Cramer, DV

Fung, J

Kim, DG

Murase, N

Starzl, TE

Todo, S

English

PubMed

D-Scholarship@Pitt

lotO Induction of Liver, Heart, and Multivisceral Graft Acceptance With a Short Course of FK 506 N. Murase, D.-G. Kim, S. Todo. D.V. Cramer: J. Fung, and T.E. Starzl WE have been interested in the induction of whole organ graft acceptance using a brief course of intramuscular FK 506 in the early postoperative periodKfK~ We use the term graft acceptance advisedly. since the long-term surviving animals we describe in this paper are not tolerant in the classical sense. EXPERIMENTAL MODELS Our experimental models. using Lewis rat recipients. were (I) heterotopic heart transplantation according to Ono and Lindsey.3 (2) orthotopic liver transplantation with a mod-ification of Kamada and Calne's technique. 4 and (3) mul-tivisceral transplantation by our own techniques.-' LIVER TRANSPLANTATION In some respects. the orthotopic liver transplantation was the most interesting preparation. The key observations. culled from more complete studies to be reported elsewhere.b •7 are summarized in Fig I. The ACI to Lewis liver transplantation is across a major histocompatibility barrier. Yet. it is possible with a 3-day course of intramus-cular FK 506. started on the day of operation or at any time up to the fourth postoperative day. to induce permanent acceptance of the majority of the liver grafts. What are the changes in the Lewis recipient that permit this acceptance of ACI livers? The recipients. by 100 and 300 days. were not immunodepressed because they could vigorously reject skin grafts. not only from third-party (Brown Norway, donors. but also from ACl rats. Thus. acceptance of the liver grafts did not endow privilege to other tissues from the original donor strain. Whether another ACI liver would be accepted has not been deter-mined. This will require removal of a chronically accepted liver and retransplantation with a second ACI liver. f: T,...trMnt with FIC·506 ( ,.28 mg/ff~ ) .. .. 'DO CtMyl) LTX No......,.. ~1M a , ~ J 4 50 6 7 a (a.YlI H+ ~iiiiiiiiiiiiiiiiiiiiiiiiiil 'DO *iiiiiiiiiiiiiiiiiiiiiiiiiiiiiil 'DO HH 012345678 ~iiiiiiiiiiiiiiiiiiiiiiiijDal +H ~iiiiiiiiiiiiiiiiiiiiiiiiiij 'DO +H ;;;;iiiilh •.• ~l~f~O~g~D~p~S+T+D ~~======================T Fig 1. Liver transplantation. It has been shown that the lymphocyte subset popula-tion does not differ from normal samples in these animals. 7 The immunologic status of· the recipients has been as-sessed in other ways.b.7 including one-way mixed lympho-cyte reactions using mesenteric lymph node cells obtained from Lewis recipients who were bearing long-surviving liver grafts. Irradiated spleen cells from ACI or third-party Brown Norway rats were added. The Lewis lymphocytes retained a normal to weakened ability to respond to the ACI alloantigens. The potency of the reaction to the Brown Norway splenocytes was normal. In the tissue culture experiments. suppressor cells in the recipient Iym· phoid tissue could not be demonstrated. 7 Similarly. failure to affect rejection in adoptive transfer experiments. using the spleen of long-surviving liver recipients as the cell source. suggested that splenic suppressor cells either were unimportant or absent as a factor in this form of liver graft acceptance.7 It was noteworthy that the transplanted animals re-mained capable of mounting a graft-versus-host (GVH) reaction against ACI donor histocompatibility antigens in vivo. This was demonstrated with the popliteal lymph· node assay technique.7 HEART TRANSPLANTATION It was more difficult with hearts to induce graft accep-tance. and the exact details of dose timing were more critical (Fig 2)." The best time to give a 1.28 mg/kg/d intramuscular course was on postoperative days 4. 5. and 6. A further difference. compared with the liver. was that graft acceptance usually was not permanent (Fig 2). Even in the best groups. the hearts were gradually rejected. long after transplantation. Nevertheless. a second ACI heart transplanted to the neck 4 weeks after the first (intraab-domina!) one had prolongation of its survival. This was not true with third-party Brown Norway hearts. indicating that the temporary heart graft acceptance was strain-specific. 7 'Present address: Cedars-Sinai Medical Center. Los Angeles. CA 90048. From the Department of Surgery. University Health Center of Pittsburgh. UniversIty of Pittsburgh; and the Veterans Administra· tion Medical Center. Pittsburgh. PA. Supported by research grants from the Veterans Administration and Project Grant No. OK 29961 from the National Institutes 01 Health. Bethesda. MD. Address reprint requests to T.E. Starzl. MD. PhD. Department of Surgery. 3601 Filth Avenue. Falk Clinic 5C. Pittsburgh. PA 15213. © 1990 by Appleton & Lange 0041-1345190/$3.00/+0 74 Transplantation Proceedmgs. Vol 22. No 1. Suppl1 (February). 1990: pp 74-75 r . ~ I I , : I I ; I r I j i INDUCTION OF WHOLE ORGAN GRAFT ACCEPTANCE ... : T' .. 'ment with FK·!506 I 1.28 mo"'glcllly ) KTX +H 012304561(daysj 012J4S61 H+ Fig 2. Heart transplantation. However. survival was not enhanced for skin grafts from either ACI or Brown Norway donors at 4 weeks after primary heart transplantation. 7 The total number of lymphocytes in the heart grafts was reduced. but the prolongation of heart grafts could not be explained by a change in the lymphocyte subset propor-tions. which were unchanged from normaL!> Failure of splenectomy to influence the outcome. and failure to demonstrate adoptive transfers with the spleens of chronic surviving heart recipients. were construed as evidence against the existence of a suppressor cell component to this form of graft acceptance. MUL TIVISCERAL AND INTESTINAL TRANSPLANTATION Consistent chronic survival after multi visceral transplan-tation has not been achieved in animals. In a previous study in unmodified Lewis recipients of Brown Norway multivisceral grafts.s the small bowel was found to be selectively vulnerable to rejection. which killed all animals between 10 to \3 days (Table I). With 14 intramuscular doses of 0.32 or 0.64 mg/kg FK 506. we now have six animals living for 24 to 72 days (Table I), These surviving rats are gaining weight and have not yet exhibited evidence of GVH disease. These results. as well as other reports at 75 Table 1. Effect of FK 506 on MuHlvlsceral Transplantation Treatment Donor Recipient With FK 506 N Survival LEW LEW 6 >100 x 5. 7,' 72.' 81' BN LEW 5 BN LEW 0.32 mg/kg: 14 d 3 BN LEW 0.64 mg/kg; 14 d 3 AbbreVIations: LEW. Lewis: BN. Brown Norway. • Technical problem t Killed in healthy condrtlOn. 10.10.10. 10, 13 >32. >25. >24 >72. >67. >66 this meeting on intestinal transplantation. have encouraged us to believe that FK 506 may permit successful transplan-tation of the previously forbidden hollow gastrointestinal viscera. DISCUSSION With short courses of intramuscular FK 506. long-term heart. liver. multi visceral. and small bowel homograti acceptance can be induced in rats. The acceptance is long-term for liver. partial and variable for hearts. and as yet undetermined for intestinal and multivisceral gratis. Those recipients bearing functioning allografts do not have classical tolerance. Although the mechanism( s) of this type of organ acceptance have not been fully determined. the practical clinical importance of such acceptance may be considerable. REFERENCES I. Murase N. Todo S, Lee PH. et al: Transplant Proe 19:1284. 1987 2. Todo S. Ueda Y. Demetris AJ. et al: Surgery 104:239. 1988 3. Ono K. Lindsey ES: J Thorae Cardiovase Surg 7:225. 1969 4. Kamada N. Caine R: Transplantation 28:47. 1979 5. Murase N. Demetris AJ. Kim DG. et al: Surgery (in press) 6. Murase N. Kim DG. Nakajima Y. et al: Transplantation (in press) 7. Murase N, Kim DG. Todo S. et al: Transplantation lin press) I i I :1 " :1 II ! :j " .! '\ , 

Induction of liver, heart, and multivisceral graft acceptance with a short course of FK 506

Kim, D

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Induction of liver, heart and multivisceral graft acceptance with a short course of FK 506

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Induction of liver, heart, and multivisceral graft acceptance with a short course of FK 506

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