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`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`April 26, 1990
`
`The New England
`Journal of Medicine
`
`Owned and Published by the
`Massachusetts Medical Society
`William G. Lavelle, M.D.
`President
`William M. McDermott, Jr., M.D.
`Executive Vice President
`
`Charles S. Amorosino, Jr.
`Executive Secretary
`
`THE COMMfITEE ON PUBLICATIONS
`OF THE MASSACHUSETI"S MEDICAL SOCIETY
`James F. McDonough, M.D., Chairman
`Henry H. Banks, M.D.
`Edward E. Jacobs, Jr., M.D.
`Brian J. McKinnon
`Frank E. Bixby,Jr., M.D.
`Howard M. Ecker, M.D.
`Daniel Miller, M.D.
`Howard Epstein, M.D.
`Percy W. Wadman, M.D.
`
`Arnold S. Reiman, M.D., EDITOR-IN-CHIEF
`Marcia Angell, M.D., EXECUTIVE EDITOR
`Edwin W. Salzman, M.D., DEPUTY EDITOR
`Gregory D. Curfman, M.D., DEPUTY EDITOR
`Edward W. Campion, M.D., DEPUTY EDITOR
`Robert D. Utiger, M.D., DEPUTY EDITOR
`
`ASSOCIATE EDITORS
`
`Jane F. Desforges, M.D.
`Ronald A. Malt, M.D.
`
`Morton N. Swartz, M.D.
`Franklin H. Epstein, M.D.
`Lee Goldman, M.D.
`
`Francis D. Moore, M.D., BOOK REVIEW EDITOR
`John C. Bailar, III, M.D., Walter Willett, M.D.,
`STATISTICAL CONSULTANTS
`John K. Iglehart, NATIONAL CORRESPONDENT
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`Marlene A. Thayer, EDITORIAL OFFICE MANAGER
`Stephen E. Cinto, MANAGER OF EDITORIAL PRODUCTION
`Lorraine W. Loviglio, MANAGER OF MANUSCRIPT EDITING
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`EDITORIAL BOARD
`
`Mary Ellen Avery, M.D.
`David Baltimore, Ph.D.
`John G. Bartlett, M.D.
`Eugene Braunwald, M.D.
`Harvey R. Colten, M.D.
`Robert M. Donaldson, Jr., M.D.
`Richard H. Egdahl, M.D.
`Bernard G. Forget, M.D.
`Antonio M. Gotto, Jr., M.D., D.Phil.
`Thomas B. Graboys, M.D.
`Martin S. Hirsch, M.D.
`Norman K. Hollenberg, M.D., Ph.D.
`
`Peter T. Macklem, M.D.
`RobertJ. Mayer, M.D.
`Kenneth McIntosh, M.D.
`Stuart H. Orkin, M.D.
`Peter Reich, M.D.
`Uwe E. Reinhardt, Ph.D.
`B. Lawrence Riggs, M.D.
`Lewis P. Rowland, M.D.
`KennethJ. Ryan, M.D.
`Harold C. Sox, M.D.
`Paul D. Stolley, M.D.
`Jean D. Wilson, M.D.
`
`EDITORIAL OFFICES
`Helen Connors, Research Assistant; Karen M. Daly, Editorial As-
`sistant; Briana Doherty, Editorial Assistant; Kathleen Eagan, Editorial
`Assistant; Dale R. Golden, Editorial Assistant; Christie L. Hager, Edi-
`torial Assistant; Susan L. Kaplan, Editorial Production Layout Artist;
`David F. March, Manuscript Editor; Sandra S. McLean, Manuscript
`Editor; Brian Middleton, Editorial Assistant; Henry S. Miller, Jr.,
`Manuscript Editor; Stephen Morrissey, Manuscript Editor; Sylvia L.
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`A. Stone, Senior Editorial Production Coordinator; Pamela S. Stry-
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`William H. Paige, ACTING DIRECTOR OF PUBLISHING OPERATIONS
`
`IMMUNOSUPPRESSION IN ORGAN
`TRANSPLANTATION
`THE search for effective and safe methods of sup-
`pressing the immune response has been evolving over
`four decades. Progress has been marked by many dis-
`appointments and a few forward leaps. Clinical organ
`transplantation has served as the proving ground for
`many of these advances, beginning in the early 1950s,
`shortly after a working model of the artificial kidney
`provided for the short-term maintenance of life in pa-
`tients with end-stage renal disease. The first attempts
`to suppress the rejection response, with whole-body
`irradiation and bone marrow transplantation, were
`unsuccessful. Since then, there have been two main
`avenues of approach to the prevention and treatment
`of graft rejection, one employing drugs and the other
`antibodies. After the discovery by Schwartz and Da-
`meshek l in the 1950s that the antimetabolite 6-mer-
`captopurine also had immunosuppressive activity,
`and its preliminary success in prolonging the survival
`of dog-kidney transplants, Hitchings and Elion2 syn-
`thesized a series of mercaptopurine derivatives, seek-
`ing a compound with an improved ratio of immuno-
`suppression to bone marrow toxicity. The fruit of this
`effort was azathioprine, first used clinically in 19623;
`this marked the beginning of the modern era of immu-
`nosuppression. Although a number of other antime-
`tabolites useful in cancer therapy were subsequently
`evaluated for their immunosuppressive action, none
`matched the therapeutic efficacy of azathioprine in
`preventing transplant rejection.
`I t was close to two decades before a more powerful
`drug, cyclosporine, came into widespread use in the
`early 1980s. 4 This compound, a natural product of
`a fungus, was identified during a screening program
`to develop new antifungal agents but was rejected
`for that purpose because of its "side effects" on the
`immune system. Cyclosporine is a lipophilic cyclic
`peptide composed of II amino acids. Although the
`success rates with kidney transplantation had been
`rising each year before the introduction of cyclospor-
`
`PROSPECTIVE authors should consult "Information for Authors," which ap-
`pears in the first issue of each month and may be obtained from the Jourruzl
`Editorial Office (address below).
`ARTICLES with original material arc accepted for consideration with the
`understanding that, except for abstracts, no part of the data has been pub-
`lished, or will be submitted. for publication elsewhere, before appearing here.
`NOTICES should be sent at least 30 days before publication date.
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`contributor. Statements or opinions expressed in the Journal reflect the views
`of the author(s) and not the official policy of the Massachusetts Medical
`Society unless so stated.
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`ards, acceptance does not imply endorsement by the JouTTUll.
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`EDITORIAL OFFIC>:S: 10 Shattuck St., Boston, MA 02115-6091.
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`The New England Journal of Medicine
`Downloaded from nejm.org at INFOTRIEVE on October 20, 2014. For personal use only. No other uses without permission.
`Copyright © 1990 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2019
`Par v Novartis, IPR 2016-00084
`Page 1 of 3
`
`

`
`Vol. 322 No. 17
`
`EDITORIALS
`
`1225
`
`ine, the new drug produced an immediate increase of
`10 to 15 percent in short-term rates of graft survivaV
`and it has been even more successful in permitting the
`widespread diffusion of heart and liver transplanta-
`tion. As prophylaxis to prevent rejection, both aza-
`thioprine and cyclosporine are generally used in com-
`bination with corticosteroids (such as prednisone),
`which are themselves potent immunosuppressants.
`Each of these agents has different effects on the im-
`mune response, and they potentiate each other in
`practice. Some protocols use cyclosporine and predni-
`sone without azathioprine. Acute rejection episodes
`are generally treated with short courses of high-dose
`methylprednisolone. Unfortunately, the well-known
`side effects of steroids are a burden and a hazard in
`transplant recipients who must take these medications
`indefinitely at some dose level.
`After almost another decade, a new immunosup-
`pressive drug, FK 506, has emerged as a result of the
`continuing screening of natural products of soil fungi. 6
`This agent has not yet been evaluated fully in the
`clinic/ but it is already causing excitement because of
`the characterization of its mode of action in relation to
`that of cyclosporine. In contrast to the polypeptide
`structure of cyclosporine, FK 506 has the structure of
`a macrolide antibiotic (such as erythromycin), yet cy-
`closporine and FK 506 exert very similar effects on
`lymphocytes; they prevent the synthesis of interleu-
`kin-2 and other lymphokines important in lymphocyte
`growth and function. Each compound binds to similar
`but different proteins, both of which are peptidyl-pro-
`lyl isomerases, enzymes that promote the folding of
`their substrates. B,9 The substrates for the isomerases
`that bind cyclosporine and FK 506 are as yet unknown
`but are likely to be part of a common pathway in
`lymphocyte growth and function. Another drug, rapa-
`mycin, 10 is structurally similar to FK 506 and has also
`been found to have immunosuppressive effects.
`The opportunity is now at hand to develop a ration-
`al basis for the design and evaluation of drugs with
`selective immune effects. There are two major prob-
`lems with the existing treatments. First, toxic effects
`on vital organs limit the amount of drug that can be
`administered. For example, azathioprine is a bone
`marrow suppressant, whereas cyclosporine is nephro-
`toxic and may also produce hypertension, hyperkale-
`mia, and liver and neurologic impairment.4 Second, it
`is difficult to balance the risk of infectious complica-
`tions from too much immunosuppression against the
`goal of preventing graft rejection. Simply removing
`the side effects of these drugs would not necessarily
`allow them to be used with impunity; moreover, some
`transplant rejections are resistant to all available
`treatments, especially in recipients who have been im-
`munized by a previously rejected transplant. The arti-
`cle in this iss ue of the Journal by Moran et al. lion the
`beneficial effects of adding the prostaglandin EI ana-
`logue misoprostol to cyclosporine and prednisone in
`the prevention of acute renal-graft rejection appears
`
`to confirm studies in animals l2 of the immunosup-
`pressive properties of long-acting methylated pros-
`taglandin E2 and should promote more intensive
`investigation of adjunctive drug therapy with prosta-
`glandins.
`Antibodies directed to the lymphoid cells of the
`immune system, though never used alone, have been
`important adjuncts to antirejection therapy. Starting
`in the 1960s, immune globulins resulting from the
`immunization of horses or rabbits with lymphocytes,
`thymocytes, or cultured lymphoblasts were adminis-
`tered to transplant recipients, at first intramuscularly
`and later intravenously, as a means of reversing rejec-
`tion episodes or as initial therapy for the first few days
`after transplantation, to prevent rejection.l:l Such anti-
`lymphocyte globulins, though generally useful, have
`been of variable potency and also have the poten-
`tial disadvantage of containing antibodies directed
`against a wide range of nonlymphoid tissues, such
`as platelets, macrophages, and connective-tissue ele-
`ments. Indeed, thrombocytopenia, fever, skin rash,
`and serum sickness-like reactions are commonly en-
`countered with such therapy. More precise targeting
`of treatment to molecules present on specific cells of
`the immune system is now possible through the use
`of monoclonal antibodies. The first antibody to be
`used in the clinic, anti-CD3,14 now licensed as OKT3,
`is directed only against T lymphocytes and has
`been extraordinarily effective in the reversal of re-
`jection. Currently, it is being evaluated for use as
`induction therapy to prevent rejection. 15 Its precise
`target is one of the CD3 molecules that compose the
`antigen-receptor complex of the T cell. The anti-
`body has the disadvantage of first activating all acces-
`sible T cells, resulting in sometimes severe febrile and
`circulatory problems for the first day or two, but it is
`tolerated well thereafter without further systemic side
`effects.
`Like the other substances used for antirejection
`therapy, OKT3 is a general immunosuppressant.
`Since monoclonal antibodies have been made against
`the cell-surface molecules that define subsets of cells,
`the possibility of more selective targeting has been
`under active investigation. For example, monoclonal
`antibody to the interleukin-2 receptor can bind only to
`T lymphocytes activated recently, sparing the cells not
`involved in an immune response during the time of
`administration. Because such an approach has been
`shown to prolong transplant survival in animals,16 tri-
`als have begun in humans. The article in this issue by
`Soulillou et al. 17 on anti-interleukin-2-receptor ther-
`apy in renal transplantation shows that such an anti-
`body can be beneficial in preventing rejection. The
`antibody compared favorably with a standard antithy-
`mocyte globulin in its ability to prevent rejection and
`promote graft survival when it was given in a prophy-
`lactic manner after transplantation; it was also much
`better tolerated. In the case of a fresh transplant, the
`activation of T lymphocytes would reflect the emerg-
`
`The New England Journal of Medicine
`Downloaded from nejm.org at INFOTRIEVE on October 20, 2014. For personal use only. No other uses without permission.
`Copyright © 1990 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2019
`Par v Novartis, IPR 2016-00084
`Page 2 of 3
`
`

`
`1226
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`April 26, 1990
`
`ing immune response to the HLA antigens of the graft,
`although incipient immunity to active infection might
`also be impaired. Although the patients in the anti~
`interleukin-2-receptor group had the same incidence
`of viral infections as those in the antithymocyte-globu-
`lin group, the rate of bacterial infection was reduced.
`Similar results are being obtained with another
`anti-interleukin-2-receptor antibody.18 It is expected
`that even more selective and effective monoclonal-
`antibody-based treatments will emerge, with an em-
`phasis on those active during the induction phase. Al-
`though treatment may ultimately be drug-based, at
`present monoclonal antibodies provide the best ap-
`proach to specific targeting in vivo, either for the tem-
`porary inhibition of a receptor or for cell destruction
`(with a native antibody or toxin conjugate).
`One of the major questions remaining in clinical
`transplantation is whether it will be possible to induce
`states of antigen-specific unresponsiveness, so that
`true tolerance is achieved with little or no long-term
`drug therapy. Although improved short-term success
`rates do translate into better long-term survival, the
`exponential rate of graft loss over time in patients with
`HLA mismatches has not changed over the past two
`decades. 5 In general, stable, drug-treated graft recipi-
`ents maintain the ability to react to their donors in the
`mixed-lymphocyte culture, whereas some have re-
`duced or absent cytotoxic T-cell responses. 19 There
`are indications that in some transplant recipients,
`T cells with cytotoxic potential can become anergic to
`the graft with time,2o although much remains to be
`learned about how this comes about and whether de-
`liberate previous exposure to transplant antigens, as
`with blood transfusions, should be a part of future
`protocols. Many important details of the regulation of
`the immune response are still unknown. Ideally, one
`would like to alter the host's initial contact with the
`graft to promote a state of donor-specific unrespon-
`siveness. The same goal obviously applies in states of
`autoimmune disease in which a specific immune re-
`sponse needs to be suppressed, and the best way to
`effect this would also be through the induction of im-
`mune tolerance. Present treatments fall short in this
`regard.
`Brigham and Women's Hospital
`Boston, MA 02115
`
`CHARLES B. CARPENTER, M.D.
`
`REFERENCES
`
`I. Schwartz R, Dameshek W. Drug-induced immunological tolerance. Nature
`1959; 183:1682-3.
`2. Hitchings GH, Elion GB. Chemical immunosuppression of the immune
`response. Pharmacol Rev 1963; 15:365-405.
`3. Murray lE, Merrill IP, Harrison IH, Wilson RE, Dammin Gl. Prolonged
`survival of human-kidney homografts by immunosuppressive drug therapy.
`N Engl 1 Med 1963; 268:1315-23.
`4. Kahan BD. Cyclosporine. N Engl J Med 1989; 321:1725-38.
`5. Terasaki PI, Cecka 1M, Takemoto S, et a1. Overview. In: Terasaki PI, ed.
`Clinical transplants 1988. Los Angeles: UCLA Tissue Typing Laboratory,
`1988:409-34.
`6. Sawada S, Suzuki G, Kawase Y, Takaku F. Novel immunosuppressive
`agent, FK506: in vitro effects on the cloned T cell activation. 1 Immunol
`1987; 139:1797-803.
`7. Starzl TE, Venkataramman R, Todo S, Fung 1, Demetris Al, Jain A. FK
`506 for liver, kidney, and pancreas transplantation. Lancet 1989; 2:1000-4.
`
`8. Siekierka 11, Hung SHY, Poe M, Lin CS, Sigal NH. A cytosolic binding
`protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase
`activity but is distinct from cyclophilin. Nature 1989; 341 :755-7.
`9. Harding MW, Galat A, Uehling DE, Schreiber SL A receptor for the
`immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature
`1989; 341:758-60.
`10. Caine RY, Collier DStJ, Lim S, et al. Rapamycin for immunosuppression in
`organ a1lografting. Lancet 1989; 2:227.
`11. Moran M, Mozes MF, Maddux MS, et al. Prevention of acute graft rejection
`by the prostaglandin E\ analogue misoprostol in renal-transplant recipients
`treated with cyclosporine and prednisone. N Engl J Med 1990; 322:1183-8.
`12. Strom TB, Carpenter CB. Prostaglandin as an effective antirejection therapy
`in rat renal allograft recipients. Transplantation 1983; 35:279-81.
`13. Filo RS, Smith EJ, Leapman SB. Therapy of acute cadaveric renal allograft
`rejection with adjunctive antithymocyte globulin. Transplantation 1980;
`30:445-9.
`14. Cosimi AB, Colvin RB, Burton RC, et al. Use of monoclonal antibodies to
`T-cell subsets for immunologic monitoring and treatment in recipients of
`renal allografts. N Engl J Med 1981; 305:308-14.
`15. Carpenter CB, Suthanthiran M, eds. The prophylactic use of monoclonal
`antibodies in renal transplantation: a consensus conference sponsored by the
`American Society of Transplant Physicians. Am J Kidney Dis 1989;
`14:SuppI2:1-77.
`16. Kirkman RL, Barrett LV, Gaulton GN, Kelley VE, Ythier A, Strom TB.
`Administration of an anti-interleukin 2 receptor monoclonal antibody pro-
`longs cardiac allograft survival in mice. J Exp Med 1985; 162:358-62.
`17. Soulillou J-P, Cantarovich 0, Le Mauff B, et al. Randomized controlled
`trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as
`compared with rabbit anti thymocyte globulin for prophylaxis against rejec-
`tion of renal allografts. N Engl J Med 1990; 322: 1175-82.
`18. Carpenter CB, Kirkman RL, Shapiro ME, et al. Prophylactic use of mono-
`clonal anti-IL-2 receptor antibody in cadaveric renal transplantation. Am J
`Kidney Dis 1989; 14:Suppl 2:54-7.
`19. Goulmy E, Stijnen T, Grocnewoud AF, et al. Renal transplant patients
`monitored by the cell-mediated Iympholysis assay: evaluation of its clinical
`value. Transplantation 1989; 48:559-63.
`20. Herzog W-R, Zanker B, Irschick E, et al. Selective reduction of donor-
`specific cytotoxic T lymphocyte precursors in patients with a well-function-
`ing kidney allograft. Transplantation 1987; 43:384-9.
`
`PRISONERS OF TECHNOLOGY
`The Case of Nancy Cruzan
`LIFE can now be sustained by medical technology
`under circumstances that just 15 to 20 years ago would
`have signified imminent death. This new power per-
`mits dramatic recoveries from some previously hope-
`less calamities. But, as with power in general, there is
`a dark side to it. Increasingly we find that life is being
`sustained indefinitely when there is no hope of recov-
`ery, simply because no one knows what else to do.
`Such a life may be filled with suffering, but sometimes
`it is devoid of anything -
`of pleasure, sensation, or
`comprehension.
`This is the state of Nancy Cruzan, a 32-year-old
`woman who, as described elsewhere in this issue, I has
`been in what most agree is a persistent vegetative state
`since a car accident seven years ago. Although the
`diagnosis is not unanimous, the prognosis is. Everyone
`agrees that she will not recover; CT scans show that
`her cerebral cortex has already atrophied.2 But she is
`not dead, and she will probably live in her senseless
`state for many more years, thanks to sophisticated
`medical care and tube feeding through a gastrostomy.
`The costs are immeasurable anguish to her family and
`$130,000 yearly to the state of Missouri.
`Three years ago, when it became apparent to even
`the most hopeful that Nancy Cruzan would not recov-
`
`The New England Journal of Medicine
`Downloaded from nejm.org at INFOTRIEVE on October 20, 2014. For personal use only. No other uses without permission.
`Copyright © 1990 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2019
`Par v Novartis, IPR 2016-00084
`Page 3 of 3