Langrehr, JM

Lee, KKW

Schraut, WH

Stangl, MJ

Starzl, TE

Todo, S

PubMed

D-Scholarship@Pitt

.. Successful Orthotopic Small Bowel Transplantation With Short-Term FK 506 Immunosuppressive Therapy K.K.W. Lee, M.J. Stangl, S. Todo, J.M. Langrehr, T.E. Starzl, and W.H. Schraut A LTHOUGH small bowel transplantation is the phys-iologic treatment of the short bowel syndrome, Its clinical implementation awaits development of immuno-suppressive regimens that ensure satisfactory control of graft rejection. Agents such as Cy A and corticosteroids are useful for transplantation of most other vascularized organ allografts. However, rejection of the transplanted small intestine has been found more difficult to prevent. proba-bly because the large lymphoid content of the intestine renders it more immunogenic and because the bamer function of the intestine magnifies defects in immunosup-pression that would otherwise be inconsequential in trans-plantation of other organs. Prolonged and, in some in-stances, indefinite survival of small bowel allografts using CyA has been demonstrated in several large and small animal models. However. in clinical small bowel trans-plantation. <~RDTc long-term functional graft survival has been achieved when CyA has been used as the primary immunosuppressive agent (Grant D, personal communica-tion. October 1989). demonstrating the need for other more effective immunosuppressive agents. The macrolide FK 506 has been shown to have potent in vitro and in vivo immunosuppressive activity and to delay rejection of kidney. I heart. C and Ii ver' allografts in a number of experimental animal models. The effectiveness of FK 506 has also recently been reported in clinical liver and kidney transplantatio~K" To determine whether FK 506 can effectively prevent the rejection of small bowel allografts. studies were undertaken in a rat model of small bowel transplantation. MATERIALS AND METHODS One-stuge orthotopIC small bowel trunsrlantation II a, rer1\,rmcd in the fully allogeneic I:lrown :\or\\uI ~oqlnl 10 Lel\j, IRTII) ral ,train comhination using male rah \Ieighing oetlleen 11010 and 2411 g. Animals In group I In = 6) received no ImmUnl"Uppre"llc Iherary. :\nlmab in group 2 In = 'II rec:elled FK 'Of, at a J",a),!e of ~ mgkg intramuscularlv on po,toperative days 0 through 4. For companson. ammals in group 3 In = II) receiveJ C\:\ at a d,'sage of 15 m!;Lkg intramuscularly on postoperative da\, II through 4: thiS dosage has previously heen shown in the same stram ("m"l-nation to result in slgmficantly prolonged graft and recipient survival and occasional (30',) indefinite sun'ival 1.\ hen adminis-tered on dav~ 0 through 7. and to result uniformll in indefinite survival \\ hen funher continued every other dal umil postopera-tive da) ~eKD S)ngeneic ~ievKiI to LewIS) transplanlatlOn was retformed in six animals. Transplantation was performed using standard mKfIlsurglCal techniques as previously described. After revasculanLation of the graft. the recipient's own small bowel was resected and the transplanted bowel was anastomosed into intestinal .:ontinllity. thereby rendering the recipient nutritionally dependent on the transplanted small bowel. Immunosuppression was begun imme-diately postoperatively. RESULTS In the absence of immunosuppressive therapy (group I), all graft recipients developed acute graft rejection charac-terized by the development of severe diarrhea and weight loss and culminating in a moribund state requiring death of the recipient: mean survival was 10.8 :!: 1.4 days. Gross and microscopic examination of the intestinal allografts showed changes consistent with acute fulminant rejection, with necrosis or perforation of the bowel wall associated with extensive mucosal destruction and marked cellular infiltration of the graft. With short courses of CyA therapy (group 3), graft rejection was delayed and recipient survival prolonged (mean survival. ~4KP :!: 3.9 days): however. long-term sur-vival. as seen with more prolonged courses of CyA. was not observed. After initially appearing healthy and gaining weight. these graft recipients developed progressivel¥ worsening diarrhea. leading to profound inanition and death_ Findings at autopsy were consistent with less ful-minant rejection. Filmy encapsulation of the grafts was evident. and perforation and necrosis of the grafts were infrequently seen. Hiqologic examination of the grafts demonstrated fibrosis and thickening of the bowel wall. In contrast. long-term (> f~l da~ sl functional graft sur-vival has been achieved in all rah receiving live doses of FK 506. with the exception of one rat dying from pneumo-nia on postoperative da\' 120 who had no gross or micro-",coric evidence of graft rejeLtil1n or graft-vcrsus-host disease. Among the long-term sun'i\lng rats. no clinical ,igns of graft rejection or graft-\er,us-host disease have been observed. When examined at lararotomv 6 months after transplantation. the intestinal allografts appeared grossi, normal. Full-thickness allograft biopsies demon-~trated normal architecture with no- evidence of rejection (Fig I I. Biopsies of the her and spleen were also histo-logic'llly normal. with no tindings of periportal infiltration From the Department of Surgery. University of Pittsburgh. Pittsburgh. PA. Portions of this work were presented at the International Sym-posium on Small Bowel Transplantation. London. England. Octo-ber 11·13. 1989. Address reprint requests to K.KW. Lee. MD. Department of Surgery. 497 Scaife Hall. PittSburgh. PA 15261. c 1990 by Appleton & Lange 0041-134590 $3.00 -0 78 Transplantation Proceedings. Vol 22. No 1. Suppl 1 (February), 1990: pp 78-79 t d [-lS 19 \y nd ul-"as ~re lfts \. ,UT-s of mo-I:ro-host nical have )nths cared mon-:ction histo-SMALL BOWEL TRANSPLANTATION ,., " .' .. ' .' -' ~ , . , .. . . . ' . ... . ''. \" ~ I.. • I~ r '. . -.. Fig 1. A biopsy of an intestinal allograft in a recipient treated with FK 506 on postoperative days 0-4 shows a normal histologic appearance 6 months after transplantation. Villi are well-preserved and there is no evidence of rejection. elr JI,rurtion of "picnic architecture suggestivc Dr ongoing elr prior graft-ver~us-host disease. Function of thc allografts has been clinically normal. Kcclplcnt weight gam has been (llmparahk to age-79 matched normal rats and syngeneic controls. Maltose absorption from the transplanted bowel. an indicator of the integrity of the mucosal brush border enzymes. has not differed significantly from controls. Measurements of se-rum total protein. albumin. triglyceride. and cholesterol levels. indicative of the recipient's nutritional state. have not differed significantly from the control groups. Mea-surements of serum glucose. blood urea nitrogen. creati-nine. and liver enzymes also have not differed significantly from the control groups. DISCUSSION Satisfactory prevention of graft rejection remains the pri-mary problem in small bowel transplantation. In this model of orthotopic small bowel transplantation. very short courses of FK 506 effectively controlled the rejection of intestinal allografts and prevented the development of clinical graft-versus-host disease. while preserving graft function sufficiently to permit normal recipient growth and to maintain a normal nutritional state. In contrast. equally short courses of Cy A in a dosage previously found to result in long-term survival when given in extended courses were less effective. The results of this study demonstrate that FK 506 is a highly potent immunosuppressive agent which may be more effective than Cy A and may be useful in small bowel transplantation. These findings suggest that improved success in clinical small bowel transplantation may be possible using FK 506 either alone or in combina-tion with other established immunosuppressive agents. REFERENCES 1. Ochial T. :\agata ~1K ;\akajima K. et al: Transplant Proc f~:~~K I'JX71,uppl hi : Ochial T. :\agata M. ;\akajima K. et al: Transplant Proc I'J I :X4. IlIX7 .1. T,lUll S. PelU':sta L. ChapChap P. et al: Transplant Proc I'JIH. I'JXil,uppl hi -l. Starll T. Tuuu S. Fung J. et al: Lancet 1000. fDgu~ " Lee KKW. S,hraut \\H: .-\m J Surg 1'1 _". I'JXfl 

Successful orthotopic small bowel transplantation with short-term FK 506 immunosuppressive therapy

Lee, K

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Successful orthotopic small bowel transplantation with short term FK 506 immunosuppressive therapy

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Successful orthotopic small bowel transplantation with short-term FK 506 immunosuppressive therapy

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