Rat-to-mouse small bowel xenotransplantation: A novel model for studying acute vascular and hyperacute xenograft rejection and xenogenic cell migration

The present study was undertaken to establish a rat-to-mouse vascularized s mall bowel xenotransplantation model to study acute vascular and hyperacute xenograft rejection, and xenogenic cell migration. Lewis rat small bowel g rafts were transplanted heterotopically to group 1, Balb/c mice, and group 2, Balb/c mice pre-sensitized with a donor spleen cell injection. The graft s were examined by serial pathology and flow cytometry. In group 1, acute v ascular rejection was present by the 5th post-operative day (POD). Immunohi stology showed a strong endothelial deposition of IgG, IgM and C3, associat ed with a minimal lymphocytic infiltrate. There was a vigorous cell migrati on from the recipient to the graft, in which recipient origin cells compris ed 80.1 +/- 6.9% of the graft mesenteric lymph node by POD 3. However, ther e was almost no cell migration from the graft to the recipient. The intesti nal xenografts in the group 2 showed massive hemorrhage, fibrin deposition, vascular congestion and thrombosis 60 min after transplantation. IgG and C 3 were present on the endothelium as early as 1 min after reperfusion. The vigorous humorally-mediated vascular damage and rapid elimination of donor cells seen with intestinal xenograft rejection are distinct from the usual picture of allograft rejection. Hyperacute rejection can be induced by reci pient pre-sensitization with donor spleen cells. The potential advantages o f studying xenotransplantation in this model include: (1) the wide range of immunologic reagents available for mice; (2) the opportunity to study the progression of vascular damage easily by performing serial biopsies in the same animal; and (3) the opportunity to study, in vivo, two-way cellular re sponse by examining cell trafficking in the mesenteric lymph nodes.