Demetris, AJ

Fujisaki, S

Furuya, T

Murase, N

Nakamura, K

Starzl, TE

Tanabe, M

Todo, S

English

PubMed

Name not available

Graft-versus-host disease in fully allogeneic small bowel transplantation: Incidence of the disease and strain combinations

D-Scholarship@Pitt

, i 'I :; Graft-Versus-Host Disease in Fully Allogeneic Small Bowel Transplantation: Incidence of the Disease and Strain Combinations M. Tanabe, N. Murase, A.J. Demetris, K. Nakamura, T. Furuya, S. Fujisaki, S. Todo, and T.E. Starzl WE PREVIOUSLY reported that fully allogeneic small bowel transplantation (SB11 from Lewis (LEW) to Brown Norway (BN) rats caused fatal graft-versus-host disease (GVHD) when the recipients were treated with a short course of FK 506. 1 Graft-versus-host disease has also been well described after parent to F 1 hybrid SBT,2 in which immune reaction between donor and recipient is completely unbalanced. This study was carried out to determine if certain strains or combinations were more or less susceptible to GVHD, similar to the parent to F I hybrid combination. MATERIALS AND METHODS Animals Inbred male LEW (RT·I~, BN (RT-l"), ACI (RT-IQ), and PVG (RT-/1 rats, weighing 200 to 300 g, purchased from Harlan Sprague-Dawley (Indianapolis, lnd), were used as donors or recipients. Mixed Lymphocyte Reaction One-way mixed lymphocyte reaction (MLR) was performed using mesenteric lymph node cells as described before.J Lymphocytes from normal LEW, BN, ACI, and PVG rats were used as responders and/or stimulators to examine in vivo proliferation activity. Operation Orthotopic SBT with portocaval drainage was performed by removing the entire donor small intestine from the ligament of Treitz to the ileocecal valve and by anastomosing end-to-side between graft aorta and recipient infrarenai aorta and graft porta! vein and recipient vena cava. The recipient intestine was removed and intestinal continuity was restored by proxima! and distal intestinal end-to-end anastomoses. The orthotopic liver transplan-tation (OLT) was carried out according to Kamada's method! Arteria! reconstruction was omitted. Body weight, activity, skin color, and defecation were checked daily for the first 14 days, foUowed by twice or more per week until day 150. Experimental Design Six strain combinations, including ACI-LEW, ACI-BN. ACI-PVG. LEW-BN, LEW-PVG, and BN-PVG were examined. In each combination. OLT was performed in both directions. and animal survival was compared. Because of the tolerogenic nature of the liver graft, some liver grafts were expected to survive indefinitely without immunosuppression.5 Any discrepant graft and anima! survival between the grafting directions suggests an immunologic imbalance between the strain combination. SBT with or without immunosuppression was also performed for each strain combination in both directions to investigate the development of GVHD. For immunosuppression. intramuscular FK S06 dissolved in HCO-60 and o-mannitol carrier solvent (gift from Fujisawa Pharmaceutical Co. Ltd. Osaka, Japan) was used with a daily dose of 0.64 mglkg for 14 days. starting on the day of operation. Statistical Analysis Survival days were analyzed for statistical significance by the generalized Wilcoxon test. RESULTS Mixed Lymphocyte Reaction As expected, lymphocytes from all strains used as re-sponders proliferated more in the presence of allogeneic than syngeneic stimulator cells. Proliferative counts in recipients who developed GVHO (eg, BN responder and LEW stimulator) were not significantly different from those of the reversed responder-stimulator direction cases (Table I). Animal Survival After OL T In ACI-BN and ACI-LEW combinations, animal survival after OLT was significantly influenced by the direction of grafting. In both combinations. ACI liver was acutely rejected by BN or LEW recipients with a median survival of 10 to 11 days. However. ACI recipients of BN or LEW liver grafts survived for more than 90 days. The direction of the grafting had less effect on survival in the BN-LEW and BN-PVG combinations. The results of PVG-ACI and PVG-LEW combinations are still being evaluated, al-though the direction of grafting did not significantly affect survival in these combinations. Animal Survival After SST In all 12 combinations. untreated recipients died of rejec-tion (pathologically confirmed) with median survival be· tween 5 and 14 days. Untreated BN recipients ofPVG or LEW grafts and one PVG recipient with a BN graft showed a transient skin rash, which resolved when the grafts were rejected. Two-week treatment with FK 506 effectively prolonged survival for more than 100 days in From the Pittsburgh Transplant Institute. Department of Surgery (M,T., N.M., T.F., S.F., S.T., T.E.S.) and Pathology (A.J.D., K.N.), University ot Pittsburgh, Pittsburgh. Pennsylvania. Address reprint requests to Thomas E. StarzI, MD, PhD, De-partment of Surgefy. 3601 Fifth Avenue, 5C Falk Clinic, Pittsburgh, PA 15213. CJ 1993 by Appleton & Lange 0041·1345J93i$3.00I+O 1214 Transplantation Proceedings, Vol 25, No 1 (February), 1993: pp 1214-1215 , I i I i I j f , I GVHD IN FULLY ALLOGENEIC SBT Table 1. Animal Survival After Orthotopic Uver or Small BOMII Tran~i.ntlltlon Median Animal Sury'lVal Davs In) SeT OLTNo Donor Recipient Treatment No Treatment FK Treatment ACI BN 11 (5)· 8.5(4) 91 (5) BN ACI >100 (4) 14 (4) >150 (4) ACI LEW 10 (9)· S (4) >111 (3) LEW ACI >89.5(4) 8.5 (4) >150 (4) LEW BN 30.5 (6)· 12 (3)t 29 (7)* BN LEW >100 (6) 10.5 (6) >150 (10) PVG BN 25 (3)· 12 (5)t 42 (7)* BN PVG >50 (4) 11 (3) >150 (7) PVG LEW 30 (3) 13 (3) >150 (4) LEW PVG >50 (3) 14 (5) >150 (4) ACI PVG >50 (6) 8 (3) >150 (3) PVG ACI >50(3) 11 (3) >150 (4) 'SIraln combinations which show IIgnificantfy different animal SUrvIVal rates belWMn It1e directions of InInsplanlabon. t Animals whICh died of falal GVHD. *Animals showed t8mjX)l8ly GVHD before grail rejecllon. §ene oflhree arumals showed tempot8JY GVHD. most of the combinations. except when BN rats were used as recipients. ACI grafts transplanted into BN recipients developed chronic rejection with median survival of 91 days. On the other hand. when BN recipients received a LEW or PVG graft. the recipients developed a skin rash, hyperkeratosis. hair loss. and weight loss after cessation of FK 506. and eventually died with median survival of 29 and 42 days, respectively. DISCUSSION GVHD after small bowel transplantation has been well documented, when immune reaction between the host and the recipient was completely unbalanced as seen in unidi-rectional transplantation from parent to F 1 hybrid strains.2 In this study. moderate immunologic imbalance was iden-tified in certain rat strain combinations. such as ACI-BN 1215 and ACI-LEW, in which the liver graft was acutely re-jected. but only in one grafting direction. In the reverse order, the graft was accepted. When a small bowel graft was used in these relatively unbalanced combinations. GVHD was not observed either with or without FK 506 immunosuppression. In 12 different fully allogeneic small bowel transplantations examined here, occurrence of GVHD was seen only in BN recipient of LEW or PVG grafts under FK 506. Similar fatal GVHD. described by DeBruin et al, was also observed in a BN recipient of WAG (RT-I") graft under CyA.6 These findings suggest that lethal GVHD seen after small bowel transplantation under immunosuppression is somewhat unique to the BN strain. It is worth noting that the BN strain is also susceptible to chronically induced autoimmunity when the rats are fed mercuric chloride or golden sodium.7 It may be purely coincidental. but the monoclonal antibody, L-21-6. which recognizes the invariant chain of the class II MHC molecule in rats. reacts with all rat strains tested (LEW, ACI, PVG, F334, and WfF) except BN (unpublished observation). Since the invariant chain is thought to pro-tect the class II molecule from endogenous antigen bind-ing, the difference detected by this antibody may be of functional significance. REFERENCES 1. Murase N, Demetris AI. Woo J. et a1: Transplant Proc 23:3246. 1991 2. Monochlk GJ. Russel PS: Surgery 70:693. 1971 3. Murase N. Demetris AJ, Woo 1. et a1: Transplantation (in press) 4. Kamada N, Caine RY: Transplantation 28:47, 1979 5. Kamada N: Experimental Liver Transplantation. Boca Ra-ton, FL. CRC Press. 1988 6. Saat RE. De Bruin RWF. Heineman E. et a1: Transplanta-tion 50:374. 1990 7. Guery J-C. Toumade H. PeUetier L. et al: Eur J Immunol 20: 101, 1990 

Graft-versus-host disease in fully allogeneic small bowel transplantation: incidence of the disease and strain combinations.

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Graft-versus-host disease in fully allogeneic small bowel transplantation: incidence of the disease and strain combinations.

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