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1 2 3 The History of Transplantation 3 4 5 Thomas E. Starzl, Ngoc Thai, and Ron Shapiro 6 Thomas E. Starzl Transplantation Institute. University of Pittsburgh School of Medicine, 7 Pittsburgh, Pennsylvania, U.S.A. 8 9 10 11 12 More than 115 years ago, it was demonstrated by Von Mering and Minkowski that pancreatec­ 13 tomy produced mellitus in dogs (I). Nearly four decades passed before attempts were 14 made to restore glucose homeostasis by pancreas transplantation with surgical vascular anasto­ 15 moses, but only for physiologic experiments (2,3). An additional three decades went by before 16 preclinical studies for the potential purpose of ameliorating diabetes were undertaken in the late 17 1950s by Brooks and Gifford (4) and DeJode and Howard (5). After surgical technical problems 18 were worked out in the canine model (summarized in Ref. 6), the first attempt to treat human dia­ 19 betes mellitus with pancreas transplantation was carried out on December 17, 1966, by William 20 Kelly and Richard Lillehei (7) at the University of Minnesota. The patient died after two months. 21 The same Minneapolis team recorded the first success on June 3, 1969 (8). "Success" during this 22 pioneer period came to be defined as patient and functional survival for at least one year. 23 Thus, the pancreas became the fourth kind of organ allograft to be successfully trans­ 24 planted over a lO-year period (1959-1969) in which the feasibility of kidney (9,10), (11), 25 and heart (12) already had been demonstrated (Table 1) (8-13). It was a stunning "proof of prin­ 26 ciple" development that was at first considered not credible by knowledgeable authorities who 27 had viewed such efforts with distain. Hopes for had been based pre­ 28 viously on experiments in neonatal mice (14) and in irradiated adult mice (15) in which it 29 was shown that the development of donor-specific tolerance was associated with the donor leu­ 30 kocyte chimerism produced by splenic or bone marrow cell infusion. In an extrapolation of the 31 mouse findings, the production of donor leukocyte chimerism by bone marrow infusion prior to 32 or at the time of organ transplantation was expected to play an essential role in achieving organ 33 engraftment. However, efforts to apply this strategy in animals were uniformly unsuccessful, in 34 part because a good histocompatibility match was a prerequisite for avoidance of graft versus 35 host disease. When discovery of the human leukocyte antigens made tissue matching feasible, 36 human bone marrow transplantation was finally accomplished, but this was not until 1968 (13). 37 In the meanwhile, two unexplained qualities of the alloimmune response had made it 38 feasible to forge ahead precociously with organ transplantation under drug immunosuppres­ 39 sion (16). The first observation was that kidney allograft rejection that developed under 40 was regularly reversible by adding large doses of prednisone. The second finding 41 was that organ allografts under the nonspecific of azathioprine and pre­ 42 dnisone appeared to self-induce variable donor-specific tolerance. Tolerance was inferred from 43 the rapidly declining need for immunosuppression after rejection reversal. However, because 44 of the ostensible absence of donor leukocyte chimerism in these recipients, organ engraftment, 45 including that of the pancreas, was attributed to different mechanisms than those of bone mar­ 46 row cell engraftment. This chimerism-exclusionary dogma was not challenged until low-level 47 (micro-) chimerism was discovered in 1992 in the blood and tissues of long-surviving organ 48 recipients (17,18). Then it was obvious that alloengraftment was a form of partial tolerance 49 that resulted from" ... responses of co-existing donor and recipient cells, each to the other, 50 causing reciprocal clonal exhaustion, followed by peripheral clonal deletion" (Fig. 1) (17,18). 51 Successfully treated organ recipients and bone marrow recipients were mirror image versions 52 of leukocyte chimerism, differing in the proportion of donor and recipient leukocytes (Fig. 2). 53 54 55 THE DOMINANT ROLE OF DRUG IMMUNOSUPPRESSION 56 57 Without the foregoing insight into the chimerism-dependent mechanisms of organ 58 engraftment, further progress hinged almost exclusively on the development of stronger 22 Starzl et al.

1 Table 1 First Successful Transplantation of Human Allografts (Survival 2': 1 Year) 2 Organ City (Re!.) Dale Physician/surgeon 3 4 Kidney Boston (9,10) 1/24/59 MerrilllMurray Liver Denver (11) 7/23/67 StarzllGroth 5 Heart Cape Town (12) 1/2/68 Barnard 6 Bone marrow Minneapolis (13) 8/24/68 Gatti/Good 7 Pancreas' Minneapolis (8) 6/3169 LilieheilKelly 8 aKiclney and pancreas allografts in uremic patient. 9 10 11 immunosuppression. The combined use of azathioprine and prednisone had been a critical 12 step in the clinical development of kidney and other kinds of organ transplantation. But 13 because allografts were being lost to acute rejections that could not be reversed, a worldwide 14 policy drift occurred in which large doses of prednisone were administered from the time of 15 operation, rather than in response to rejection. The addition in 1966 of a short course of post­ 16 transplant antilymphocyte globulin (ALG) to azathioprine and prednisone (the "triple drug 17 cocktail") substantially reduced needs (19,20) and was used for the first successful non­ 18 renal organ transplantations (8,11,12). Nevertheless, the heavy mortality, and particularly the 19 devastating morbidity caused by long-term prednisone dependence, made organ transplan­ 20 tation (even of kidneys) as much a disease as a treatment in the view of critics. Widespread 21 transplantation of the nonrenal organs (including the pancreas) was forestalled until the 22 advent of cyclosporine (21,22) and (23). 23 As the more potent drugs became available, they were simply folded into the modified 24 formula of heavy prophylactic immunosuppression that had been inherited from the 1960s and 25 1970s. Used in this way, the multiple drug cocktails fueled the golden age of transplantation of 26 the 1980s and early 1990s. The dose ceilings of the individual primary and secondary drugs 27 were imposed by drug toxicity, while the dose floors were revealed by breakthrough rejection. 28 For example, the upper limit of azathioprine dosage [or comparably used substitutes such as 29 cyclosphosphamide (24) or mycophenolate mofetil (MMF) (25)] was dictated by myelotoxicity 30 that could be monitored conveniently by serial white blood counts. The more complex limiting 31 side effects of the ca1cineurin inhibitors (cyclosporine and tacrolimus) are shown in Table 2. Of 32 specific interest in the context of pancreas transplantation, both cyclosporine and tacrolimus 33 are diabetogenic, in addition to their nephrotoxicity and neurotoxicity (26). The other T-cell 34 directed agent, sirolimus, has its own distinctive panoply of dose-limiting side effects (27). 35 By using these agents in different combinations, it was possible with the various drug 36 cocktails to reduce acute rejection to almost a non-problem during the last two decades. 37 The unresolved issues now became the drug-specific side effects, chronic rejection, and the 38 39 40 41 42 43 44 Failure 45 Immune 46 ~~------~~~--.;:;;;,;;~~~~~;::;..;;;:~~;;;; Success 47 Reaction ...... -...... GVH .c"!'-~-~...... _.. - .. ---...... _-_...... -...... -.. 48 Donor ------.. Failure 49 50 51 52 Time after Transplantation 53 54 Figure 1 Contemporaneous host versus graft (HVG) (upright curves) and graft versus host (GVH) (inverted curves) responses after organ transplantation. If some degree of reciprocal clonal exhaustion is not induced and maintained 55 (usually requiring protective immune suppression), one cell population will destroy the other. In contrast to the usually 56 dominant HVG reaction of organ transplantation (shown here), the GVH reaction usually is dominant in the cytoablated 57 bone marrow recipient. Therapeutic failure with either type of transplantation implies the inability to control one, the 58 other, or both of the responses. The History of Pancreas Transplantation 23

1 Two-Way Paradigm (Organ) Two-Way Paradigm (Bone Marrow) 2 GVH----__. Mulu;,1 Nalun'li .. 3 I •.• Immunosuppression /"""~ 4 • ~ It~ /:. e, •.e :",", ,.)"."\:l. 5 e/A •• ~:~ .. \ 6 / .i.'. :... : '~nl1f ~' 7 8 -Ile,ed Bone ee *1' Un..';.:~: ;.~::', \\r*m " ;r .~., !._' .&;\ __L ~. 9 Marrow Velo/Suppressor Cells Not Quile 10 Velo/Suppressor Cells Unconditioncd Cytokine ProHle ChAnges Defensel.:'!;,s Recipient YIOklnC Prolile Changes Recipient Ellhanclng Antibodies Cyloablall<:Hllx-rav. druq'" Enhancing Antibodies I 11 Li '------HVG ___--I 12 HVG (Rejection) -..J 13 Figure 2 Two-way paradigm in which transplantation is seen as a bidirectional and mutually canceling immune reaction 14 that is predominantly host versus graft with whole organ grafts (lem and predominantly graft versus host with bone 15 marrow grafts (right). 16 17 18 risks of long-term immunodepression. The list of complications from protracted immunode­ 19 pression per se was a long one, which could be divided into two broad categories: 20 susceptibility to and the development of de novo malignancies. 21 22 23 PANCREAS TRANSPLANT PROCEDURES VS. IMMUNOSUPPRESSION ERA 24 Neither the development nor the merits of the different pancreas transplant operations could 25 be discussed intelligently without parallel consideration of the immunosuppression that was 26 available at the time these procedures were introduced. The point can be most easily made by 27 perusing the 1988 textbook, Pancreatic Transplantation, prepared by Carl G. Groth (Huddinge 28 Hospital, Huddinge, Sweden) (28) after it was apparent that cyclosporine had upgraded the 29 prospects for a range of organ transplant procedures. In addition to the contributions by 30 the Stockholm team members, Groth's book contains chapters from the seminal Minneapolis 31 pancreas program and from programs in Cambridge (England), Iowa City, Lyon, Munich, and 32 Pittsburgh. Because it provides a snapshot of pancreas transplantation in transition, the book 33 is a historical treasure. In its pages, opinions about surgical technique, pancreas procurement 34 and preservation, and other issues were discussed (circa 1987) by team leaders who continued 35 to influence pancreas transplantation for the next dozen years and beyond. 36 37 38 Azathioprine Era 39 The first attempts at clinical pancreas transplantation were plagued by inadequate control of 40 rejection despite the administration of frequently myelotoxic doses of azathioprine, large 41 42 43 Table 2 Nonimmunologic Profile of Calcineurin Inhibitors (Four + Worst): All Dose 44 Related 45 Tacrolimus Cyclosporine 46 Nephrotoxicity ++a ++ 47 Neurotoxicity + + 48 Diabetogenicity + + 49 Growth effects 50 Hirsutism 0 +++ 51 Gingival hyperplasia 0 ++ 52 Facial brutalization 0 + Hepatotropic effects ++++ +++ 53 Gynecomastia 0 + 54 Other metabolic effects 55 Cholesterol increase 0 ++ 56 Uric acid increase +? ++ 57 'Less hypertension. 58 Source: From Ref. 26. 24 Starzl et al.

1 amounts of prednisone, and "induction" ALG. In addition to being diabetogenic, 2 were inimical to wound healing. The technical aspects of the pancreas transplant procedures 3 developed during this period reflected efforts to work around these inadequacies of immuno­ 4 suppression. In their first human operation at the University of Minnesota (7) on December 17, 5 1966, Kelly and Lillehei transplanted the head and tail of a cadaveric pancreas to the left iliac 6 fossa of a uremic recipient after removing the graft duodenum and ligating the pancreatic 7 duct. A kidney from the same donor was placed in the right iliac fossa. The recipient 8 immediately became insulin independent, but died at two months from a combination of 9 rejection and sepsis. 10 By 1973, Lillehei and associates had implanted 13 more whole human pancreas grafts, 10 11 in combination with cadaver kidneys from the same donor and the final three alone (8,29). 12 In cases 2 to 6 pancreatic secretions of the allograft were exteriorized (cutaneous graft duode­ 13 nostomy), while in cases 7 to 13 the exocrine drainage was directed via the graft duodenum 14 into the host jejunum, using a Roux-en Y technique (8). In patient 14, a patch of graft 15 duodenum containing the ampulla of Vater was anastomosed to recipient bowel. The only recipi­ 16 ent (the sixth) in this pioneer series of 14 cases to achieve long-lasting insulin independence 17 beginning on the day of operation (June 3, 1969) died shortly after reaching the one-year mile­ 18 stone with a functioning pancreas after losing the kidney graft and returning to dialysis. The 19 13 other pancreas graft losses resulted from technical complications including vascular throm­ 20 bosis, death with a functioning graft, and, most commonly, lethal complications associated with 21 exocrine pancreatic drainage. Similar discouraging results with pancreas transplantation during 22 the early 1970s in Sao Paulo (Brazil), Chicago (lllinois), Irvine (California), Zurich (Switzerland), 23 and in mostly unreported cases elsewhere caused abandonment of whole organ pancreas 24 transplantation for more than a decade. 25 The grim early experience continued to influence surgical policies worldwide until the 26 end of the 20th century. With the premise that the Achilles heel of the operation was the need 27 for exocrine drainage, new strategies emerged to avoid entry into the host bowel, to eliminate 28 the graft duodenum from the graft or to prevent or reduce the volume of the graft 29 exocrine secretions. In 1973, Gliedman et al. (30) reported excision of the graft duodenum 30 and the adjacent pancreatic head with transplantation of the rest of the pancreas; the segmen­ 31 tal pancreatic duct was anastomosed to the recipient ureter. When two of these recipients lived 32 insulin free for two and four years (31), momentum shifted for the next dozen years to the 33 essentially exclusive use of distal pancreas grafts. Rather than exocrine diversion into the uri­ 34 nary tract or bowel, however, most surgeons either drained exocrine secretions from the 35 pancreatic segment into the free peritoneal cavity or blocked the segmental duct by ligation (29) 36 or by injection of a polymer (32). Only Groth and Tyden in Stockholm systematically resisted 37 the trend by anastomosing the duct (or the draining segmental surface) to the bowel (33). 38 39 Cyclosporine Era 40 41 With better control of rejection and less steroid dependence made possible by cyclosporine, 42 there was a resurgence of interest in pancreas transplantation as well as modifications of 43 the surgical operation. Use of segmental cadaveric allografts continued until well into the 44 1980s, and remains an option today when live pancreas donors are used. In early 1982, we 45 re-examined the reasons for abandonment of whole pancreas transplantation, and undertook 46 reassessment of the procedure in dogs (34). Our conclusion was that the most logical operation 47 of whole organ transplantation described by Lillehei and Kelly had been discontinued in 48 favor of the inferior option of segmental pancreas transplantation. Consequently, a limited 49 clinical trial of whole organ pancreas transplantation was begun in Pittsburgh in March 50 1983 (35). In a crucial modification of the original Lillehei procedure, we developed a tech­ 51 nique for draining the allograft exocrine secretions into the host jejunum through a "bubble" 52 of graft duodenum into which the ampulla of Vater emptied. The duodenal bubble was 53 anastomosed to the side of the host jejunum (Fig. 3) (35,36). 54 Although the number of cases was small, the influence of the trial was amplified by the 55 presence in Pittsburgh at the time of fellows or visitors who had come to observe the burgeon­ 56 ing liver transplant program and who also saw how easy and successful was the whole organ 57 pancreas transplantation. One such fellow (1981-1983), Dr. Munci Kalayoglu, subsequently 58 joined a team at the University of Wisconsin headed by Dr. Hans Sollinger, which had The History of Pancreas Transplantation 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Figure 3 Use of donor "duodenal bubble" for exo­ crine pancreatic drainage introduced in Pittsburgh in 25 1983. 26 27 28 previously compiled a series of segmental transplantations with exocrine drainage into the 29 bladder. After Kalayoglu's arrival in Madison, Sollinger and Kalayoglu changed from segmen­ 30 tal to whole organ transplantation. Similarly, Dr. Robert Corry of the University of Iowa was 31 persuaded during a sabbatical leave in Pittsburgh in late 1983 and early 1984 to adopt the 32 whole pancreas transplantation procedure (37). 33 At their home institutions, Corry and Sollinger initially drained the graft duodenal bub­ 34 ble into the host jejunum. However, both teams soon advocated anastomosis of the bubble to 35 the anterolateral wall of the host bladder (Fig. 4) (38,39). Bladder drainage was adopted soon 36 thereafter for most cases at the University of Minnesota (39). With the enthusiastic endorse­ 37 ment from these three centers [reflected in separate chapters in Groth's book (40-42») the 38 bladder drainage technique was widely accepted. Serial measurement of urine amylase con­ 39 centration became a means of immune surveillance, i.e., a drop in urine amylase signaled 40 rejection. Complications from the bladder drainage were initially viewed as acceptable. 41 However, digestion of the urethra by activated pancreatic enzymes, less serious but common 42 examples of cystitis, uncorrectable metabolic acidosis caused by the continuous loss of 43 bicarbonate, and a myriad of other problems necessitating conversion to enteric drainage 44 began to diminish enthusiasm for bladder drainage by the mid 1990s. By this time, Corry 45 (now at the University of Pittsburgh) had switched back to enteric drainage via the duodenal 46 bubble. After the advent of tacrolimus, this became the reconstruction of choice at almost all 47 centers (43-45). 48 49 Tacrolimus Era 50 51 Despite Corry's enthusiastic advocacy of tacrolimus, the drug was not widely used for pan­ 52 creas transplantation until the mid 1990s because of its dose-related diabetogenicity. This view 53 changed dramatically when a multicenter collection of cases demonstrated the ability of the 54 new drug to rescue most of the treatment failures that were occurring under cyclosporine­ 55 based immunosuppression (46). Moreover, the superior control of rejection with minimal 56 dependence on prednisone using tacrolimus-based immunosuppression from the outset has 57 further eroded the arguments for exocrine diversion to the bladder. It also became possible 58 with the simplified tacrolimus-based regimens to eliminate the perioperative induction 26 Starzl et al.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 duodenum 24 (graff) 25 26 27 28 29 30 31 32 Figure 4 Drainage of pancreas exocrine secretions into the recipient bladder. This was the most commonly used 33 procedure from 1985 until the mid or late 1990s. 34 35 36 therapy with ALG that had become a standard component of cyclosporine-based immuno­ 37 suppression during the mid 1980s. Since 1995, general agreement about the superiority of 38 tacrolimus-based immunosuppression was finally reached (33,43-45,47-49). 39 40 41 A New Era? 42 43 The long-term efficacy of pancreas transplantation is not yet clear. Only 16 recipients in the 44 world are known to have functioning pancreas allografts that were transplanted before 1986 45 and none who were treated before 1981 (50). With the improvements that occurred since the 46 1980s, there have been many reports indicating that the survival of diabetic kidney trans­ 47 plant recipients is improved by cotransplantation of a pancreas (43-49). However, there 48 has been at least one United Network for Organ Sharing-based analysis suggesting that 49 the risk of death from staged kidney-pancreas transplantation has been greater, even in 50 recent times, than in kidney-alone recipients who had been listed for a pancreas but failed 51 to get one (51) (see also counter-arguments in Chapter 1). Apart from pancreas graft-related 52 complications or functional failures, late recipient deaths have continued from cardiac, infec­ 53 tious, and peripheral vascular disease, and from de novo malignancies. Many, if not most, of 54 these late complications can be traced to, or are aggravated by, the need for chronic 55 immunos u ppression. 56 The ideal solution would be to make organ recipients more tolerant and thereby less 57 immunosuppression-dependent. This objective became realistic with the elucidation of the 58 donor leukocyte chimerism-associated mechanisms of acqUired tolerance (17,18) and The History of Pancreas Transplantation 27

Tolerogenlc Immunosuppression Over Immunosuppression 2 3 ------1------.....II .. nr.... lr... 4 ------5 •• R('j('clloll ~ c c .' 6 Co 7 Ln ... ",o( Chjll. : 8 d,)!1(lf ~P(~CI!'t ~ I,'C')\'", I ilc{l\lalll}ll 9 I'XhillJ~tl()n 10 11 I > 12 '-'

13 1::11(> 14 15 Figure 5 Mechanisms of immunosuppression_ (Left): Conversion of rejection (thick dashed arrow) to an immune 16 response that can be exhausted and deleted by combination of pretreatment and minimalistic posttransplant 17 immunosuppression. (Righ~: If the clonal response is eliminated by excessive posttransplant immunosuppression, exhaustion-deletion shown on the left is precluded, and subsequent graft survival is permanently dependent on 18 immunosuppression. Abbreviations: GVH, graft versus host; HVG, host versus graft; Tx, transplantation. 19 20 21 the recognition that organ engraftment is a form of partial tolerance (52,53). With this insight, it 22 was obvious that the seminal mechanism of alloengraftment and acquired tolerance (i.e., clo­ 23 nal exhaustion-deletion) can be subverted by the "conventional" use of heavy prophylactic 24 immunosuppression (Fig. 5, right) (53). In 2001, it was proposed that this undesired conse­ 25 quence could be prevented by observance of two therapeutic principles: recipient pretreatment 26 and the use of minimal posttransplant immunosuppression (Fig. 5, left) (53). 27 Between July and December 2001, the late Robb Corry carried out a pilot trial based on 28 these principles in 10 recipients of simultaneous pancreas and kidney allografts and four 29 recipients of pancreas transplants alone. All of the donors were human leukocyte antigen­ 30 mismatched, heart-beating cadavers with the same ABO types as the recipients. The patients 31 were infused prior to organ revascularization with approximately 5 mg/kg rabbit antithymo­ 32 cyte globulin (Thymoglobulinlt) and were coinfused with 1-2g methylprednisolone to 33 prevent cytokine reactions (54). On the first postoperative day, twice-daily tacrolimus 34 monotherapy was begun with a target 12-hour trough level of 10 ng/ mL. After four to six 35 months, patients who had been on stable tacrolimus monotherapy for at least two months 36 had extension of the interval of tacrolimus doses ("spaced weaning") to once a day, every 37 other day, or longer if this was compatible with stable graft function (Fig. 6). 38 A short-term follow-up of the patients was reported in 2003 (54). The results at three 39 years and the current results are summarized in Table 3 for each case. Eleven (78%) of the 40 14 recipients remained insulin free for three years, but in two of these patients, hyperglycemia 41 recurred after 36 months. Thus, nine (64.2%) still are insulin free after 43 to 49 months. Eight of 42 the nine insulin-free patients are on treatment with a Single drug and four are on spaced doses 43 of tacrolimus (Figs. 6 and 7). Importantly, seven of the 10 patients who also received kidneys 44 had life-supporting renal function at three years with serum creatinine concentrations <::;2 mg/ 45 dL in six. After Corry was killed in a motor vehicular accident in February 2002, the trial was 46 placed on hold. 47 By the time of his death, Corry was aware that the management principles under evalu­ 48 ation were sound and required only fine-tuning. First, the initial step of weaning to every 49 other day would have to be taken more cautiously. Second, weaning of monotherapy to inter­ 50 vals greater than every other day should be delayed until at least one year unless evidence of 51 drug-specific side effects (e.g., nephrotoxicity, neurotoxicity, or diabetogenicity) called for ear­ 52 lier action. In 2003, the policy of tolerogenic immunosuppression was reinstituted with these 53 foregOing modifications. In addition, lymphoid depletion was done with the broadly reacting 54 antilymphoid monoclonal antibody, alemtuzumab (Campath@) rather than with Thymoglobu­ 55 lin. The superior early results with this management are described in Chapter 1. The chapter, 56 along with the rest of this book, has been dedicated to Corry's memory. A Robb Corry 57 Professorship has been established at the University of Pittsburgh, the inaugural occupant 58 of which is Ron Shapiro. 28 Starzl et al.

1 2 3 4 5 6 7 6 8 9 ~ Creatinine (mg/dl) 10 f~_:* .... : 11 :b~ 12 1000~ 13 500 ~ Lipase (u/dl) 14 15 0~~~~~~--'-~~~~7~'-'~' 16 17 ...... Glucose (mg/dl) 1 18 3 °5 °0 ....- ...- ...- ....------...... 0 ~ : I:' , .:' ns ....: ••••• : 19 20 Figure 6 The course of a simultaneous 21 -+- Cpeptide (ng/ml) pancreas-kidney recipient pretreated with 22 antithymocyte globulin. The dose frequency 23 of daily monotherapy was reduced to every other day at four months and to three times 24 a week at eight months after transplant (top 25 c; 1000 j o Steroid Dose PO .s 100 panel). Creatinine, lipase, glucose, and C· 26 ri Biopsy ill 10 peptide (middle panels), have been stable 27 o • Steroid Bolus throughout. This patient did not receive 28 o 1 ~B?7G1~r-lIe.~,------,----~--,----- any steroids or other additional treatment e N and was biopsied five times with no evidence 29 N ~ 30 of damaging acute rejection. 31 32 33 34 35 Table 3 Tolerogenic Immunosuppression for Pancreas Recipients (Corry, 2001): Results at Three Years 36 Monolherapy Creatinine Fasting glucose 37 Number TX (dose frequency) (mg/dl) (mg/dl) 38 Simultaneous pancreas-kidney 39 1 7/01 Daily 2.0 80-90 40 2 8/01 Daily 1.3 80-100 41 3 8/01 Once/wk 1.0 70-80' 42 4 9/01 Failed 22 rna Failed 5 rno 43 5 9/01 Daily 4 90-100 44 6 10/01 Failed 22 mo 90-140b 7 11/01 Thrice/wk 1.0 80-100 45 8 11/01 Daily 1.7 80-110 46 9 12/01 Failed 13 rno Failed 7 rna 47 10 12/01 Thrice/wk 1.3 80-90 48 Pancreas alone 49 1 7/01 Thrice/wk 1.7c 70-100 50 2 9/01 Daily multidrug 1.2c 90-140b 3 10/01 1.0c Failed 5 mo 51 4 12/01 Daily 1.6c 70-90 52 Monotherapy: all tacrolimus except Case 1 (rapamycin). 53 -, Not applicable because of graft loss(s) and drug discontinuance. 54 'After three years, the patient developed disseminated metastases from breast cancer, and died insulin-free at 43 months. 55 "Became insulin-dependent after three years. 56 CNative kidney. Note: Pancreas grafts functioning at three years: 11/14 (78.5%). currently 9/14 (64%); kidney grafts functioning at three years and 57 now: 7/10 (70%). 58 Abbreviation: TX, transplantation. The History of Pancreas Transplantation 29

1 _daily L-1 qod .3 x week 2 ~ 30 . 1 x week -{)-Ievel OJ 3 ...J_ 4 ~ ~ 15 = c: 5 2- g 6 I- 7 6 8 9 3 . , • Creatinine (mg/dl) 10 o~~~·J~ Figure 7 The course of the first pancreas 11 recipient pretreated with antithymocyte 12 globulin. The dose frequency for this pan~ creas-alone recipient was reduced quickly 13 1::: L 1Lll . lipase (u/dl) , 14 after six months reaching a minimum of o ~~... J_bD."".a. ... ,.JI;' ••~ ...... 15 one dose per week at one year. A bioche­ 300 mically indicated, pathology-confirmed 16 ~ ,0 Glucose (n.1 9/dl) rejection at 23 months was reversed with 17 150 ...... h_+-9I 'r!J\~~ steroids, a dose of alemtuzumab (lower 18 o panel), and the temporary resumption of 19 daily tacrolimus that suosequently was 12 , 20 re-weaned to three times a week. The 21 6 benefit of recluced exposure to tacrolimus is apparent in the creatinine levels depicted 22 o in the second panel; i.e., the patient's kid­ 23 Steroid PO Lj Slrolimus ney functioned better with less treatment 24 ~ Biopsy taken • Steroid Bolus and worse with more treatment. Other than 25 ...s 00'1100 II Campath during the rejection episode, graft function, ~ 10 ' ! as reflected in the lipase, glucose, and c~ 26 o I 0 27 1 ... ~--~.J. -a- peptide levels, has been stable throughout. M .,. Later patients (Fig. 6) were weaned less 0 0 0 28 ;::: '";::: ;::: ~ aggressively. 29 - 30 31 32 33 REFERENCES 34 35 1. Von Mering J, Minkowski O. Diabetes mellitus nach pankreas-exstirpation. Zentralbl Klin Med 1889; 10:393-394. 36 2. Gayet R, Guillaumie M. La regulation de la secretion interne pancreatique par un processus 37 humoral, demontree par des transplantations de pancreas. Compt Rend Soc Bioi 1927; 97:1613-1616. 38 3. Houssay BA. Technique de la greffe pancreatico-duodenale au cou. Compt Rend Soc Bioi 1929; 39 100:138-140. 40 4. Brooks JR, Gifford GH. Pancreatic homotransplantation. Transplant Bu111959; 23:100. 41 5. DeJode LR, Howard JM. Studies in pancreaticoduodenal homotransplantation. Surg Gynecol Obstet 42 1962; 14:553-558. 6. Brekke IB. Experimental background. In: Groth CG, ed. Pancreatic Transplantation. Philadelphia, 43 PAc WB Saunders Company, 1988:21-35. 44 7. Kelly WD, Lillehei RC, Merkel FK, Idezuki Y, Goetz Fe. of the pancreas and 45 duodenum along with the kidney in diabetic nephropathy. Surgery 1967; 61:827-837. 46 8. Lillehei RC, Simmons RL, Najarian JS, et al. Pancreaticoduodenal allotransplantation: experimental 47 and clinical experience. Ann Surg 1970; 172:405-436. 48 9. Murray JE, Merrill JP, Dammin GJ, et al. Study of transplantation immunity after : clinical and experimental investigation. Surgery 1960; 48:272-284. 49 10. Merrill JP, Murray JE, Harrison JH, Friedman EA, Dealy JB Jr., Dammin GJ. Successful homotrans­ 50 plantation of the kidney between non-identical twins. N Engl J Med 1960; 262:1251-1260. 51 11. Starzl TE, Groth CG, Brettschneider L, et al. Orthotopic homotransplantation of the human liver. 52 Ann Surg 1968; 168:392-415. 53 12. Barnard CN. What we have learned about heart transplants. J Thorac Cardiovasc Surg 1968; 56:457-468. 54 13. Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 1968; 2:1366-1369. 55 14. Billingham RE, Brent L, Medawar PB. "Actively acquired tolerance" of foreign cells. Nature 1953; 56 172:603-606. 57 15. Main JM, Prehn RT. Successful skin homografts after the administration of high dosage X radiation 58 and homologous bone marrow. J Nat! Cancer Inst 1955; 15:1023-1029. 30 Starzl et al.

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