Fung, JJ

Starzl, TE

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DrStarzl Dr Fung FK506and cyclosporine appear to modulate the same physio-logical and immunologic parameters Transplantation Thomas E. Starzl, MD, PhD, John J. Fung, MD, PhD The three principal struts of transplantation are organ preservation, immunosuppression, and tissue typing. Major pragmatic advances have been made possible by improved static preserva-tion with the University of Wisconsin solution. The safe preservation limits for all organs, but particularly the liver, have been greatly in-creased since 1987. The most important ingredi-ents of the University of Wisconsin solution are thought to be the impermeants that prevent cell swelling. Two research directions are identifi-able in the literature-one, eliminate unneeded constituents of the University of Wisconsin solu-tion, and the other, increase the additives, which already number more than 10. 1 The growth of transplantation during the last decade owes much to cyclosporine. The use of cyclosporine with steroids, to which other agents can be added in more or less elaborate cocktails, made possible the transplantation of cadaveric kidneys, livers, hearts, and other organs with an effectiveness scarcely dreamed of 10 years ago. Yet, the full profile of cyclosporine actions is incomplete.2 A side from its immunosuppressive qualities, the spectrum of seemingly unrelated cyclospor-ine activities is bewildering.2 Nephrotoxicity and hypertension are the best known and principal dose-limiting side effects. Metabolic, cosmetic, and neurotoxic side effects may also occur. Some symptoms may be so subtle that they are not mentioned unless specific iJl!.quiries are made. The foregoing side effects of cyclosporine and its desired inhibition of the immune system had not been thought to be interrelated by a common mechanism. This has been changed by clinical observations with another immunosuppressive agent called FK 506 (Fujisawa Corporation, Osa-ka, Japan), which has a totally different structure than cyclosporine. FK 506 is a macrolide obtained from cultures of Streptomyces tsukubaensis. Like cyclosporine, it inhibits the activation of T lymphocytes, in part by depressing the produc-tion and expression of multiple cytokines of which interleukin 2 and interferon gamma have been the most extensively studied. 3 The in vivo immuno-suppressive qualities ofFK 506 have been studied in mice, rats, dogs, monkeys, baboons, and hu-mans. 4 To date, there has been only one investiga-tional new drug trial for FK 506, and this has taken place at the University of Pittsburgh. How-ever, multicenter trials are scheduled to begin in the spring of1990 in Europe and in approximately one dozen American centers. So far, investiga-tional new drug applications have not been devel-oped for indications other than in transplanta-tion. Extensive clinical trials with FK 506 were be-gun in February 1989,5,6 first, for the rescue of patients who had intractable liver allograft rejec-tion or toxic reactions under immunosuppres-sion, which included cyclosporine," and subse-quently as primary therapy. By February 1,1990, 36 kidneys, 151 livers, and 14 hearts, lungs, or heart-lung grafts had been transplanted with an immunosuppression regimen of FK 506 and low-dose steroids. All of the thoracic organ recipients and more than 90% of the liver recipients are alive. The kidney recipients, who represented an unusually complex and difficult collection of cases, have a graft survival rate of 80%, with a patient mortality rate of 3%.7 Overall, the low mortality, high graft survival, good graft function rates, and relative nondependence on steroids reflect a large and safe therapeutic window for FK506. The side effects of FK 506 tend to affect the same organ systems as cyclosporine, although frequently not to the same extent and sometimes not in the same direction. It may be less nephro-toxic than cyclosporine, usually does not produce hypertension, reduces instead of increases serum cholesterol levels, and has little effect on serum uric acid levels. It does not cause gingival hyper-plasia or coarsening of the facial features and, instead of hirsutism, there may be hair loss. The diabetogenic and neurotoxic effects ofFK 506 are similar to those of cyclosporine. Because FK 506 usually does not elicit a biochemical red flag such as azotemia to warn of overdosage, minor signs of neurotoxicity such as tremors, tingling of the hands and feet, light sensitivity, insomnia, night-mares, and mood changes have been useful to help guide dosage adjustments (T.E.S, J.J.F., Mark Porter, MD, unpublished data, 1990). In rats and dogs, FK 506 and cyclosporine have other effects that could have therapeutic signifi-cance in humans. Both drugs cause augmentation of the regeneration response after partial hepa-tectomy,7 and they prevent the hepatocyte atro-phy and organelle disruption that occur after por-tacaval shunt (T.E.S., Kendrick A. Porter, MD, Vincenzo Mazzaferro, MD, et ai, unpublished data, 1990). T he fact that two such chemically different drugs as FK 506 and cyclosporine appear to mod-ulate the same physiological and immunologic parameters would be difficult to explain were it not for discoveries about their binding sites. The cyclosporine binding site is a cytosolic protein with a molecular weight of 17 0008 called "cyclo-philin," which possesses petidyl-prolyl isomerase (PPIase) activity.9,10 Petidyl-prolyl isomerase is an enzyme discovered in mammalian tissuesll that catalyzes the slow cis-trans isomerization of pro-line peptide bonds in oligopeptides and acceler-ates rate-limiting steps in the folding of several proteins during their synthesis. By virtue of its isomerization of partner molecules, PPIase could modulate various intracellular signal transduc-tion processes, contributing to the manifold phys-iological effects enumerated previously. Petidyl-2686 JAMA. May 16, 1990-Vol 263, No. 19 Transplantation-Starzl & Fung Reprinted from JAMA® The Journal of the American Medical Association May 16, 1990, Volume 263 Copyright 1990, American Medical Association prolyl isomerase is widely distributed in many tissues, not just in lymphocytes. For example, cyclophilinlike receptors are in the photorecep-tors of Drosophila. In mutant DrosophUa defi-cient in cyclophilin, rhodopsin production is de-fective. 12 This observation could establish a link with the neurotoxicity caused by PPIase-inhibit-ingdrugs. It was thought at first that cyclophilin and PPIase were identical. 9.10 This hypothesis became untenable when the cytosolic binding site of FK 506 (molecular weight, 11 800) was found to be distinct from cyclophilin, but to also possess PPIase activity. 13.14 Thus, cyclophilin and the FK 506 binding site seem to be members of an emerg-ing class of novel and ubiquitous cytoplasmic pro-teins that regulate T-cell activation but also regu-late other metabolic processes. FK 506 probably will have other applications than in transplantation. Dramatic remissions us-ing FK 506 have already been observed in hemo-lytic-uremic syndrome, steroid-resistant ne-phrotic syndrome caused by focal segmental glomerulonephritis, psoriasis, and malignant pyoderma gangrenosum (unpublished data, 1989). Because FK 506 augments hepatic repair and regeneration' (T.E.S., Kendrick A. Porter, MD, Vincenzo Mazzaferro, MD, et aI, unpub-lished data, 1990), it may be especially valuable for patients who have chronic liver disease with or without an autoimmune origin. Other new agents to control rejection also are being tested clinically. Murine monoclonal anti-bodies (OKT3 is the prototype) can be directed against the whole T-Iymphocyte population. Clin-ical trials in France15 and the United States16 are in progress with anti-interleukin 2-receptor anti-bodies, which have a more highly focused target. These preparations are immunosuppressive, but their inherent immunogenicity and inconve-nience of administration may limit their useful-ness. Anti-T lymphocytes have also been used as carriers of cytocidal immunotoxins. 17 Tissue matching is important with intrafamilial transplantation, but controversy continues about the value of HLA matching for cadaveric trans-plantation. The issue has become one of public policy because tissue matching is used for kidney distribution nationally. Because by law the Unit-ed Network of Organ Sharing has been required to collect reports on the almost 20 000 cadaveric kidney transplantations performed in the United States since November 1987, an analysis of this material to resolve the dispute is eagerly awaited. At the International Transplantation Society meeting (August 1990), a principal topic for de-bate will be the justifiability of making tissue matching the basis for kidney distribution. Recently, several elective partial liver trans-plantations from live donors have been performed at the University of Chicago, including the much JAMA. May 16. 1990-Vol 263. No. 19 publicized event in late 1989 of an elective partial liver transplantation from a healthy mother to her daughter born with biliary atresia. The skill and courage of the management teams were test-ed by significant but not unexpected operative complications in the recipients. However, at last report, all donors and recipients were well. Earli-er in 1989, the same procedure was performed in Australia, Brazil, France, and Japan, with vari-able results. All observers agree thatliving donor liver transplantation should be attempted only by experienced transplantation teams and at centers with the most sophisticated ancillary resources. This study was supported by research grants from the Veter-ans Administration and project grant DK 29961 from the Na-tional Institutes of Health , Bethesda, Md. 1. Southard JH, van Gulik 'I'M, Ametani MS, et al. Important components ofthe UW solution. Tran8plantation. 1990;49:251-257. 2. Kahan BD. Cyciosporine. N Engl J Med. 1989;321:1725-1738. 3. Kino '1', Hatanaka M, Miyata S, et al. FK-506, a novel immu-nosuppressant isolated from a Streptomyces, II: immunosup-pressive effect of FK-50G in vitro. J Antibiotics. 1987;40:1256-1265. t. StarzlTE, TodoS, GrothC, FungJJ, eds. FK506: a potential breakthrough in immunosuppression-clinical implications. Transplant Proc. 1990;22:5-113. 5. Starzl TE, Todo S, Fung JJ, Demetris AJ. Venkataramanan R, .Jain A. FK 506 for human liver, kidney, and pancreas trans-plantation. Lancet. 1989;2:1000-1004. 6. Todo S, Fung J.J, Demetris AJ, Jain A, Venkataramanan R, Starzl TE. Early trials with FK 506 as primary treatment in liver transplantation. lh1l1.'plant Proc. 1990;22:13-16. 7. Franca\'illaA, BaroneM. TodoS, ZengQ, PorterKA, Starzl TE. Augmentation of rat liver regeneration by FK 506 com-pared with cyclosporine. Lancet. 1989;2:1248-1249. 8. Harding MW, Handschumacher RE, Speicher DW. Isolation and amino acid sequence of cyclophilin. J Biol Chern. 1986;261:8547-8555. 9. Takahashi N, Hayano T. Suzuki M. Peptidyl-prolyl cis·tmns isomerase is the cyclosporin A-binding protein cyc1ophilin. Nature. 1989:337:473-475. HI. Fischer G, Wittmann-Liebold B, Lang K, KeifhaberT, Schmid FX. Cyclophilin and peptidyl-prolyl cis-trans isomer-ase are probably identical proteins. Nalw'e. 1989;337:476-478. 11. Fischer G, Bang H. The refolding of urea-denatured ribo-nuclease A is catalyzed by peptidyl-prolyl cis-trans isomerase. Biochem Biophys Acta. 1984;828:39-42. 12. Shieh BH, Stamnes MA, Seavello S, Harrtis GL, Zuker CS. The ninaA gene required for visual transduction in Dro· sophila encodes a homologue of cyc1osporin A-binding protein. Nature. 1989;338:67-70. 13. Siekierka JJ, Hung SHY, Poe M, Lin CS, Sigal NH. A cytosolic binding protein for the immunosuppressant FK 506 has peptidyl-prolyl isomerase activity but is distinct from cyc1o-philin. Nature. 1989;341:755-757. 14. Harding MW, Galat A, Uehling DE, Schrieber SL. A re-ceptor for the immunosuppressant FK 506 is a cis-trans pepti-dyl-prolyl isomerase. Natli1·e. 1989;341:758-760. 15. Cantarovich D, Le MauffB, Hourmant M, Giral M, Jacques Y, Soulillou Jp. Anti-interleukin 2 receptor, monoclonal anti-body in the treatment of ongoing acute rejection episode of human kidney graft: a pilot study. Transplantation. 1989; 47:454-457. 16. Kirkman RL, Shapiro ME, Milford EL, Tilney NL, Wald-mannTA, Zimmerman CEo Early experience with anti-Tae in clinical renal transplantation. Transplant Proc. 1989:21:1766-1768. 17. Kernan NA, Byers V, Scannon P.J, et al. Treatment of steroid-resistant acute graft-vs-host disease by in vivo adminis-tration of an anti-T-cell ricin A chain immunotoxin. JAMA. 1988;259:3154-3157. Anti-T lymphocytes have also been used as carriers of cytocidal immunotoxins Controversy continues abo'ut the value of HLA matching for cadaveric transplantation Transplantation-Starzl & Fung 2687 Printed and Published in the United States of America 

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Contempo 90: Transplantation

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