Hamster-to-rat bone marrow xenotransplantation and humoral graft vs. host disease Miki T, Lee YH, Tandin A, Subbotin V, Goller A, Kovscek A, Fung JJ, Valdivia LA. Hamster-to-rat bone marrow xenotransplantation and humoral graft vs. host disease. Xenotransplantation 2001; 8: 213±221. # Munksgaard, Copenhagen Abstract: Bone marrow transplantation (BMT) may induce tolerance across xenogeneic barriers. We have established a xenogeneic BMT model where hamster BM is transplanted into splenectomized LEW rat recipients resulting in high levels of engraftment. Unfortunately, graft vs. host disease (GVHD) with severe dermatitis developed in all rat recipients. We were successful in treating or preventing the dermatitis of this xenogeneic GVHD by the use of the T-cell suppressant tacrolimus. However, this compound did not prevent the development of a fatal liver injury in the rat recipients. This study was designed to elucidate the pathogenesis of this liver injury appearing in T-cell suppressed rat recipients of hamster BM. Splenectomized and irradiated (10 Gy) LEW rats received 300310 6 unfractionated hamster BM cells. These BMT recipients were divided in 3 groups: Group I recipients (n58) did not receive further immunosuppression. Group II animals (n510) received tacrolimus 1 mg/kg/d for 7 d. Group III recipients (n56) were given the same daily dose of tacrolimus on a long-term basis. Chimerism was detected by ¯ow cytometry. Cytotoxicity of recipient's sera against rat and hamster lymph node cells was measured by complement-dependent cytotoxicity (CDC) test. Immuno¯uorescence was used to detect hamster antirat antibodies on several recipient organs. In Group I, 2 out of 8 animals engrafted (25%) and survived for a median of 21 d showing the severe dermatitis characteristic of GVHD. In group II (n510), 9/10 rat recipients engrafted (90%) and survival was increased to a median of 53.7 days. However, these surviving recipients developed fatal GVHD not different from that observed in Group I recipients. All animals in Group III (n56) engrafted and did not show the characteristic dermatitis of GVHD. Their survival, however, was shortened to a median of 30.3 d by a severe liver injury. This injury was characterized by hepatocyte necrosis in zones 1 and 2 with polymorphonuclear (PMN) cell in®ltration. Deposits of hamster immunoglobulins were present around the necrotic areas and in the portal veins. Moreover, antirat antibodies appeared in the circulation. These antibodies were sensitive to dithiothreitol (DTT) treatment indicating that they were of the IgM class. This study shows that xenogeneic GVHD may have a dual presentation in the hamster-to-rat model: a classical cellular GVHD not distinct to the allogeneic one and a humoral GVHD affecting solely the recipient liver. The degree of humoral injury is potentiated by T-cell suppression. Toshio Miki, 1 Yi-Horng Lee, 1 Alessia Tandin, 1 Vladimir Subbotin, 2 April Goller, 1 Annastasia Kovscek, 1 John J. Fung 1 and Luis A. Valdivia 1 1 Thomas E. Starzl Transplantation Institute and the Departments of Surgery and 2 Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Key words: bone marrow transplantation ± graft vs. host disease ± hamster ± rat ± xenotransplantation Address reprint requests to Luis A. Valdivia, Thomas E. Starzl Transplantation Institute, E-1546 Biomedical Science Tower, 200 Lothrop Street Pittsburgh, PA 15261, USA (E-mail: valdivia+@pitt.edu) Received 2 October 2000; Accepted 30 December 2000 Xenotransplantation 2001: 8: 213±221 Printed in UK. All rights reserved Copyright # Munksgaard 2001 XENOTRANSPLANTATION ISSN 0908±665X 213