Porter, KA

Putnum, CW

Starzl, TE

English

PubMed

Putnam, CW

Name not available

Eleven and two-thirds years survival after canine orthotopic liver transplantation

D-Scholarship@Pitt

f, ! -. , , ~ ~ . 168 TRANSPLANTATION Vol. 23, No.2 explanation for the blocking activity observed in some patients. The cytotoxicity induced by normal effectors was not affected in our assay by the addition of several sera containing more than 200 mg of urea per 100 ml. There is experimental evidence that inhibition of ADCC can be produced by immune complexes (6,12,13) and by antibodies against lympho-cyte surface antigens (9) via a common mech-anism, namely competition for Fc receptors (19). Immune complexes that can inhibit ADCC are generated in mixtures of antibodies with lymphocytes (19). In kidney patients anti-HLA and anti-B cell antibodies, which are potent inhibitors of ADCC (10,18,20,23), are often present. The autologous blocking found in some of our transplant and dialysis patients may be because of the formation of immune complexes between antibodies and soluble antigens from transfusions or kidney grafts. E. DuPOm2 G. OPELZ L. A. GUSTAFSSON S. M. MIKULSKI P. I. TERASAKI Department of Surgery School of Medicine University of California Los Angeles, California 90024 LITERATURE CITED 1. Barnett IG, Maclennan ICM: 1972 Ann Rheum Dis 31: 425 2. Campbell AC, Skinner JE, Maclennan ICM, et al: 1976 Clin Exp Immunol 24: 249 2 Recipient of a Fellowship from the Belgian Fonds de la Recherche Scientifique et Medicale. 3. Cordier G, Broc:hier J, Revillard JP: 1976 Clin Immunol Immunopathol 5: 351 4. d'Apice AJF, Morris PJ: 1974 Transplantation 18: 20 5. Descamps B, Gagnon R, Debray-Sachs M, et al: 1975 Transplant Proc 7: 635 6. Dickler HB: 1974 J Exp Med 140: 508 7. Ettenger RB, Terasaki PI, Ting A, et al: 19713 ~ EngI J Med 295: 305 8. Fauci AS, Dale DC: 1975 Blood 46: 235 9. Halloran P, Schirrmeimer V, Festenstein H: 1974 J Exp Med 140: 1348 10. Hersey p. Cullen P, Maclennan ICM: 1973 Transplantation 16: 9 11. Jewell DD. Maclennan ICM: 1973 Clin Exp Im-munol 14: 219 12. Maclennan ICM: 1972 Transplant Rev 13: 67 13. Maclennan {CM: 1972 Clin Exp Immunol 10: 275 14. Perlmann P, Maclennan ICM: 1974, p 34; In Brent, L, Holborow J (eds). Progress in Immu-nology 11. North Holland Publishing Co., Am-sterdam 15. Perlmann P, Perl mann H, WigzeU N: 1972 Transplant Rev 13: 91 16. Rachelefsky GS, McConnachie PR, Ammann AJ, et al: 1975 Clin Exp Immunol 19: 1 17. Scheinberg MA, Cathcart ES: 1976 Clin Exp Immunol 24: 317 18. Schirrmacher V, Festenstein M: 1976 Trans-plant Rev 30: 140 19. Schirrmacher V, Halloran P, Ross E, et al: d75 Cell Immunol 16: 362 20. Solheim BG, Thorsby E, Moller E: 1976 J Exp Med 143: 1568 21. Terasaki PI, McClelland JD: 1964 Nature 204: 998 22. Ting A, Terasaki PI; 1974 Cancer Res 34: 2694 23. Trinchieri G, deTiarchi M, Mayr W, et al; 1973 Transplant Proc 4; 1631 Received 15 September 1976. Accepted 22 October 1976. ELEVEN AND TWO-TInRDS YEARS' SURVIVAL AITER CANINE ORTHOTOPIC LNER TRANSPLANTATION' The first animal to survive chronically after orthotopic liver transplantation was a mongrel dog that received a hepatic homograft on March 23, 1964. The recipient was estimated to be 2 1 This work was supported by Research Projects MRIS 8118-01 and 7227-01 from the Veterans Ad-ministration and by Grants AM-17260 and AM-0772 from the National Institutes of Health. years old. The unrelated mongrel donor was of a different color and appearance. ImmunosUP-pression was with azathioprine which was stopped after 120 days. Treatment was never resumed. The transplanted liver was bi0;?sied on several occasions during the next 5 :K~ars and was always thought to be normal (2,4). After a brief illness, the dog died on the night of December 8, 1975, at the estimated age of 14 years and after a total survival post-transplan-I , I February, 1977 tation of 11 years a appeared to be well c before death. For most of the JXI dog had normal lh-e: However, during the there was intermitte elevation of the serurr few weeks before de, was increased to 2.5 r At autopsy,. the liv weighed 2.7% of the 12.5 kg. The liver h, and was harcl. There . collaterals suggestin The reconstructed w the liver and the port. barely detectable site rialize the liver, a St continuity with the anastomosed to the i Although the hepati, mal, the homograft , tied atherosclerosis. ALKALINE PH (Bodonsky I..; (S F Bll (mg AZA1 . FIGURE 1. Serum ~fver transplantation ~ndividual determina Ind' 'f lcate 1 SD above a ~ normal, were reper Y the horizontal brc. Vol. 23, NO.2 .j JP: 1976 Clin ransplantation Sachs M, et II: 508 \, et al: 1976 N ~S: 235 restenstein Ii: an ICM: 1973 3 Clin Exp lin. It Rev 13: 67 ? Immunol 10: 1974, P 347 III ?TY!SS in Immu. 'hing Co., Am. gzell N: 1972 PR, Ammann 10119: 1 976 Clin Exp : 1976 Trans-5 E, et al: 1975 E: 1976 J Exp ;4 Nature 204: Res 34: 2694 W, et al: 1973 OTOPIC donor was of Immunosu»' which was t was never vas biopsied lext 5 years -nal (2,4). on the night ted age of I. ;t-transplan-I I I , . I I I February,1977 BRIEF COMMUNICATIONS 169 tation of 11 years and 81/2 months. He had appeared to be well clinically until 1 or 2 days before death. Fo: most of the post-transplant period, the dog had normal liver function tests (Fig. 1). However, during the last 12 months of life, there was intermittent transaminasemia and elevation of the serum alkaline phosphatase. A few weeks before death, the serum bilirubin was increased to 2.5 mgllOO ml. At autopsy, the liver was of normal size. It weighed 2.7% of the body weight, which was 12.5 kg. The liver had a nutmeg appearance and was hard. There were no abnormal venous coli", :rals suggestive of portal hypertension. The reconstructed vena cava above and below the liver and the portal vein were normal, with barely detectable sites of anastomosis. To arte-rialize the liver, a segment of donor aorta in continuity with the hepatic artery had been anastomosed to the infrarenal recipient aorta. Although the hepatic artery was grossly nor-mal, the homograft aorta had extensive calci-fied atherosclerosis. ORTHOTOPIC LIVER TRANSPLANT 3-23-64 ... 40 ALKALINE PHOSPHATASE 30 (Bodonsky Units) 20 10 Biliary reconstruction was with cholecysto-duodenostomy after ligation of the distal com-mon duct. The gallbladder, the common duct, and all the intrahepatic ducts were filled with small or medium-sized stonel" ~::D -:lse with a soft, variably colored green to 01 ange sludge. The stone analysis showed predominantly bili-rubin with only trace amounts ;)f cholesterol and bile salts. Other significant findings at autopsy were pulmonary edema, coronary artery disease, and left ventricular hypertrophy. Th3 immedi-ate cause of death was congestive heart failure. Histopathological evaluation of the homo-graft revealed portal fibrosis and linking of the enlarged portal tracts to one another by connec-tive tissue septa (Fig. 2). There was concentric scarring around the interlobular and septal bile ducts and proliferation of ductules at the mar-gins of the portal tracts. Many of the larger bile ducts were dilated and filled with inspissated bile. The epithelium of the affected ducts was ulcerated and there were aggregates of small lymphocytes, plasma cells, and macrophages • OlEO 12-8-75 ... PMg+-~~~~~i-i-i-i-i-4-gigi-i----~·-__ -__ +-SGOT (S,F Units) BILIRUBIN (mll/IOO mil AZATHIOPRINE 100 80 • :~ 1~~!lb-+ I-I-!-I-j-I- L-;---Mi---------~----~~~~----______ ~ 3 2 I ----------- __ e_ e_ e_._ ...... - e_e.e_ M~~~~~~~~~--------------4-012.1456,234567 B 91011 /2 .145678 MONTHS YEARS MONTHS TIME , FIGURE 1. Serum biochemistries during the 11 years and 81/2 months of survival following orthotopic hver transplantation on March 23, 1964. The values recorded during the last 8 months of life represent Individual determinations. All other points on the graph are mean values for each time period; the brackets ~dicate 1 SD above and below the mean. Beginning with the 7th year of follow-up, bilirubin concentrations, unormal, were reported as ... 1.2 mg.%. The upper limit of normal in our laboratory for each test is marked by the horizontal broken line. , ! I, .... ~ .J -'J ;J . ( . , · ". · · r1 'i I I 170 TRANSPLANTATION Vol. 23, No.2 FIGURE 2. Canine hepatic homograft at autopsy 11 years and 81/2 months after transplantation. Fibrous septa link enlarged portal tracts (arrows). There is proliferation of bile ductules and concentric scarring and mononuclear cell infiltration around the bile ducts. Hematoxylin and eosin, x 100. around the ducts. A few bile "thrombi" were present in the centrilobular part of the bile canaliculi. Liver cell damage was slight. The arteries and arterioles were normal. These changes are typical of chronic large duct biliary obstruction. There was no evidence of rejection. The thymus, mesenteric and mediastinal lymph nodes, and Peyer's patches appeared to be normal. The spleen had been removed at the time of transplantation. Examination of the rest of the tissues con-firmed the narrowing of the coronary arteries by atherosclerosis, the hypertrophied left ven-tricle, and the congestion and edema of the lungs. The atherosclerosis in the homograft aorta was severe, with large patches of calcifi-cation and bone formation with marrow. By contrast the recipient aorta was normal. The kidneys were normal. Thus, although the dog died primarily of car-diovascular manifestations of old age, a poten-tially lethal biliary duct complication was pres-ent which would have independently caused death within a short time. A partial obstruction of the cystic duct was apparently the main cause of the extensive stone and sludge forma-tion that had affected both the extrahepatic and intrahepatic ducts. The intrahepatic biliary plugging with inspissated bile casts was similar to a syndrome that we (1,3) and Waldram et al. (5) have noted in humans. Such findings in animals and man point again to the recon-structed biliary duct system as the Achilles' heel of liver transplantation. The completely normal findings in this dog's lymphoid system were of interest, since no im-munosuppression whatever had been given for 11112 years. THOMAS E. STARZL KENDRICK A. PORTER CHARLES W. PUTNUM Veterans Administration Hospital Department of Surgery University of Colorado Medical Center Denver, Colorado 80262 Department of Pathology St. Mary's Hospital Medical School London, England , j Febroory,1977 LITE 1. Martineau B, f Surgery 72: 6 2. Starzl TE, Mar Surgery 58: J 3. Stanl TE, Pon gery (in pres THE CELLl.' There have be rejection and the nomenom (9, 15 manifestation o! known to be the, their transformat chemically acti V! has also been derr trate that occurs to skin allograft.< that the high bU! these cells could US). It was original antibody respon, much delayed, rE tion of the graft. evidence that hl significant role i ever, antibodies" SOOn after grafti and have been sr. titer at about thE tion is complete I Aigire and his c( moral antibodies imPOrtant role i despite the fact t high titers of spe seem that, althoL ~nografts is prim lcally competent ~lay an ancillary Ing humoral faete destruction of sc I1nsatisfactory, at far as the majori' gt.aftg are concel by a cellular rath Since the initi lnUS-dependent I I SuPPOrted in r GM-02236.02 from: . . '.23.No.2 ion. Fibrous ;carring and ·dge forma-nepatic and ltiC biliary .... as similar Valdram et findings in the recon-le Achilles' n this dog's ;ince no im-~n given for , Center :hool , I f , I , • February. 1977 BRIEF COMMUNICATIONS 171 LITERATURE CITED 1. Martineau B, Porter KA. Corman J. et al: 1972 Surgery 72: 604 2 Stanl TE, Marchioro TL. Porter KA. et al: 1965 Surgery 58: 131 3. Stanl TE. Porter KA. Putnam CW, et al: Sur-gery (in press) 4. Starzl TE. Putnam CW: 1969 Experience in he-patic transplantation. W B Saunders Co. Phil-adelphia 5. Waldram R, Williams R. CaIne RY: 1975 Trans-plantation 19: 382 Received 7 October 1976. Accepted 1 November 1976. THE CELLULAR INFILTRATE IN CARDIAC ALLOGRAFT REJECTION IN MICE' There have been many studies of allograft rejection and the cellular response to this phe-no"wnom (9, ~RI 16). The main cytological mal.ifestation of the allograft response is known to be the activation of lymphocytes and their transformation into blasts (4,20). A histo-chemically active population of macrophages has also been demonstrated in the cellular infil-trate that occurs as an immunological response to skin allografts in mice and it was thought that the high build-up of lysosomal activity in these cells could be responsible for rejection (18). 11 was originally thought that the humoral antibody response to an allograft was very much delayed, reaching its peak after destruc-tion of the graft. This was cited as part of the evidence that humoral factors do not play a significant role in the rejection process. How-ever, antibodies are demonstrable in the serum soon after grafting from the 4th day onward and have been shown to reach their maximum titer at about the same time the graft destruc-tiol' 'c complete (2). The classic expenments of Algire and his colleagues () indicate that hu-moral antibodies alone probably do not play an important role in solid allograft destruction, despite the fact that such hosts produce fairly high titers of specific H-2 antibodies. It would seem that, although destruction of solid tissue allografts is primarily mediated by immunolog-ically competent cells, humoral factors may play an ancillary role. The evidence incriminat-ing 1;:: moral factors as major contributors to the de~:l uction of solid tissue allografts remains unsatisfactory, and the current view is that, as far as the majority of types of solid tissue allo-grafts are concerned, destruction is mediated by a cellular rather than a humoral immunity. Since the initial observations that the thy-mUs-dependent (T) line of lymphocytes was I Supported in part by Grants HL 13108-06 and d~!·MOOPS-MO from the National Institutes of Health. necessary for graft rejection (17), several T cell as well as non-T cell candidates for effector cells in cell-mediated immunity have been proposed. Antibody-dependent cell-mediated lysis of tar-get cells in vitro may be carried out by a subset of B cells and/or surface adherent cells belong-ing to the monocyte-Macrophage-reticulum cell line (5, 6, 7,19,22). In terms of in vivo graft rejection, however, it is likely that the effector cell population must come into contact with graft tissue and therefore be represented in the immune cellular infiltrate. Since it is now pos-sible to identify lymphocytes in frozen tissue sections which bear surface antigens character-istic of the T cell and B cell (Ig bearing) lines (8,10-13), we initiated a series of experiments to identify the cells involved in the immune cell infiltrates to cardiac allografts in mice. The purpose of this study is 3-fold: to attempt to establish the type of cells present in the graft-host rejection site, the time relationships of the appearance of these cells, and fmally to fmd out whether the type of cell changes as the graft becomes established. Mice Three groups of mice were used. A. Allogeneic group. Donor hearts were from newly born (12 to 24 hr) BALB/cJ mice. The recipients were healthy adult C57BL/6J mice. B. Preimmunized group. This group was similar to group A except that adult C57BL/6J recipients were preimmunized wiih 1 x 107 washed BALB/cJ spleen cells injected i. p. 10 days prior to transplant. C. Syngeneic group. Both the newly born donor hearts and the recipient adult mice were of the BALB/cJ strain. Antisera A. Anti-T. Rabbit anti-BALB thymus serum was prepared as previously described () 2). This i \. I' f : I \. 1 . I I :w ;. ~ .. : .'1 , .. .. • # i : _. " -~ r: · ~K · .. , '. · .. .. I I :1 ;l .. :J .. 

Eleven and two thirds years' survival after canine orthotopic liver transplantation

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Eleven and two thirds years' survival after canine orthotopic liver transplantation

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