RS-61443 PREVENTS MICROVASCULAR REJECTION OF PANCREATIC-ISLET XENOGRAFTS

Inadequate vascularization and microvascular rejection are major limit ations for successful free pancreatic islet xenotransplantation, Commo nly used immunosuppressive regimens may alter the process of vasculari zation, and are ineffective at preventing graft rejection, In this stu dy, we investigated, in vivo, the action of the new immunosuppressive agent RS-61443 on angiogenesis and microvascular rejection of rat panc reatic islets after xenogeneic transplantation into the dorsal skinfol d of Syrian golden hamsters, In nontreated xenografts, intravital fluo rescence microscopy demonstrated a regular process of vascularization during the first 6 days after transplantation. On days 10, 14, and 20, graft rejection was observed, characterized by microvascular leukocyt e accumulation (244+/-59 mm(-2)), loss of endothelial integrity, and c apillary perfusion failure, Islet xenografts of animals treated with R S-61443 (40 mg/kg per day) demonstrated inhibition of vascularization with the consequence of a markedly reduced size of the grafts' microva scular network (0.05 +/- 0.007 mm(2)), when compared with that of nont reated xenografts (0.09 +/- 0.015 mm(2); P<0.05). However, treatment w ith RS-61443 effectively prevented microvascular graft rejection, as i ndicated by the absence of leukocyte accumulation (24+/-9 mm(-2); P < 0.01), endothelial damage, and nutritive perfusion failure, Thus, RS-6 1443 treatment may represent an interesting approach for improving the outcome of pancreatic islet xenotransplantation.