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REFACE

he Era of Cyclosporine: Twenty Years Forward, Twenty Years Back

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he agent we know as cyclosporine is a product ofTolypocladium inflatum gams that was isolated from a

oil sample retrieved from the high, treeless Norwegianlain of Hardanger Vidda in 1968. The immunosuppressiveffects of this agent are due to its targeting of calcineurin,hich potently inhibits signaling of T lymphocytes.In light of Scandinavian mythology, it seems only logical

hat this premiere agent in the transplantation armamen-arium would be discovered in a land in which weapons ofemarkable precision, design, and versatility are legendary.ccording to Norwegian myth, the ship Skidbladnir, ownedy the fertility god, Freyr, always sailed directly toward itsarget. And although large enough to accommodate all theods, Skidbladnir was so ingeniously constructed that itould be folded up to fit in its owner’s pocket. Odin, god ofhunder, owned the legendary spear called Gungnir, whichever failed to meet its mark; the god’s hurling of this

mportant weapon was said to mark the first of all wars.imilarly, Odin’s great metal war hammer, called Mjollnir,ould not fail to meet its target and would always return tohe thrower’s hand.

Cyclosporine was introduced into widespread clinicalractice two decades ago, after the results of early clinicalxperience, particularly the epochal multicenter random-zed trial led by Stiller in Canada. This revolution inransplantation however, was almost taken off course: First,t was discarded after proving ineffective as an antibiotic.econd, cyclosporine was not considered a promising agentince it was inactive in the conventional screening protocolesigned at Sandoz to assess potential immunosuppres-ants. Third, Borel, after reporting at the British Immunol-gy Congress that the drug blocked T cell activation, andhile aboard a train to Amsterdam to attend the Leukocyteulture Conference, was informed by the University ofinnesota team that no improvements were needed owing

o the excellent results achieved with their immunosuppres-ive regimen.

Norwegian legend notwithstanding, in the present era ofesearch on selective targets, it seems hard to fathom notnly the serendipitous discovery of a drug that has served ashe cornerstone of immunosuppressive therapy for the pastwo decades but also the advances made in clinical use ofhe drug despite a lack of understanding of its mechanism

f action. Not until about 10 years after the introduction of s

2004 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 36 (Suppl 2S), 5S�6S (2004)

yclosporine, did Schreiber describe the calcineurin targethat explains the efficacy of cyclosporine and its pharmaco-ogic antagonism with tacrolimus.

Although tacrolimus, whose molecular structure is dis-inct from that of cyclosporine, shares the calcineurin targetnd is even more potent than the former agent, there isittle evidence of a difference in either efficacy or theommon major toxicity—renal dysfunction—between thewo drugs. Likewise, despite decades of investigation ofyclosporine and other calcineurin inhibitors, there is scantvidence to suggest that the molecular structures thatediate the renal dysfunction can be teased apart from

hose responsible for the efficacy. Furthermore, the cal-ineurin isoforms in various tissues seem to all be relativelyqually blocked by drug action. Elucidation of the vasomo-or functional versus the arteriopathic and tubular struc-ural changes has, however, enhanced our understanding ofhe renal dysfunction. Unfortunately, this toxicity repre-ents the major pitfall of cyclosporine therapy; indeed,hronic allograft nephropathy leading to reduced allografturvival has been attributed to calcineurin inhibitors.

Although some physicians advocate withdrawal (or evenvoidance) of calcineurin inhibitor therapy to minimizeenal dysfunction, an emerging strategy exploits combina-ions with synergistic immunosuppressive drugs. The first-eneration proliferation signal inhibitors, sirolimus andverolimus, show not only potent synergy when used withyclosporine but also vasculo-protective effects. Unfortu-ately, these agents also potentiate calcineurin inhibitor-

nduced renal dysfunction, at least a portion of which is relatedo pharmacokinetic interactions. Mycophenolic acid does notause renal dysfunction, but its pharmacodynamic interactionsith either cyclosporine or tacrolimus are only additive.Other weapons are currently emerging for use in combi-

ation with cyclosporine. Probably the strongest neweapon on the horizon is FTY720, which not only interacts

ynergistically with cyclosporine but also displays neitherephrotoxic activity nor metabolism by cytochrome P450A4 or extrusion by P-glycoprotein. FTY720 may serve ashe archetype for the design of new immunosuppressiverugs in the next 20 years. The use of FTY720 withimulect, an anti-CD25 chimeric human-mouse antibody,ill likely permit greatly reduced exposures to both cyclo-

porine and everolimus, a steroid-free combination that will

0041-1345/04/$–see front matterdoi:10.1016/j.transproceed.2004.01.115

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lmost certainly provide a robust matrix to inhibit severalteps in the cytokine paradigm well past the next decade.he horizon for the development of immunosuppressive

herapies thereafter will likely focus on targeting lympho-yte-specific cascades in a manner that leads to a state ofllo-unresponsiveness, thus mitigating acute and chronicejection. A second wave during this era of drug design willlmost certainly feature therapies with vaso-protective ac-ions to promote graft longevity.

This issue of Transplantation Proceedings documents andays tribute to the era of cyclosporine, recounting itsiscovery through its development to delivery to transplantatients. Again, Norwegian mythology provides a metaphoror the story: the majestic ash tree Ygdrasill, which sup-

orted the universe, was supplied by three springs. One i

pring was tended by the Norns, three goddesses whoispensed the past, present, and future. The springs of thether two roots were the sources of wisdom and wit on thene hand and a poison adder that perpetually gnawed at theoot on the other. The story of cyclosporine is the stuff ofegend, a tale of fateful discovery and luck brought toruition by human wisdom and ingenuity and thwarted byhe continual challenges of toxic effects and rejectionnherent in the transplantation enterprise. The real high-ights of the past two decades of cyclosporine-based trans-lantation regimens are the innumerable patients leadingroductive lives by virtue of this life-extending and life-nhancing therapy. The historic journey of cyclosporine hasuch to tell us about the past, present, and future of

mmunosuppression.