Demetris, AJ

Fung, JJ

Qian, S

Starzl, TE

English

PubMed

D-Scholarship@Pitt

Allogeneic Orthotopic Liver Transplantation in Mice: A Preliminary Study of Rejection Across Well-Defined MHC Barriers S. Oian, J.J. Fung, A.J. Demetris, and T.E. Starzl A mouse model of orthotopic liver transplantation (OLT) has recently been established in our center. 1 In this study, OLT was performed between allogeneic mouse strains where the major and minor MHC antigenic barriers are well defined. Survival and the histopathologic patterns of rejection were correlated with the identity of MHC barrier. MATERIALS AND METHODS Ten to twelve· week-old male inbred mice were obtained from the Jackson Laboratory, Bar Harbor, Me. Orthotopic liver transplan-tation was perfonned as described by Qian and coworkers. 1 Briefly, following cholecystectomy and cuff preparations. the liver grafts were placed orthotopically after the native liver had been removed. The suprahepatk vena cava anastomosis was com-pleted with a 10-0 running suture. The cuff technique was used for anastomosis of both the infrabepatic vena cava and portal vein. No attempt was made to reconstruct the graft arterial supply. The donor bile duct was connected to that ofthe recipient by inserting a polyethylene tube in both. Blood loss was replaced with Ringer's Lactate solution. No immunosuppressive therapy was used in this study. Animals !i\;ng less than I week postoperatively were considered as surgical deaths, and were excluded from analysis. An autopsy was perfonned on all animals sun.iving more than I week, and tissue from the liver graft was submitted for histologic analysis. In addition, wedged resection biopsies were perfonned in some long-term survivors to assess the structural integrity of the graft and to check for rejection. RESULTS lsografts All BALB/c liver isograft recipients survived for more than 100 days (see Table). Microscopically, random sampling of several healthy isograft recipients showed mild portal tract expansion, because of mild ductular proliferation in a few animals. However. no cholestasis was noted. Allografts The survival of allograft recipients is shown in Table I. Liver grafts transplanted across both class I and II major and minor MHC barriers (C3H -+ C57 BUIO: BALB/c --+ C3H; and BtOBR --+ BtoD2) survived for only short periods (median. 15 to 16days; range, 8 to 41 days). On the other hand. liver aIklgraft recipients (ATH -+ ATL) of only class II disparate grafts and that of ASW -+ ATH and BlOD2 -+ BIOHTG combinations, transplanted across H-2D locus differences. survived longer than 100 days. Histopathologic studies showed that when class I and II major and minor histocompatibility barriers were breached, a brisk form of cellular rejection .... as found. It was characterized by a portal mononuclear inflammatory infiltrate with portal vein infiltration. and damage and extension into the lobules associated with infarcts. How-ever. a more indolent form of liver rejection was seen when the H-2A and H-2E or H-2D loci were crossed. It was characterized by mild portal inflammation. which was often arranged in aggregates around bile ducts. Bile duct epithelial cell pyknosis and focal duct loss was seen in ATH -+ ATL combination. DISCUSSION This is the first attempt at defining the role of the MHC antigens in mouse liver allograft rejection: it has been previously done for skin and heart allografts.:!..J The results of this preliminary study showed that the se,'erity of liver graft rejection appeared to be related to the degree of disparity at the histocompatibility complex. A histologi-cally similar form of acute cellular rejection \I.as seen when both class I or II in combination with minor histocompat· From the Depa'tnents of Surgery and Patrology (A.J.D.). University of Pittsburgh, School of Medicine, Pittsburgh, Pennsyl--vania. Address reprint requests 10 Shiguang Qian. MD, University r:l Pittsburgh, Transplant Research Laboratory, 203 DeSoIO Street Room 8200. Pittstugh, PA 15260. Cl 1991 by Appleton & Lange 0041-13451911$3.001 + 0 TABLE 1. Survival of Uver Grafts Donor Recipin 0ispariIy BAlBIc BAl..S'c C3H C578lJl 0 K"AkE"O" + mH BAL8Ic C3H KdAdEdf)" + mH Bl0BR Bl0 D2 K" A kE"O" ATH ATL A"E-ASW ATH 0-81002 810HTG [)d Transplantation Proceedings. Vol 23, No 1 (February), 1991: pp 705-706 AcUI Survival lei) >100, >100, >100, >100, >100, 8,15,41 8, 13, 15. 15, 16 9, 10. 16, 18,18 38, >100, >100. >100, >100 16, >100, >100. >100. >100 14, >100, >100. >100 Median SuMva lei) >100 15 15 16 >100 >100 >100 705 700 ibility antigens were violated. Crossing class II loci or a single class I locus resulted in survival of longer than 100 days. However. several of these long-term survivors have developed a pattern of rejection which is histologically similar to "chronic" rejection as seen in human liver allograft recipients. 4 Further studies are currently under-way to more precisely define the role of the MHC antigens in liver allograft rejection and to determine whether an QIAN. FUNG. DEMETRIS ET AL acceptable animal model of chronic rejection can be de-veloped. REFERENCES I. Qian S. Fung 1J. Demetris AJ. el al: (submitted) 2. Counce S. Smith P. Barth R. et al: Ann Surg 144: 198. 1956 3. Corry RJ. Winn HJ. Russell PS: Transplant Proc 5:733.1973 4. Starzl TE. Demetris AJ: Curr Probl Surg 27: 1990 1 t 

Allogeneic orthotopic liver transplantation in mice: a preliminary study of rejection across well-defined MHC barriers.

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Allogeneic orthotopic liver transplantation in mice: a preliminary study of rejection across well-defined MHC barriers.

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