Progressreport Current statusof intestinal transplantation · Gut, 1989, 30, 1771-1782 Progressreport Currentstatusofintestinal transplantation Thesuccessful developmentofclinical

Gut, 1989, 30, 1771-1782

Progress report

Current status of intestinaltransplantation

The successful development of clinical intestinal transplantation remains anexciting challenge for the transplant surgeon, immunologist, and gastro-enterologist. Bowel transplantation was first attempted in 1901 by Carrelwho transplanted portions of small intestine into the neck of dogs.' Interestwas rekindled in 1959 when Lillehei showed that autotransplantation of thesmall intestine into the dog was feasible.' Despite recent major improve-ments in techniques, however, and the introduction of new immuno-suppressive regimens which have seen the flourishing of liver, heart, heart/lung and pancreatic transplant programmes, the clinical results of smallintestinal transplantation remain dismal.Two major problems confront us; first, the complex immunological

phenomena occurring after small bowel transplantation, which include bothclassical graft rejection and graft versus host disease, do not appear to beeasily controlled by current immunosuppressive protocols, and requireelaborate treatment of both graft and host.-' Second, the physiologicalfunctions of the graft are severely deranged by the process of transplantationand further immunological damage will not only hamper recovery butdestroy the barrier functions so vital to recipient survival.A series of clinical intestinal transplants were performed in the early 1970s

by several institutions, with only one survivor beyond two weeks. Morerecently small intestinal transplants have been carried out in several majortransplant centres in Europe and North America and two Europeanrecipients have survived beyond six months (personal communication).While small intestinal transplantation remains hazardous, however, it cannot be considered a true therapeutic option for patients who are satis-factorily maintained on total parenteral nutrition. The purpose of thisreview is to summarise the progress made so far and to highlight the areas inwhich further research is required before small bowel transplantationbecomes a practical therapeutic option.

The immunological problem

Small bowel transplantation between two unrelated individuals within agiven species causes two distinct but coexistent immunological reactions.First, cell mediated graft rejection by the recipient and second, graft versushost disease, in which lymphocytes (within Peyers patches and mesentericlymph nodes) transplanted along with the graft attack the recipient. Theseresponses were first recognised in the rat by Monchick and Russell and laterconfirmed by Kirkman et al.' They transplanted fully vascularised loops ofsmall intestine bringing out the ends of the graft as cutaneous endentero-stomies. Transplantation without immunosuppression using Lewis (Lew)donors and Brown Norway (BN) recipients resulted in primarily graft

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destruction eight to 11 days after surgery. They were able to dissect theirstudies immunologically by using inbred parental Lewis or Brown Norwayrats and (Lewisx Brown Norway) F, hybrids. These hybrids rats possessedmajor histocompatibility antigens of both parents and therefore could notrecognise Lewis or Brown Norway parental tissue as foreign. Thus when Flwere used as donors for either Lewis or Brown Norway recipients, graftrejection occurred without graft vierslus host disease. Similarlv when Lewisor Brown Norway intestine is placed in (LewisxBrown Norway) Flrecipients graft versuis host disease developed but rejection did not occur.i'This model has now become a standard tool for the investigation of smallbowel transplantation immunology.

In the rejection model ((LewisxBrown Norway) F1-> Lewis) graftrejection occurs six to nine days after surgery. At necropsy there is adense infiltration of the graft with mononuclear cells, gross mucosal oedemaand sloughing. The native gut appears essentially normal.~'- More detailedstudies of the evolution of rejection have shown that three days aftertransplantation there is only slight mucosal damage, restricted to the crypts.sThere is also a vascular lesion evident affecting the arterioles and venules atthe junction of the mucosa and submucosa. Endothelial cells are enlargedand are associated with intravascular lymphoid cells. By day 6 there is villusshortening but the villous epithelial cells are morphologically normal withprominent brush borders; the crypts are prolonged with extensive celldamage. The lamina propria becomes distended with a mononuclearlymphoid cell infiltrate. By the time of complete rejection (day 9) there isgross villous shortening and the epithelial cells have lost there brushborders. There is no increase in intraepithelial lymphocytes. The crypts arenow also shortened and the vascular lumen is completely occluded` Theseobservations suggest that the vascular endothelium and crypt epithelium arethe initial sites of injury. As villous cells originate from the crypts the villousdamage could be secondary to crypt damage. In addition ischaemiasecondary to vascular occlusion could play a role."

In the graft versus host disease model (Lewis->(Lewisx Brown Norway)F,) death occurs approximately 13-16 days after transplantation." I"6lClinically the rats develop a classic hunched posture, pink paws, ruffled fur,and diarrhoea (from the native gut). Spienic and lymphoid enlargemelitoccurs in the early stages of the disease followed by atrophy.'' Athistology the intestinal graft is normal. By day 5 the lymphatic tissue of thegraft (Peyers patches and mesenteric lymph nodes) and host lymphatictissue (Iymph nodes and spleen) undergo progressive lymphoid depietion.This is initially accompanied by proliferation of histiocytoid cells andimmunoblasts. These immunoblasts disappear over the following days,giving way to lymphopenia until normal lymph node and splenic architectureis lost.- An enteritis develops in the llost bowel between the ninth and12th day with a generalised mononuclear cell infiltrate in the lamina propria.This is followed by patchy crypt necrosis and villus shortening. By day 14 themucosa is beginning to slough. The epidermis becomes thickened andinfiltrated with mononuclear and polymorphonuclear cells. Organs such asthe kidney and pancreas remain normal."

Graft versus host disease is caused by donor lymphocytes migrating intothe host. This can be reduced. even abolished. if the mass of lymphoid tissuein the graft is reduced by either irradiation before transplantation '-

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Current status of intestinal transplatnttion17

resection of mesenteric lymph nodes.' Graft versus host disease does notoccur after transplantation of intestine from T-cell depleted parental donorsinto F, hybrid recipients." The graft versus host disease response can berestored by reconstitution of the donor with syngeneic T-cells prior to graftdonation. This confirms that donor T lymphocytes mediate graft versus hostdisease." Furthermore a local graft v host response can be produced byinoculating spleen cells from (Lewisx Brown Norway) F, rats with clinicalgraft versus host disease (after small intestinial transplantation) into thefootpad of syngerneic recipients." This results in ipsilateral inguinal lymphnode enlargement. Similar lymph node enlargement in (LewisxBrownNorway) Fl rats can be produced by injecting splenic cells from normalLewis rats. This suggests that there are donor lymphocytes - that is fromLewis rats, in the spleen of (Lewisx Brown Norway) F1 recipient rats whichcause graft versus host disease.' This has been confirmed by studies aftersmall intestinal transplantation between DA and PVG parental rat stainsusing monoclonal antibodies raised against donor strain specific majorhistocompatibility complex antigens. Graft derived cells accumulate in largenumbers in all host lymphoid tissue in untreated animals. This phenomenonis transient and occurs simultaneously with the development of spon-taneously resolving clinical graft versus host disease. The same features areidentified in immunosuppressed animals although the cellular infiltrate intothe host is far greater. This infiltrate spontaneously regresses two to threeweeks after transplantation and the animal and graft survive indefinitely. ''

Rejection and graft versus host disease reactions are less clearly defined inthe dog. Dogs survive six to 12 days after transplantation without immuno-suppression." The spectrum of graft rejection is not a uniform at necropsy,indeed mucosal changes may be slight and indistinguishable from autotrans-planted controls.'""' In rejection there is an infiltrate of lymphocytesand plasma cells into the lamina propria on the fourth day.s` As in therat, epithelial damage begins in the crypts and the villi become progres-sively shorter before sloughing. ` These features of rejection are inconsistentand it has often been difficult to give a cause of death."' 1721 It is worthemphasising that the histological appearance of rejection may be subtleand villous shortening with an increase in mitotic figures in the cryptsbeing the only features. 7 Such architectural features are not specificfor rejection and can be seen after ischaemia.' Indeed the cardinalhistological signs of rejection; fibrinoid necrosis, mononuclear cell infil-tration and luminal obliteration of blood vessels are infrequently foundin the canine model and the diagnosis of rejection must be circumspect.?'The disparity in the results of these studies may be due to the patchy natureof the rejection reaction. Overall the immunological response of the dog tosmall bowel transplantation is variable with some dogs displaying classicalrejection, some graft versus host disease and others in whom there isa mixed picture.'7There is a suggestion that an immunological balance exists between

rejection and graft versus host disease. In one study, untreated dogs diednine days after transplantation with features of graft versu.s host disease."Graft irradiation with 150 rads before transplantation resulted in rejectionwithout graft versus host disease. After an intermediate dose of 50 rad,longer host survival was noted, with less aggressive rejection than in theheavily irradiated graft. The question arises as to whether immuno-

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competent cells within the graft protect against rejection. Further study isrequired to substantiate this hypothesis.

Immunosuppression with Cyclosporin A

The efficacy of cyclosporin A has been investigated intensively in variousmodels of small bowel transplantation (Table 1). In the unidirectional ratrejection model ((Lewisx Brown Norway) Fl-*Lewis) a number of groupshave been able to achieve prolonged recipient survival with parenteralcyclosporin A without histological features of graft rejection."'5-'-' Indeedsome studies have shown that cyclosporin A is only required for sevendays.6i" It should be noted that graft survival is difficult to assess in some ratstudies as the graft is not in continuity with the native gut; defunctionedloops tend to atrophy because of the lack of luminal contents.6 ''71

Cyclosporin A is less successful in preventing graft versus host disease inthe unidirectional graft versus host disease model (Lewis->(Lewisx BrownNorway) FI) (Table 1). Some groups have reported no difference inrecipient survival or histological findings from untreated controls " thoughothers have achieved good results.'- Failure of cyclosporin A to prevent graftversus host disease has also been reported in bone marrow transplantationwhich requires either higher doses, or alternative additional immuno-suppression.`" In the fully allogeneic rat model (Lewis->Brown Norway)results with cyclosporin A have in general been encouraging, but low dosecyclosporin A (< 15 mg/kg/day) results in reduced survival.7

Consistent longterm host survival has not been achieved in dogs treatedwith cyclosporin A (Table 1); a few dogs have survived for longer than six

Table I Recipwient surtivilal after small bowel transplantation wlen using Cyclo.sporin A

Studcs AnirnicalNuitritioti Inmtninstosiuppres sian Reu(ipientisurvival

Rejection aloti('6 Rat Native gut CsA 15 mg/kgid ip for 7 days >1() d (n =5)*

22 Rat Native gut CsA 15 mg/kg/d po 3/11 rats >56 d24 Rat Native gut CsA 1 img/kg/d ip for 7days 1W%, > 15)dd

cGrajt versus Ilost (disease (alont('6 Rat NatiVe gut CsA 1 mg/kg/d for 44 days 44-54 d (n =4)14 Rat Nativegut CsA 1 mg/kg/d for 14days 71%) at 150d (n 28)25 Rat Native gut CsA 15 mg/kg/d sc for ddays 20(4 (5.4) d (n =7)

Rejectioan wit/i graft v'ersus Ihost disease4 Man Tx gut CsA 6-9 mg/kg/d for 4 then 4 mg/kg/d 1t d (n= 1)17 Dog Tx gut As above+methylprednisolone i22 (14 (0) d (n= 12)19 Dog Tx gut CsA 17 mg/kg/d+prednisolone 1257 (58X6) d (n= 12)20 Dog Tx gut CsA 25 mg/kg/d 1(133 (39.4) d (n= 11 )23 Rat Tx gut CsA 1. mg/kg/d im 10t( >8 mo*27 Rat Natise gut CsA 1() mg/kg/d for 4 days then 25 mg/kg tor 30 days 18 5(5.7)d(n= 8)28 Rat Native gut CsA 25 mg/kg/for 14 days >21 d*29 Rat Natise/Tx gut CsA 2(1 mg/kg/d sc 112 (92) d (n= 1()3(0 Dog Tx gut CsA 16 mg/kg/d ix tapering toX nig/kg/d at day 8 45 (38) d (n= 9)31 Dog Natise gut CsA 2(0 mg/kg/d pa 63.3 (h1.5) d (n= 6)32 Dog Tx gut CsA 16 mg/kg/d is tapering to 8 mg/kg/d 27.7 (13.8) d (n=6)33 Pig Tx gut CsA 1. mg/kg/dis for 10days then 30nig/kg/dpatfor4 mol21 (33) d (n =6)34 Pig Natise gut CsA 25 mg/kg/d po 34 (13) (d (n= 11)

Nutrition indicates whether nutrients were absorhed by the native gut or by transplanted (tx) gut. Recipientsurs ix al indicatect the maximum recipient survisal when a number of immunosuppression regimes were used.*The sursisal time was either not stated or the animals were killed for experimental purposes.CsA =cyclosporin A.

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Current status ofintestinal transplantation

months.'29203U3'2 In some studies death within the first eight postoperativeweeks was entirely due to graft rejection."3 In others, however, only someof the deaths could be ascribed to rejection.l'3"' Death through malnutri-tion, secondary to graft versus host disease has been reported as a cause ofdeath though no diagnostic features could be found. This highlights thedifficulty of diagnosis of graft rejection and graft versus host disease as thehistological features can be non-specific or slight.2'

In the pig longterm host survival is possible but high blood concentrationsof cyclosporin A appear to be essential." Best survival rates have beenachieved when cyclosporin A (15 mg/kg/day) is given intravenously forseven to 10 days after surgery and then orally at 30 mg/kg/day. Oraladministration alone, even at high dosage, does not appear to achieveadequate blood levels.34A different approach to small bowel transplantation is to use grafts from

immunologically naive foetal donors rather than adults. Work in the1970's on transplantation of mouse foetal small intestine implanted underthe renal capsule showed that survival and growth of transplanted foetalintestinal isografts was possible. The mucosa of allografts without immuno-suppression were destroyed in six to seven days.3 This has been performedin rats where the intestine has been placed in the paravertebral gutter; thegraft develops its own blood supply from the surrounding tissues. Althoughcyclosporin A has been shown to prevent rejection it is not yet clear whethersuch grafts can support host nutrition.

Other forms of immunosuppression

Conventional immunosuppression with prednisolone and azathioprineappears to be ineffective.3 Transplantation across the major histo-compatibility complex reduces graft survival and matching of majorhistocompatibility complex antigens will be essential in clinical transplanta-tion.39 Pretransplant blood transfusion with donor specific blood can extendhost survival time.27 The value of this is difficult to assess as suboptimal dosesof cyclosporin A were used in this study and survival times were not as goodas those achieved with cyclosporin A alone. In most studies of rats venousdrainage of the graft is directly into the inferior vena cava. This may have adetrimental effect on graft survival when compared with portal venousdrainage as the liver is an immunological filter.' Graft rejection in theunidirectional rejection model is less rapid when the graft is drained throughthe portal vein in preference to the inferior vena cava (11.8 versus 22-8days).4 Such a finding may be immaterial, because in clinical transplantationthe recipient portal vein is likely to be thrombosed from primary disease.Graft irradiation or lymph node resection to reduce the quantity oflymphoid tissue transplanted can prevent graft versus host disease.' 1432 Invivo irradiation may not be practical as it may in the long term causeradiation enteritis, but in vitro irradiation with intestinal shielding is a realpossibility. Donor pretreatment with polyclonal antilymphocyte serum hasbeen shown to prevent graft versus host disease in the unidirectional rat graftversus host disease model. In fully allogeneic models such treatment maylead to increased graft rejection by the recipient. The practical constraints ofclinical transplantation may make transfusion of the donor prior to organharvesting impractical.)

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Graft Function

The critical functional test of tranisplanted small bowel is whethier it canprevent malnutrition in the absence of nutrienit absorption from native gut.A number of investigations have shown that rats with fully allogeneic graftsreplacing the native intestine are able to gain weight at a cornparable rate toisograft or unoperated controls.`' " Blood glucose concentrations intransplant recipients after the instillation of maltose into the intestlinallumen are similar to controls.'"-" This is not only a test of absorptivefunction but also of mucosal integrity as maltose is hydrolysed by the brushborder enzyme maltase to glucose before its absorption. Serum triglycerideand cholesterol concentrations are also normal indicating lipid absorptionand metabolism to be preserved." Thus rat small bowel grafts appear to heable to absorb nutrients adequately. As longterm survival of dogs withi smallbowel transplantation has not been reliably achieved there are lessfunctional data than with the rat. Dogs living for more than six months aftertransplantation are well but no details about weight and functionalparameters have been reported." "` Many allografted dogs lose weight aItersurgery, however, and have diarrhoea.

In most animal models venous drainage is into the infcrior vena cavawhich creates a subtotal portosystemic shunt. This leads to a rise in serumammonia and amino acids similar to those found in models of hepaticencephalopathy.4'4 These changes can be minimised by feeding a lowprotein diet.`'An inevitable consequence of small bowel transplantation is graft

denervation. This is of importance because salt and water absorption isunder tight neurological control by the autonomic nervous system. Water,electrolyte, glucose and glycine absorption has been studied in the ratunidirectional rejection model ((LewisxBrown Norway) Fl-*Lewis)treated with cyclosporin A.'4 In allografts there is a reduction of water andsodium absorption rates from a glycine-saline infusate, a reduction ofsodium absorption rate from a glucose-saline infusate and net chloridesecretion when mannitol-saline is perfused. These transport defects can notbe accounted for by immunological factors; there are similar defects inisografts (which by definition can not undergo rejection). Surgical partialdenervation of the native intestine reproduces the transport defects. Thisstudy does not address the nature of the defect causing the increase in netchloride secretion from mannitol-saline, but it suggests that the reduction innet absorption rates could be because of enhanced secretion. Althoughthe entire neural supply is severed in transplantation this defect is mostconsistent with a loss of sympathetic innervation which is thought to act as a'brake' inhibiting secretion.l"" As the loss of sympathetic innervationappears to be important a2-adrenergic drugs may be of benefit. This studysuggests that diarrhoea may result from transplantation even if immuno-logically successful. Diarrhoea, however, has not been observed in ratssurvivinig long term."' This may be because sufficient length of bowel istransplanted so there is complete absorption of the luminal contents despitea reduction in net absorption rates. Another unexplored possibility is thatinnervation is reestablished. There does appear to be a degree of mucosaladaptation in longterm surviving rat models (Deltz E, personal communica-tion). Nevertheless, regardless of the explanation, if absorption is compro-

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mised because of rejection as well as denervation severe diarrhoea will result.Motor function is also disturbed by denervation. In denervated canine

jejunuoileum migrating motor complexes are present but are uncoordinatedand are not interrupted by feeding as they are normally. In allograftsmyoelectric activity is present and intestinal transit is three times more rapidthan autograft controls causing diarrhoea."'"' There are little data,however, on the periodicity and coordination of migrating motor com-plexes. More studies are needed to establish the effects of transplantationand denervation on motor function.An unique aspect of intestinal transplantation is that rejection reduces

cyclosporin A absorption. In small bowel resected dogs, cyclosporin Ablood concentrations after oral administration are 45-fold less than innormal dogs indicating the importance of the small intestine as a site ofabsorption. Lymphatic uptake accounts for most of the absorption from thegut as cyclosporin A concentrations are 12-fold higher in the thoracic ductthan blood.'" It is likely that lymphatic connections are reestablished four tosix weeks after transplantation as methylene blue injected into mesentericlymph nodes can be observed to pass into mesenteric lymph and host at thistime,235' however, cyclosporin A malabsorption continues up to 10 weeksafter transplantation." The explanation is not clear but could be due todiarrhoea induced by the olive oil vehicle. (Cyclosporin A is only barelysoluble in water and so is dissolved in olive oil when administered orally.)Pretreatment with olive oil ameliorates the cyclosporin A malabsorption,presumably by adaptation to the fat enriched diet..' In the clinical contextcyclosporin A will have to be administered parenterally for an extendedperiod after transplantation to ensure adequate blood concentrations.

Graft harvesting and storage

Small intestinal grafts for human transplantation will be harvested mainlyfrom cadaveric donors and a new method will be required for storage.Lillehei was unable to extend graft preservation beyond five hours bycooling to 50C.2 With graft perfusion, the administration of chlorpromazineand hyperbaric oxygen and cooling preservation could be extended up to 48hours.- Preservation for 24 hours has been achieved with hypothermicperfusion of human plasmanate.5- Other methods have, at best, providedbowel survival of only 50%. Simple hypothermic storage of canineintestine can be done by perfusing with ice cold Ringers-lactate."' All dogsreceiving allografts stored in this way for 12 hours survived beyond five days(mean 45.4 days) and 67% of dogs receiving allografts stored for 24 hourssurvived for five days (mean 22 5 days). The authors attribute the graftsurvival without the use of metabolic inhibitors to in situ flushing andintraluminal irrigation before cooling which reduces endotoxaemia anddamage from pancreatic enzymes.`3

Monitoring and diagnosis of rejection

Histology remains the gold standard for the diagnosis of rejection. Withhuman small bowel transplants it is possible to obtain daily biopsies if oneend of the graft is brought up to the skin as a cutaneous stoma.4 Thehistological features of rejection (particularly in the early stages) may be

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confined to the submucosa necessitating full thickness biopsies for accuratediagnosis. This would not be feasible on a daily basis.'

Functional absorption tests have been suggested for monitoring rejectionbut these seem too elaborate for routine use."" At present there is noaccepted blood test for rejection as there is with the kidney (creatinine),liver (LFTS) or heart (CPK). Serum N-acetyl hexoaminidase is a lysosomalacid hydrolase which is raised in association with intestinal ischaemia. ' Theassay is simple and can be completed in less than three hours.'` In apreliminary study N-acetyl hexoaminidase has been shown to rise beforegraft rejection though further validation is required.2' N-acetyl hexoamini-dase has the disadvantage that it is not a specific measure of immune activitybut more of intestinal damage. This disadvantage may be overcome byassaying procoagulant activity which is a measure of effector function ofimmunologically activated cells of the monocyte-macrophage lineage.6 In astudy in the rat procoagulant activity was found to have high specificity andsensitivity.' Procoagulant activity has also been used to monitor a case ofhuman small bowel transplantation. Procoagulant activity was low whenthere was no evidence of rejection and rose as lymphocyte infiltrationbecame apparent in mucosal biopsies.4

Small bowel transplantation in man

As many patients with the short bowel syndrome or small intestinal failurecan be successfully treated with home parenteral nutrition the indicationsfor small bowel transplantation will be limited unless its mortality andmorbidity is low. Nevertheless, home parenteral nutrition is not withoutproblems and is associated with significant morbidity, particularly inchildren.'7 Therefore the indications for small bowel transplantation wouldinclude failure of home parenteral nutrition and congenital causes of smallbowel failure such as microvillus atrophy.'"

If successful, small bowel transplantation offers the advantage of patientindependence. Home total parenteral nutrition is expensive, costing £35 000per patient year. It is likely that small bowel transplantation would becheaper (the annual cost of cyclosporin A treatment for a kidney transplantis approximately £2000).'9 In the precyclosporin era a number of transplantswere performed all of which were unsuccessful, (Table 2). The first two caseswere performed by Detterling in Boston in 1964, neither of which were fullyreported.. Both were in children; the first died 12 hours after transplanta-tion, the second lived for several weeks, after removal of the graft fornecrosis on day 2 post transplantation. The longest surviving transplantpatient was a 37 year old woman who had undergone a massive small bowelresection for Gardners syndrome.i A 1*7 m length of small intestine washarvested from her HLA-identical sister. After two weeks an episode ofrejection was successfully reversed with steroids. She was able to eat for twomonths and died 76 days after transplantation with E coli septicaemia. Graftversus host disease was suspected before the patients death but could not beproved.'To date five cases of small bowel transplantation using cyclosporin A has

been reported.4 616' The first patient was a 26 year old woman suffering fromGardners syndrome with an ileostomy who had undergone resection of herentire small bowel because of a large desmoid tumour. One year later small

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Table 2 Surt'ital of lumatn small bowel recipien.s

Date Age Caues of(lcatli Survival

1964 Infant*t Ciraft necrosis 12 h1964 Child* Graft necrosis Several wseeks1967 46 yr* Pulmonary embolism 12 h1968 36 yr* Graft necrosis 12 d1969 35 yr* Graft necrosis 26 d1970 If) yr* Graft necrosis 7 d197(0 37 yr F coli sepsis 76 d1986 26 yr§ CsA toxicity 10f d1988 >** >1 Yr§1988 it >6 mo§§1988 6 yr|| Exsanguination ( d1988 31/2 yril Lymphoproliferation 193 d1988X 17 mo¶FHaemorrliage 4d1988 9 moT Lymnphoproliferation 109 d

*Data from (3); tlncompletely reported; tGraft remosed at 7 days:§Data from 4: I1Data from 6 1 ¶Data from62; **Ricour personal communication; ttDeltz E, personal communication: §§Patient still alise withfunctioning graft at time of writing. Note: This table is necessarily incomplete as a number of transplants hasenot been reported.

bowel transplantation was undertaken because of failure of home totalparenteral nutrition. She received a graft of proximal jejunum to terminalileum and was immunosuppressed with intravenous cyclosporin A. Theblood groups of the donor and recipient were 0 and A respectively. On thefourth day she developed a brisk haemolytic anaemia caused by anti-Aantibodies derived from donor lymphocytes. On the ninth day graftrejection was suspected by a rising procoagulant activity activity andconfirmed by stomal biopsy. She died on day 10. At necropsy the cause ofdeath could not be determined with certainty but cyclosporin A neuro-toxicity was suspected; the graft itself was undergoing rejection.4

Starzl has reported a technique in which the pancreas is transplantedtogether with a cuff of duodenum.`B This method allows the whole pancreasto be transplanted and is technically easier than other methods. Althoughbetter results are now being achieved with the pancreas, the duodenumundergoes progressive inflammatory changes and a severe protein losingenteropathy ensues. It is not clear whether this is because of rejection,ischaemia or other factors. This effect can be minimised by using justsufficient duodenum around the ampulla of Vater for anastomosis to therecipient jejunum.

This technique has recently been extended to transplantation of multipleabdominal viscera. Starzl and his colleagues have used this approach to treattwo children (aged six and three and a half years) with the short gutsyndrome and liver failure secondary to total parenteral nutrition.` Theprocedure involves the transplantation en bloc of stomach, small intestine,colon, pancreas and liver. The monoclonal antibody OKT3 was givenperioperatively to suppress graft versus host disease and cyclosporin Apostoperatively for rejection. One patient died perioperatively the otherpatient lived for 193 days before dying from an Epstein-Barr virus-associated lymphoproliferative disorder. At the time of death there was noevidence of rejection or graft versus host disease. Williams and colleagueshave performed a similar procedure on two young children (17 and ninemonths) with short bowel syndrome and liver failure associated with total

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parenteral nutrition." The procedure was similar to that of Starzl except thatthe colon was not transplanted. The donor organs were irradiated with 10Gy before transplantation. The first child survived only four days howeverthe second child lived for 109 days before dying of a malignant, B-celllymphoproliferative disorder. At necropsy there was no evidence ofrejection of the small intestine or liver. These cases illustrate that it ispossible to prevent small intestinal rejection if the patient survives theperioperative period. Effective immunosuppression, however, seems to beat the cost of fatal infection or malignancy.

Conclusions and future prospects

Significant progress has been made since the pioneering experiments ofLillehei.' Indefinite graft and host survival has been achieved in rats bymany investigators and the grafts appear to provide sufficient nutrition forgrowth. There has been less success with other species, however, partlybecause of the difficulty in achieving adequate immunosuppression andimportant questions remain regarding salt and water absorption and graftmotility. The use of selective irradiation of the graft and quadruple therapy(antilymphocyte serum, cyclosporin A, azathioprine and prednisolone) maybe the only immunosuppressive regimen which will permit longterm graftsurvival. Although not yet reported, two transplants have recently beencarried out in Europe in which there has been greater than six months graftsurvival (privileged communication). In addition the European IntestinalTransplantation Study Group has been set up in Kiel to coordinate researchinto clinical intestinal transplantation. The recent congress of theTransplantation Society confirmed the considerable interest which has nowdeveloped in this field and we may be able to look forward to the day whensmall intestinal transplantation is a realistic prospect.

A J M WATSON AND) P A lEARDepts of Gastroenterology and Surgery,St Bartholomew's Hospital,West Smithfield,Lonidon ECIA 7BE.

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2 Lillehei RC, Goott B. Miller FA. The physiological rcsponsc of the small bowcl of the dogto ischaemia incuding prolonged in vitro prescrvation of the bowel with successfulreplacement and survival. Ann Surg 1959; 150: 543-60.

3 Kirkman RL. Small bowel transplantation. Transplantation 1984X; 37: 429-33.4 Cohen Z, Silverman RE, Wassef R, et al. Small intestinal transplantation using cyclosporin.

Transplantation 1986; 42: 613-2 1.5 Monchick GL. Russcll PS. Transplantation of the small bowel of the rat: Technical and

immunological considerations. Surgery 1971; 70: 693-702.6 Kirkman RL, Lear PA, Madara JL, Tilncy NL. Small intestinc transplantation in the rat-immunology and function. Surgety 1984; 96: 2X8(0.

7 Silverman R, Cohen Z, Levy G, Craig M, Cullen J, Langer B. Immune responses in smallintestinal transplantation in the rat: Correlation of histopathology and monocyteprocoagulant activity. Slurgerx, 1987; 102: 395-400.

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vcrsus-host discase by small intestinal allotransplantation in rats. Transplantation 1985; 40:343-7.

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12 Cohen Z, Macgrcgor AB, Moorc KTH, Falk RE, Langer B, Cullcn JB. Caninc small boweltransplantation: A study of thc immunological responscs. Arc/i Surgg 1976; 111: 248-53.

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Progressreport Current statusof intestinal transplantation · Gut, 1989, 30, 1771-1782 Progressreport Currentstatusofintestinal transplantation Thesuccessful developmentofclinical