Small bowel transplantation: past, present and future.

Dig Dis 1992:10:258-273

David Sigalet N.M. Kneteman

A.B.R. Thomson

Small Bowel Transplantation: _ „ _ . ,_ Past, Present and Future

Departments of Surgery and Medicine. University of Alberta. Edmonton. Canada

Abstract As techniques for immune suppression improve, the clinical utility of small bowel transplantation will increase. Recent reports of long-term (over 1 year) survival with totally enteral nutrition following bowel transplantation have increased in terest in this area and prompted the present review of the state of the art of small bowel transplantation. Background method ology is emphasized, in order to allow for more critical review of reported models, and to provide a framework for compar ing results. The functional capacity of bowel following trans plantation. and the effects of immune suppression on bowel function are reviewed in detail. Prospects for future direction in basic and clinical research are discussed.

Introduction The short bowel syndrome (SBS) that re sults from massive losses of the small bowel continues to be a difficult problem despite the common use of long-term total parenteral nu trition. (TPN). TPN is expensive (annual cost of TPN was greater than $ 65.000 per year in 1991) [1; Jones, pers. commun.], limits the life-style of the patients and their families [2], and requires long-term venous access. Long term TPN in children is even more proble matic, with increased nutrient requirements,

difficulty with patient compliance, and the risk of associated liver damage, especially in the very young infant [3]. Because of these factors the life long mortality from direct complications of long-term TPN in the pe diatric age group is 15% [4], Massive resec tions of the small bowel in children most com monly result from necrotizing enterocolitis, volvulus, and strangulated abdominal wall defects [4], In the adult population, massive bowel resection most commonly result from mesenteric vascular accidents, inflammatory bowel disease, and trauma [5], These condi-

Dr. D. Sigalet Department of Surgery Montreal Children’s Hospital 2300 Tupper Montreal. Quc. (Canada)

© 1992 S. Karger AG. Basel 0257-2753/92/ 0I05-0258S2.75/0

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Keywords Absorption Immune suppression

some of the variables of the experimental models used. Foremost of these is the interspecies variation in immune response follow ing transplantation. Inbred strains of rats have a limited rejection response, while outbred strains of large animals such as pigs and dogs demonstrate much more vigorous rejec tion. Secondly, technical aspects such as the use of isolated Thiry-Villa loops, or the route of venous drainage of the engrafted bowel (caval or portal) may affect the immune re sponse. and graft function [16]. Finally, sur vival ofa graft should not imply that it will be capable of absorbing nutrients.

Experimental Techniques and Models: The Dog Transplantation of vascularized organs was first attempted by the French surgeon Alexis Carrell. His pioneering efforts at the turn of the century demonstrated the feasibil ity of SBT [7], using isolated loops of jejunum transplanted into the neck of dogs. Because of the problems of immunosuppression, interest languished until the late 1950s. when Lillehei et al. [ 17] in Minnesota were investigating the effects of ischemia on gut organs. They found that cooling and perfusion with heparinized saline would reliably allow preservation of the small bow'd for 4 h. and that this preserved bowel could be reimplanted and would func tion indefinitely as an autograft [18]. The model they developed consisted of a one stage operation: the superior mesenteric vessels were isolated, clamped and divided, the bowel was flushed and then revascularized using the mesenteric vessels ofa similarly pre pared recipient, reestablishing bowel continu ity using end to end anastomosis of the native duodenum and ileum to the graft. They also used isolated loops of bowel placed in the neck, permitting the study of immunosup

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tions result in a stable incidence of new pa tients who require long-term nutritional sup port. In North America roughly I person/2 million population would be a candidate for bowel transplantation annually (excluding pa tients with inflammatory bowel disease) [6]. Small bowel transplantation as a treatment for SBS has been considered since the early 20th century. At that time Carrell [7] demon strated the technical feasibility of such trans plants. but commented that the rejection phe nomenon would require definitive treatment before such operations could be considered further. As new therapies for immunosup pression have developed, a flurry of experi mental studies in small bowel transplantation (SBT) has ensued, with the occasional attempt at clinical use. Until recently, large animal studies and the experience in humans have been unfavorable. However, high dose mono therapy with cyclosporin (Cs) has been shown to prevent rejection in oulbred pigs undergo ing SBT [8], Similar regimens have had lim ited success in attempts at SBT in humans [912]. SBT. with combined liver transplanta tion. has proven successful in 6 cases to date [13: Grant, pers. commun.]. It may be that combining SBT with either full or reducedsize liver transplantation may be an extra step in immunomodulation that is required to per mit SBT in man. Given these encouraging preliminary re sults. interest in SBT as a potential therapy for patients will increase. It is important to un derstand the limitations and potential prob lems that SBT as an alternate therapy to long term TPN would have. This article will ex pand upon the previous reviews of techniques for SBT [14. 15] emphasizing the experimen tal models used, the rejection process and our attempts to control it, and outline possibilities for future developments. In reviewing these studies of bowel trans plantation. it is important to bear in mind

Experimental Models: The Rat The description of heterotopic bowel transplantation in the rat by Monchik and Russell [28] in 1971 greatly facilitated study in this field. The rat model has since served as the standard for initial investigations of im munosuppression. function, and techniques. In this model, the bowel is isolated using the aorta below the SMA and the portal vein as the vascular pedicle. It is then revascularized

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in the recipient using the infrarenal vena cava, and aorta. The bowel is left as a ThirvVilla fistula with proximal and distal stomas (heterotopic graft). They also documented function of this bowel by resecting the native bowel and reestablishing gastrointestinal (GI) continuity using the transplanted segment (orthotopic graft). Kort et al. [29] described a one-stage procedure in 1973, wherein the na tive bowel was resected at the initial opera tion, with immediate reestablishment of GI continuity. However, this was plagued with a high rate of technical failures (40%). Deltz described a two-stage procedure which had improved survival (80%) [30]. At the same time. Lee and Schraut [31] described their experience with the one-stage procedure; they had improved the technique described by Kort et al. so that survival of isografts was greater than 80%. This then became the stan dard model for investigation of SBT in rats. The majority of these studies have been per formed using a portal-caval anastomosis for venous drainage of the graft. However, Kort et al. [29] demonstrated the possibility of using a portal-portal anastomosis, to provide a more physiological posttransplant state. This has been thought to confer some immu nological advantages to the graft [ 16. 29. 32]. and to establish a more physiological route for venous drainage from the graft [33]. How ever, it remains a more difficult procedure, and so has not been widely used. More recent ly, other variations have been introduced, in cluding combined small bowel and colon transplantation [34], the use of the renal pedi cle for the vascular connections [35] and the use of the superior mesenteric artery as the arterial connection [36], These models have not been shown to offer any specific advan tages over the previously described methods. Within the rat model of SBT the availabil ity of genetically defined strains of animals has greatly facilitated investigation of the im

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Bowel Transplantation


pressive agents and graft function in a con trolled fashion; rejection of the graft would not lead to the death of the animal [18]. They had no success with allografts. Other groups developed variations of these basic models, including shorter segment of bowel trans planted in or out of continuity with the gut using systemic venous drainage [ 19, 20]. Min imal survival advantage was found using the immunosuppressants available at that time, azathioprine, antilymphocytic globulin (ALG) and steroids [19-21], The dog model was used to evaluate the rejection process in detail (see next section). After the introduction of Cs in the late 1970s. the orthotopic model of bowel transplanta tion in the dog was the first used to assess its effects on SBT [22. 23]. The significant pro longation of graft survival demonstrated by Reznick et al. [22] in a landmark study was encouraging, but the overall rate of success was low; further details are discussed in the section on Immunomodulation Techniques. Continued work with the dog model of SBT is reported, but the variability in the immunological differences between animals makes interpretation of survival data with im munosuppression difficult [22. 24. 25], As well, differences in response to ischemia and reperfusion may limit its applicability to stud ies in man [26. 27],

Experimental Models: The Pig The pig is an excellent model of human bowel physiology, with a more defined genetic lineage than the dog [38. 39]. Although earlier attempts had been made [40.41 ], Ricour et al. [42] were the first to successfully perform SBT in the pig and achieve allograft survival. Sub sequent studies have shown that although high levels are required, Cs monotherapy per mits allograft survival and recipient growth following orthotopic SBT in the pig [8. 4245], The techniques used parallel those used in the dog. with both portal and caval routes of venous drainage being described. It is inter esting that in those reports where allograft survival has been described, the graft was drained via the portal circulation of the recip ient [8. 42. 44], while those reports where rejection occurred, caval drainage was em ployed [43. 45],

Immune Responses following SBT: Rejection and Graft-versus-Host Disease As noted in the introduction, the technical problems of SBT were solved by the early investigators. However, the problems of graft rejection and graft-versus-host disease (GVHD) have remained formidable obsta cles. The small bowel is unique amongst vas cularized organ transplanted: the well-being of the recipient depends upon the continued integrity of the mucosal barrier. Rejection damages this barrier early, resulting in fluid losses, impaired nutrient absorption, and pro

viding a portal of entry for enteric bacteria, in an already immunosuppressed animal [46], Further, the transplanted bowel has a large population of immunocompetent cells, which can become activated following transplanta tion into a nonidentical recipient. This leads to a phenomenon known as GVHD, initially described following bone marrow transplan tation. The factors which are necessary for sig nificant disease development were summa rized by Billingham [47]. (1) The graft must contain immunologically competent cells. (2) The host must possess important trans plantation isoantigens that are different from the donor, so that the host appears foreign to the graft. (3) The host itself must be incapable of mounting an effective immunological reac tion against the graft for some period of time, allowing the graft to initiate a reaction against the host. This was recognized by Monchik and Russell [28] in their initial studies of bowel transplantation in rats. They manipu lated the reactions between the graft and host by using inbred strains of rats: tissue from the FI progeny of a cross between two syngeneic strains [i.e. Brown Norway (BN) and Lewis (L) rats] into the parental strain allows for rec ognition of the graft as foreign (rejection or host-versus-graft), but not GVHD (LBNFl-^Lew). Conversely, transplantation of parental donor tissue into the FI hybrid (Lew-»LBN-Fl) permits only the GVH re sponse. They demonstrated that the domi nant response when both HVG and GVH reactions are possible (BN-»Lew. the twoway rejection response) is the HVG rejection: however, this may have been a matter of tim ing. since the animals did not live long enough to develop classical GVHD. They also described the histology of allo graft rejection: at day 3, there were no changes, but at day 7 an infiltrate of lympho cytes in the mucosa was apparent, with ede ma. loss of villous height and flattening of the

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munological consequences of SBT [28, 37]. The availability of monoclonal antibodies to various cell populations in the rat should pro vide further valuable information.

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In the clinical setting a reliable and sensi tive method to monitor for rejection is impor tant. The nonspecific, and patchy nature of the early stages of acute rejection noted above were found to limit the utility of suction biopsy in monitoring for rejection in the one clinical case that has been well documented [II], These factors, as well as the potential complications of repeated blind biopsy, have prompted investigators to search for alternate methods of monitoring for rejection [49. 53]. The functional capacity of bowel has been exploited as a marker by various investigators [21, 54], The best characterized of these markers is the maltose absorption test de scribed by Billiar et al. [55], This assay mea sures the ability of the bowel mucosa to split maltose into glucose and then transport this across the enterocyte into the circulation, where it is detected by monitoring serum glu cose levels. The resulting rise is diminished when rejection is at its initial stages. Similarly useful predictions of allograft rejection are documented by measuring the permeability of the bowel. The most useful test of this type uses 5lCr EDTA instilled into the lumen of the graft. The bowel is normally impervious to this compound; an increase in absorption occurs with early graft rejection [56]. This test has been used clinically and was found to cor relate well with biopsy evidence of rejection [13]. A number of other possible markers of early allograft rejection have been suggested, including leakage of polyethylene glycol across the gut wall [57], changes in the ultra structure of mucosa on biopsy [58], and alter ations of gut hormone levels [59], None of these alternative strategies have been shown to have an advantage which justifies their increased complexity. Aside from rejection, the transplant recipi ent may develop GVHD as described above. The characteristics of this disease are well

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epithelium. By day 14. there was complete loss of the normal villous architecture, and widespread inflammation and fibrosis. They noted that these findings were similar when only the rejection response was possible (LBN-F1 -»Lew) and when the two-way rejec tion and GVHD response was possible (BN-»Lew). These observations were further refined by Rosemurgy and Schraut [48] using a one-way rejection model (LBN-F1-»Lew). They further divided the rejection response into three phases: At day 6 and 7, lympho cytes and plasma cells begin to infiltrate the lamina propria. In phase II. over the 8th and 9th days, the infiltrate intensifies, and extends to the muscularis propria. There is associated shortening and blunting of the villi and scat tered epithelial sloughing. In phase III, which occurs after the 10th day. there is complete mucosal destruction, and transmural infiltra tion with lymphocytes and polymorphonu clear leukocytes. Similar changes were ob served in a two-way rejection model (Lew-» BN), and significantly, these were not altered by low dose Cs treatment (10 rng/kg/ day), given orally) [49], Previous workers, studying the rejection process in untreated dogs, had described a similar process, but with a more rapid onset at 4 days posttransplant, with complete mucosal sloughing by 7 days [17. 19.20. 50]. High dose Cs treatment alters this drastically; the mu cosa is spared, and a lymphoplasmacytic infil trate develops in the nerves and vessels of the submucosa and muscularis [51]. This occurs in a progressive fashion, with an end point of graft fibrosis and loss of function, with death of the recipient. This lesion is histologically distinct from GVHD. and does not occur in the native bowel [24, 51,52], The histopathology of acute rejection in pigs is similar, but chronic infiltration of the submucosa and muscularis have not been noted [8. 41-45],

rejection and GVHD can occur, and contin uous recipient immunosuppression is re quired. GVHD is not a lethal problem in any model of orthotopic small bowel transplanta tion where both rejection and GVHD can occur [8. 31. 51, 68]. Using this two-way model in the rat and treating the recipient with a one-week course of Cs posttransplant. GVHD causes a more mild disease than is seen with one-way models where only GVH reaction can occur. Animals develop a nonlethal transient loss of weight, with paw and ear erythema 4-6 weeks posttransplant [68]. However, using the one-way GVH model and a heterotopic graft, immunosuppression to at least 45 days is required to prevent lethal GVHD [37], In large animal models of SBT (both orthotopic, and heterotopic grafts, with and without immunosuppression [8, 44, 51]) there have been no problems which can be shown to be due to classical GVHD. although some workers have reported what they con sider to be a blunted version of GVHD in dogs [52. 72]. In the limited clinical experience reported to date this has not been a significant problem either [ 12, 13]. The immunosuppres sion that GVHD produces must also be con sidered after SBT [73]; overimmunosuppres sion can set the stage for the development of lymphoproliférative disorders [74-76]. In summary. GVHD can cause the death of the recipient after SBT in models where one-way GVHD without rejection is the only immune response possible, but in situations where a two-way response is possible, it has not been a major problem.

Immunosuppression: Experimental Studies After the description of the techniques re quired for successful SBT in dogs, the princi ple factor limiting its use in clinical practise

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described in the rat model of heterotopic SBT [28. 60-63], In one-way models where only GVHD can occur (Lew—»LBN-F1) the ani mals arc well until the 9th day posttransplant [61]. Redness and swelling of the ears, nose and paws are seen initially. They then develop dry, scaly skin, with alopecia, diarrhea, and lose weight rapidly, dying on the 14th postop erative day. The animals have marked loss of intra-abdominal fat. hcpatosplenomegaly and marked destruction of residual native bowel, with sparing of the transplanted graft. T cells must be present in the graft for GVHD to develop [37. 64, 65]. These are the relevant "immunocompetent' cells of the graft de scribed by Billingham [47], It has been dem onstrated that donor lymphocytes move rap idly out of the transplanted bowel, and can be detected in the peripheral blood of the recipi ent within hours of transplantation [13. 66. 67], By 21 days posttransplant, lymphoid cells within the bowel are mostly of recipient ori gin. with a normal proportion of T and B cells [ 66]. GVHD can be prevented by various strate gies which attack the population of immuno competent cells of the graft, such as irradia tion of the graft prior to transplantation ( 1.000 rad ex vivo [60, 61.63]). or by pretreat ment of the donor with antilymphocyte serum [61. 65. 68, 69]. Cs (15 mg/kg/day orally for 14 days) or resection of the lymph nodes of the graft mesentery will allow 71 and 100% survival, respectively [60. 70], in this same model. The requirement for immune suppression of the recipient for GVHD development has been demonstrated [71], Other strategies for preventing GVHD are discussed under Im munosuppression. It is important to recognize that the GVHD seen in this experimental one-way model in inbred rats is not necessarily rele vant in the clinical situation where two-way

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days until day 28 allowed indefinite survival of grafts in unidirectional rejection and twoway rejection and GVHD models [31.77], As noted above in the section on GHVD, a simi lar dose of Cs will also control the GVHD occurring after transplantation [60. 77], Strat egies which pretreat the donor or host to pre vent GVHD [63, 65, 69], or the use of a one way model permitting rejection only [60. 68] allows for the successful control of allograft rejection by a short course (7 days) of lower doses of Cs (5 mg/kg). However, if GVHD can occur, immunosuppression to 28 days is re quired to prevent the development of GVHD with orthotopic grafts [34], while if the graft is in a hétérotopie location, continued, higher dose Cs is required [37], Undoubtedly, GVHD plays some role in the ongoing re quirement for immunosuppression in these models. The model of bowel transplantation avail able which most closely resembles the situa tion in man is the pig. Monotherapy with Cs has allowed successful transplantation in this model [8, 42], however, high doses are re quired [43.44], Grant et al. [8] have described a protocol of intravenous Cs (15 mg/kg/day) for 10 days posttransplant, and then 30 mg/kg/day orally. Lower doses of Cs. with seg mental bowel transplants have been used, but are not as reliable [44], Combined steroid and Cs use increased the rale of infectious compli cations. and did not reduce the rate of rejec tion [8]. It is interesting to note that stopping Cs after roughly 3 months of continuous ther apy did not lead to allograft rejection [8]. The recipient may develop tolerance to the bowel allograft in a similar fashion to that described for liver transplants [78], Other drugs which control rejection (and GVHD) posttransplant arc being developed. FK-506 is a potent immunosuppressant agent which has been shown to prolong survival of heterotopic [79] and orthotopically [80] trans-

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became the immune suppression required [18]. Throughout the 1960s and 1970s, a number of different agents and manipulations were tried with little success. These were pri marily attempts at controlling rejection using immunosuppressive drugs posttransplant. The group of Preston et al. [19] found that short segments (< 2 0 cm) of jejunum would survive for up to 200 days in continuity with the GI tract if treated with prednisone and azathioprine. Taylor et al. [20] showed that azathioprine would similarly prolong the sur vival of allografts placed in the neck, to 30 days. Hardy et al. [21 ] demonstrated that antilymphocyte serum with azathioprine and prednisone allowed graft survival to 38 days. Cohen et al. [72] showed that a low dose of radiation (50 rad. given ex vivo after the bowel had been harvested) prolonged allo graft survival to 28 days. In each of these stud ies. the eventual fate of the graft was fibrosis, and loss of all apparent function. The first important breakthrough for immunomodulation was the use of Cs to control rejection posttransplant [22], The average survival in 11 dogs treated with Cs(25 mg/kg/ day. i.m. for the first 28 days, and then orally) was 91 days, while untreated controls sur vived an average of 12.5 days. However, it is important to note that only 3 dogs survived more than 60 days and 2 of these succumbed to rejection at 210 days. The importance of using parenteral Cs was demonstrated in a fol low-up study from this group where a third set of animals was given Cs orally: 7 of 10 died of acute rejection at an average of 30 days post transplant [23], The use of combined Cs and steroids has not significantly improved these results [24, 25], Once it had been shown that Cs prolonged the survival of intestinal allografts in dogs, a series of studies in the more controlled rat model appeared. It was shown that a dose of Cs of 15 mg/kg/day X 6 days, then alternate

(3/11) using low doses of Cs (10 mg/kg/day i.m.) [44], Liver transplantation has long been known to have a profound effect on rejection of other grafts [89-91], The nature of this phenome non is still poorly understood, but may related to nonself antigen processing by the trans planted liver or the release of major histocom patibility complex antigens in a soluble form, which then block cytotoxic antibodies [91], In clinical transplantation, improved survival of renal grafts following liver transplantation has been clearly documented, even in the pres ence of preformed antibodies to the graft [92], At present, there is only one experimental study which has examined the survival of bowel after combined liver small bowel trans plant [93], This study used a cluster model, which included the stomach, pancreas, and colon besides the liver and small bowel. No survival advantage w-as found for the bowel, when compared to isolated SBT. and death of the animals was due to rejection of the small bowel. More specific studies arc needed to examine the effects of combining liver and small bowel transplant, especially in larger animals.

SBT, Clinical Experience All attempts at SBT in man prior to the introduction ol'Cs were unsuccessful [94-96], The longest survivor lived for 76 days; even with an H LA-identical donor and (delayed) treatment with steroids, azathioprine and an tilymphocyte globulin, rejection and over whelming sepsis from enteric flora proved fatal [94], Following the success of SBT using Cs in dogs and pigs, a number of attempts at human transplantation using Cs have been reported [9. 10-12,97], The results have been poor. Typically, rejection is seen in graft biop

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planlcd bowel, and may be superior to Cs. 15deoxyspcrgualin has also been shown to be adequate immunosuppression for heterotopic graft survival [81]. A number of more novel immunosuppressants such as rapamycin and RS-61443 are currently being evaluated [82. 83], which may prove useful in SBT, either as single agents, or in combination with others. An alternative approach to controlling re jection is graft pretreatment. As discussed un der the section of GVHD. pretreatment can diminish the GVH responses, and reduce the long-term immune suppression required. The various strategies employed (radiation, mes enteric lymphadenectomy. A LG. and mono clonal antibody) appear to be equally effective [60.63.68-71], It is likely that their beneficial effect is mediated by reducing GVHD. rather than affecting the rejection of the graft itself. There is little evidence to support this ap proach in large animals or humans. Radiation did prolong graft survival in a dog model, without other immunosuppression [72], but was not effective in a pig model when used in conjunction with Cs [84]. Pretreatment of the donor with recipient specific blood transfu sions actually worsened the posttransplant GVHD [85], and when combined with radia tion appeared to speed up the rejection pro cess. Pretreatment of the recipient with do nor-specific transfusions was beneficial [86], An alternative approach to reducing rejec tion is to reduce the length of the graft [87, 88]. Kimura ct al. [87] have shown in the one way (rejection or GVH) rat model that with shortened transplanted segments (< 3 0 cm) GVHD is not lethal, while with longer seg ments GVHD becomes increasingly proble matic. The intensity of rejection, however, was relatively constant. This allowed survival of animals with shortened grafts using lower doses of Cs [87], This approach has been examined using a pig model, and has been partially successful with some survivors

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deficiency as described by Grant et al. [ 13], As reported by this group, a typical immunosup pression protocol for isolated liver transplan tation (OKTv Cs. AZT and prednisone, with OKTi prelreatment of the donor) has con trolled rejection and GVHD [13. Grant, pers. commun.]. As described in the previous sec tion regarding experimental immunosuppres sion, there is no direct experimental work to validate this approach; howver. the good re sults of combining liver and bowel transplan tation (6/6 patients survived with no episodes of graft threatening rejection) must be con trasted with the poor results of isolated bowel transplants (4/17 grafts functioning, with 4 deaths due to transplant complications) [9. 11, 12], Whether or not to include an associ ated liver graft from a patient with only SBS. and no primary liver pathology remains to be seen. Continued improvements in survival af ter liver transplantation (over 90% in nonemergent cases) [99] make such an approach a consideration. This would increase the de mand for liver donors: however, retransplan tation of the liver from the recipient of a com bined liver/small bowel graft (the ‘domino’ technique, as used in present heart/lung and heart transplantation) is theoretically possi ble. Patients with life-threatening complica tions of SBS should be considered for small bowel transplantation. Given the present evi dence that combined liver and small bowel grafts have improved survival, a combined graft, or a ‘cluster’ graft should be performed if possible. However the complexities of pa tient selection, and the technical and immu nological aspects of the procedure mandate that the preliminary work in this field be con centrated in the centers with clinical and ex perimental experience in this area. Ongoing evaluation of the results will permit an accu rate assessment of the risk/benefit ratio of this procedure [100].

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sies on the 4th to 10th day posttransplant. Bowel fluid losses increase tremendously. Ste roids. and ALG have diminished the rejection response [10. 11] but usually rejection has progressed necessitating graft removal around the 15th day posttransplant. Prelreatment of the graft with OKT3 antibody has not re duced the apparent immunogenicity of the bowel [11.12], Rejection has occurred despite portal drainage of the graft, but most patients requiring bowel transplantation have cither a thrombosed portal vein, or multiple previous operations, making an anastomosis to the portal circulation more difficult technically [II. 12, 15]. Cs regimens reported have in cluded intermittent and continuous infusions [9-12], with levels of Cs that are therapeutic for kidney and liver transplants (200-400 ng/ml by whole blood monoclonal R1A [98]). Toxicity of immunosuppression has been a common problem; Cs has resulted in renal toxicity [10], while combined therapy (ste roid. ALG. azathioprine) has resulted in in fectious complications [9-11]. Children re ceiving bowel as part of a graft of multiple vis cera have developed lymphoproliférative dis orders [75, 76], Clearly, these case reports demonstrate that with the current status of immune therapy, isolated small bowel trans plants in man will remain difficult to perform. If a very close HLA match is obtained, rejec tion may be easier to control; however, this has not been confirmed experimentally [94], The evolution of the ‘cluster’ or multivisccral transplantation grew out of the anatomi cal relationships of the abdominal viscera, rather than an attempt to manipulate the rejection process [75, 76]. However, the ob servation that combined immunosuppression with Cs. prednisone and ALG allowed pro longed survival of the associated bowel was important. It was logical to extend this to include a combined small bowel and liver graft for SBS with associated antilhrombin III

Lillehei et al. [17] showed in the initial investigations ofSBT using dogs that animals could survive indefinitely following auto transplantation. No specific studies of nu trient absorption were performed, but they did note that gross malabsorption of fat was evident for 2-3 weeks, but then subsided. They were also able to demonstrate regenera tion of the severed lympathics after 3 weeks [101]; this did not occur in allografted dogs not receiving immunosuppression probably because they did not live long enough [102]. Ballinger et al. [103] performed more de tailed studies of GI function following auto transplantation in dogs. They demonstrated that following transplantation of the small bowel dogs had a period of 2-3 weeks of diar rhea. weight loss and abnormal motility. Fat absorption was reduced to 40% (normal: 8890%). These changes reversed over the ensu ing months and had normalized by 6 months. A very similar pattern of changes was pro duced by denervating the bowel and dividing the lymphatics; they concluded that the func tional alterations they observed after trans plantation were from the denervation and lymphatic disruption, and that they were re versible. Using a different model of an isolated Thiry-Villa fistula of autotransplanted bowel, Sarr and Duenes [104] have demonstrated that the transplanted bowel can develop an interdigestive myoelectric complex, but that these are not normally controlled since they were not suppressed by feeding, or temporally related to the electrical activity of the intact bowel. A possible relationship between these changes in neural activity and the function of the bowel was demonstrated by Watson et al. [ 105]. They showed in the rat that heterotopic

isografts and denervated Thiry-Villa fistulas had reduced absorption of glucose, glycine, water, and sodium. Chloride was most signifi cantly affected, with net secretion in some instances. They noted that the crpyts are un der greater autonomic nervous control than the villi, and that the crypts tend to secrete chloride while the villi absorb it. They postu lated that transplantation, or the denervation process may allow for continued hypersecre tion. due to a loss of tonic inhibition of the crypts by the autonomic nervous system [106], A similar study performed in dogs failed to demonstrate such changes [107, 108]; further studies will be required to deter mine if this pattern of altered function with denervation occurs in larger animals. Short-term evaluations of the electrophvsiological parameters of the bowel (performed at 9 days posttransplant) showed that sponta neous potential difference and resistance were unaffected by transplantation itself [37. 109], Overall, these findings suggest that the trans plantation process itself, independent of re jection and ischemic injury, significantly af fects the motility, neural and transport func tions of small bowel. The foregoing studies all were performed on isolated loops of trans planted bowel. In the few studies that have been reported on orthotopic, syngeneic or autografted bowel, significant reductions in nu trient absorption have been described. This is most pronounced for fat, but was also noted for carbohydrate, up to 11 months posttrans plantation in dogs [ 11 ()].

Bowel Function: Allografts Prior to the introduction of Cs, several lim ited studies were reported examining the function of allografted bowel. Holmes et al. [54] demonstrated that transplanted bowel was capable of absorbing glucose, but that

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Function of Transplanted Bowel: Autografts and Syngeneic Grafts

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transport was similar to that seen in autografted bowel [ 108], There have been even fewer studies of the functional capabilities of orthotopic allo geneic small bowel transplants. In the rat model, allografted animals have been shown to have low serum triglycerides, and vitamin A levels, with high fecal fat losses a year fol lowing transplantation, despite apparent good health and growth [116], One detailed study of nutrient absorption and electrophvsiological function of transplanted bowel which is actually supporting the animal's nutrition has been reported [117], In this study, bowel func tion and nutrient absorption in vivo were near normal, but permeability, glucose up take. and electrophysiological parameters were greatly changed following transplanta tion. In large animal models, long-surviving pigs have been shown to have normal serum lipid profiles, normal xylose absorption, and normal levels of fecal fat [8], but actual nu trient absorption has not been quantified fur ther. These questions are important, because the length of bowel required to sustain the recipient posttransplant is a critical parame ter. Given the present trials of bowel trans plantation in humans, this requires further investigation.

Cs: Effects on Bowel Function To date, only limited studies of the effects of Cs on bowel function have been published [118, 119], However, there is evidence that Cs may affect nutrient absorption. Transplant patients of all types receiving Cs have been noted to have occasional episodes of pro found diarrhea, which is usually attributed to the olive oil vehicle of Cs. Watson et al. [105]. in their investigation of the function of dog allografts of small bowel, noted that autografted bowel in animals receiving Cs had

Sigalcl/Kneteman/Thomson



radiolabellcd glucose uptake was a poor marker of intestinal function and rejection. The leakiness of the bowel wall induced by rejection resulted in the nonspecific diffusion of glucose into the systemic circulation: how ever. the specificity of this as a marker for rejection was improved by using lower con centrations of glucose [111]. Tracer studies also demonstrated that both alio- and auto grafts in dogs would absorb short chain fatty acids (lauric) soon after transplantation (day 2). but long chain fatty acids (oleic) required regeneration of lymphatics before significant absorption occurred [112]. Ruiz et al. [113] showed that allografts could absorb ¿/-xylose, and vitamin A. albeit poorly, with maximal absorption of xylose being 40% of normals. A number of studies have investigated the function of allografts treated with Cs. Begin ning at the enterocyte level. Kirkman et al. [37] and Madura and Kirkman [109] showed that the rejection process reduces the transepithelial potential difference of the bowel, and reduces the resistance. These effects were partially, but not completely ameliorated by Cs (15 mg/kg). The function of brush border membrane enzymes (peptidases and disaccharidases) appears to be normal so long as rejection does not occur. However the studies that have been done investigating this have not been well controlled [114]. A series of investigations have been per formed examining the absorptive function of allografted loops of bowel in the rat (the het erotopic model). Glucose, glycine, and elec trolytes are all absorbed normally so long as rejection is not occurring. However, with the earliest signs of rejection morphologically, function deteriorates [105. 115]. In the dog model of heterotopically transplanted bowel, there was a persistent loss of protein from allografted bowel, which resulted in profound hypoproteinemia [108]. So far as could be determined, glucose, glycine and electrolyte

diminished glucose, alanine, and lauric acid absorption. Sigalct el al. [118] have shown that moderate doses of Cs ( 15 mg/kg/2 days, subcutaneously) do not affect weight gain or nutrient absorption in the rat. but do reduce glucose uptake in vitro. Higher doses (30 mg/kg) given orally or subcutaneously have similar effects in vitro, with reduced weight gain and nutrient absorption from the diet [119]. These changes may occur from a direct effect of Cs on the sodium-glucose cotrans porter oflhe bowel epithelial cells, as has been described in the kidney [120]. Further studies are necessary to clarify the mechanisms un derlying these observations: however, it is clear that Cs does have an effect on bowel function which may be significant when used in patients with impaired GI function. In summary, the introduction of Cs as an immunosuppressant has allowed for con trolled studies of allogeneic SBT. A variety of models have demonstrated the feasibility of

such transplants in allowing continued sur vival and growth of the recipient. Preliminary successes with human small bowel transplant have been achieved, but many questions re main regarding graft function, and the opti mal strategies for preventing rejection. As we learn more about transplant immunology we will be able to design more specific strategies, which will allow graft survival while minimiz ing toxicity to the host [121]. The present level of activity in this area will only increase as we improve our techniques.

Acknowledgements Dr. Sigalct was supported by the Alberta Heritage Foundation for Medical Research Clinical Fellowship No. 12-609, and the Merck-Frosst 1990 Canadian Association of Gastroenterology Research Fellowship. The expert secretarial assistance of S. Evans-Davics is gratefully acknowledged.

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Inflammatory bowel disease in India - Past, present and future.

Pediatric transplantation and tolerance: past, present, and future.

Fetal stem cell transplantation: Past, present, and future.

Liver transplantation for hepatocellular carcinoma: past, present and future.

Liver transplantation in Korea: past, present, and future.

Concise review: umbilical cord blood transplantation: past, present, and future.

Diaschisis: past, present, future.

Marchantia: Past, Present and Future.

Death: past, present, and future.

Integrons: past, present, and future.

Landfilling, past, present and future.

Macrophages: past, present and future.

Ribavirin: Past, present and future.

Psychosomatics: past, present and future.

Tonography: past, present, and future.

ALPPS: past, present and future.

Heparin: Past, Present, and Future.

Endocytosis: Past, present, and future.

Neurofibromatosis: past, present, and future.

Hysteroscopy: Past, Present and Future.

Behavior genetics: past, present, future.

Total laryngectomy - past, present, future.

Interstitial brachytherapy: past-present-future.

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