiler FR: Treatment of acute rejection episodes and induction of tolerance in rat skin allotransplantation by 15-deoxyspergualin. Transplant Proc 22:1626-1630,1990 63. Nemoto K, Hayashi M, Ito J, et a1: Deoxyspergualin in lethal murine graft-versus-host disease. Transplantation 51: 712-715, 1991 64. Yabuuchi H, Nakajima Y, Segawa M, et al: Prominent prolongation of islet xeongraft survival in combination therapy with FK 506 and 15-deoxyspergualin. Transplant Proc 23: 859-861,1991 65 . Carobbi A, Aroneda D, Patselas J, et al: Effect ofsplec nectomy in combination with FK 506 and 15-deoxyspergualin on cardiac xenograft survival. Transplant Proc 23:549-550, 1991 66. Okazaki H, Sato T, limbo M, et al: Prophylactic use

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of deoxyspergualin in living related renal transplantation. Transplant Proc 23:1094-1095,1991 67. Koyama I, Amemiya H, Taguchi Y, et al: Prophylactic use of deoxyspergualin in a quadruple immunosuppressive protocol in renal transplantation. Transplant Proc 23: 10961098,1991 68. Takahashi K, Tanabe K, Ooba S, et al: Prophylactic use of a new immunosuppressive agent, deoxyspergualin, in patients with kidney transplantation from ABO-incompatible or preformed antibody-positive donors. Transplant Proc 23: 1078- 1082, 1991 69. Takahashi K, Ota K, Tanabe K, et al: Effect of a novel immunosuppressive agent, deoxyspergualin, on rejection in kidney transplant recipients. Transplant Proc 22: 1606-1612, 1990

9 70. Amemiya H, Dohi K, Otsubo 0, et al: Markedly enhanced therapeutic effect of deoxyspergualin on acute rejection when combined with methylprednisolone in kidney recipients. Transplant Proc 23:1087-1089, 1991

71. Groth CG, Ohlman S, Ericzon BG, et al: Deoxyspergualin for liver graft rejection. Lancet 336:626, 1990 72. Badger AW, Albrightson-Winslow CR, Kupiec-Weglinski JW: SK&F 105685: A novel immunosuppressive compound with efficacy in animal models of autoimmunity and transplantation. Transplant Proc 23: 194-195, 1991 73. Kahan BD: Synergism, how assessed and how achieved. American Society of Transplant Surgeons, Second Postgraduate Course, Chicago, IL, June 1991