Hoffman, A

Langrehr, JM

Lee, KKW

Schraut, WH

Stangl, MJ

Starzl, TE

Todo, S

PubMed

Name not available

Comparison of short-term immunosuppressive therapy with cyclosporine and FK 506 in small-bowel transplantation

D-Scholarship@Pitt

-------_._ .. -•. _---------IL ;5 d e e Comparison of Short-Term Immunosuppressive Therapy with Cyclosporine and FK 506 In Small-Bowel Transplantation K.K.W. Lee, M.J. Stangl, S. Todo, J.M. Langrehr, A. Hoffman, T.E. Starzl, and W.H. Schraut SINCE small-bowel transplantation was first described experimentally in the Iale 19505, control of graft rejection has been recognized as the primary obstacle to its successful clinical implementation. Early experimental and clinical studies demonstrated that immunosuppressive regimens based upon azathioprine, antilymphocyte globu-lin, and corticosteroids were not sufficient to ensure long-term recipient and graft survival. More recently long-term functional survival of intestinal allografts has been achieved with cyclosporine in a variety of experimental animal models and has led to renewed attempts at clinical small-bowel transplantation. Allhough long-term survival has been achieved in some instances, prevention of graft rejection remains a major problem. The neutral macrolide FK 506 has been shown on a molar basis to be a more potent inhibitor of in vivo and in vitro assays of immune function than cyclosporine. I It has also been shown to significantly delay rejection of kidney, 2 heart,3 and liverA allografts in a number of different exper-imental models. A rat model was therefore used to study the effectiveness of FK 506 in prolonging the survival of intestinal allografts and to compare its effectiveness with that observed for cyclosporine. MATERIALS AND METHODS One-stage orthotopic small-bowel transplantation utilizing sys-temic venous out1low was performed in the fully allogeneic Browa Norway (BN. RTln) to Lewis (LEW. RTIl) rat strain combina-tion using standard microsurgical techniques. Animals were al-lowed water ad libitum and were restarted on nonnal laboratory diets on the second postoperative day. The general health. ap-pearance. and behavior of the animals was closely monitored. Body weight was measured at frequent regular intervals. and routine biochemical studies were periodically perfonned on serum samples. With long-tenn surviving graft recipients. graft inspec-tion and biopsy were performed via laparotomy. Autopsies and histopathologic: studies were performed on animals undergoilll rejection. Four experimental groups were prepared. In group I (N .. 6). transplantation was performed without immunosuppressive ther-apy. In group II (N = II). graft recipients rec:eived cyclosporine (IS mglka dissolved in 10% IntraIipid) on days 0 to .. administered via intramusc:uIar injection. In group III (N - 17). cyclosporine was administered in the identical dose on days 0 to 6 and thea every other day until day 28. In group IV (N = 8). recipients received FK 506 (2 mg/kg dissolved in normal saline) on days 0 to 4 administered via intramuscular injection. RESULTS Rats undergoing allogeneic transplantation without im-munosuppressive therapy (group I) all developed acute rejection with a mean survival of 10.8 :t 1.4 days. Gnifts showed signs of acute rejection, which included distention and thinning of the bowel wall and inflammation of the graft mesentery. Histologic examination revealed acute mucosal destruction and a heavy cellular infiltrate. Group II rats receiving short courses of cyclosporine therapy began losing weight on approximately day 18 and had slightly prolonged mean survival (24.3 :t 3.9 days). These grafts showed evidence of less acute rejection, with filmy encapsulation of the grafts. less prominent ceUular infil-tration of the grafts. and fibrous thickening of the bowel wall. All rats in groups III and IV receiving either FK 506 or extended courses of cyclosporine have remained alive for more than ISO days and free of signs of graft rejection. In both groups weight gain has been comparable to that observed in normal age-matched LEW rats; behavior and bowel function have appeared clinically normal. At lapa-rotomy 6 months after transplantation. allografts in groups III and IV grossly appeared normal. Histologic examina-tion of full-thickness graft biopsies appears normal with no signs of rejection; neither the liver nor the spleen show evidence of ongoing or prior graft-versus-host disease. Nutritional state as reflected by total protein, albumin. cholesterol. and triglyceride levels is normal in both groups. No evidence of cyclosporine- or FK S06-related toxicity has been observed. DISCUSSION The present study demonstrates that long-term recipient and graft survival can be achieved in this model of ortho-topic small-bowel transplantation when very short courses of FK 506 are given. Similar long-term graft and recipient survival can be achieved with extended courses of cyclo-sporine (group III). confirming an earlier report,.5 but when the same dosage of cyc1osporine is given for only five doses. long-tenn survival does not ensue as it does with FK S06. These results demonstrate that FK 506 is a potent immunosuppressive agent that may be more effective than From the Department of Surgery. University of Pittsburgh School of Medicine. Pittsburgh, Pennsylvania. Address reprint requests to K.K.W. Lee, MD, Department of Surgery, University of Pittsburgh School of Medicine. Pittsburgh, PA. iC) 1990 by Appleton & Lange 0041-134S19OJS3.00I +0 Transplantation ProceedIngs. Vol 22. No 6 (December), 1990: pp 2485-2486 2485 

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Comparison of short-term immunosuppressive therapy with cyclosporine and FK 506 in small-bowel transplantation

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