1005 We have reported that xenogeneic chimeras can be created in rats by bone marrow transplantation (BMTx) from hamsters. However, all recipients with successful engraftment succumbed to GVHD, which can be either cellular and/or humoral in origin. LEW rats underwent splenectomy (Spx) on day -7 and TBI of 10 Gy 3 d before BMTx. 300×106 unfractionated hamster BM cells were infused intravenously. Recipient treatment groups were divided as shown in the table. Rat recipients were observed for clinical signs of GVHD. Chimerism was detected by flow cytometry using a rat anti-hamster Ab. Sera from these chimeras were taken and anti-rat and anti-hamster antibody titers were measured by complement dependent cytotoxicity (CDC). Histopathological studies were donc with H&E. Serum transfer experiments were performed using a hamster anti-rat spleen cell Ab that was injected into the portal vein of naive rats who were sacrificed 18 h later for histological study of the liver. Results were as follows:TableGroup 1 allowed engraftment in 2/8 rats. While only one recipient developed the classical dermatitis of allogeneic GVHD, both rats had extensive infarction of the liver with focal hepatocyte necrosis in zones 1 and 2, areas that were infiltrated by polymorphonuclear leukocytes which was characteristic of humoral injury. The central vein and pericontral hepatocytes (zone 3) were not compromised, ruling out venoocclusive disease. In Group 2, 90% of the rats were engrafted; 6/9 animals showed dermatitis and 3/9 showed pure humoral injury. In Group 3, although tacrolimus prevented dermatitis, all animals developed the fatal liver injury that resulted in decreased survival when compared to Group 2. CDC test showed that xenoreactive natural antibodies (XNA) were present in both species against each other. XNA against hamster lymphocyte disappeared in BMTx recipients. However, cytotoxic antibody against rat lymphocytes had appeared in some of the rats suffering from humoral injury to the liver. This kind of injury could be reproduced in naive rats by intraportal injection of hamster anti-rat spleen cell antibody. In conclusion, xenogeneic GVHD may have a dual presentation: 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 suppressants such as tacrolimus. This humoral injury may be the result of mature hamster B lymphocytes present in the donor BM.