Hamster-to-rat bone marrow xenotransplantation and humoral graft vs. host disease

Bone marrow transplantation (BMT) may induce tolerance across xenogeneic ba rriers. We have established a xenogeneic BMT model where hamster BM is tran splanted into splenectomized LEW rat recipients resulting in high levels of engraftment. Unfortunately, graft vs. host disease (GVHD) with severe derm atitis developed in all rat recipients. We were successful in treating or p reventing the dermatitis of this xenogeneic GVHD by the use of the T-cell s uppressant tacrolimus. However, this compound did not prevent the developme nt of a fatal liver injury in the rat recipients. This study was designed t o elucidate the pathogenesis of this liver injury appearing in T-cell suppr essed rat recipients of hamster BM. Splenectomized and irradiated (10 Gy) LEW rats received 300x10(6) unfractio nated hamster BM cells. These BMT recipients were divided in 3 groups: Grou p I recipients (n=8) did not receive further immunosuppression. Group II an imals (n=10) received tacrolimus 1 mg/kg/d for 7 d. Group III recipients (n =6) were given the same daily dose of tacrolimus on a long-term basis. Chim erism was detected by flow cytometry. Cytotoxicity of recipient's sera agai nst rat and hamster lymph node cells was measured by complement-dependent c ytotoxicity (CDC) test. Immunofluorescence was used to detect hamster antir at 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 (n= 10), 9/10 rat recipients engrafted (90%) and survival was increased to a me dian of 53.7 days. However, these surviving recipients developed fatal GVHD not different from that observed in Group I recipients. All animals in Gro up III (n=6) engrafted and did not show the characteristic dermatitis of GV HD. Their survival, however, was shortened to a median of 30.3 d by a sever e liver injury. This injury was characterized by hepatocyte necrosis in zon es 1 and 2 with polymorphonuclear (PMN) cell infiltration. Deposits of hams ter immunoglobulins were present around the necrotic areas and in the porta l veins. Moreover, antirat antibodies appeared in the circulation. These an tibodies were sensitive to dithiothreitol (DTT) treatment indicating that t hey were of the IgM class. This study shows that xenogeneic GVHD may have a dual presentation in the h amster-to-rat model: a classical cellular GVHD not distinct to the allogene ic one and a humoral GVHD affecting solely the recipient liver. The degree of humoral injury is potentiated by T-cell suppression.