BACKGROUND: One of the main obstacles to clinical islet xenotransplantation is the injurious instant blood-mediated inflammatory reaction (IBMIR) that causes rapid binding of platelets to the islet surface, activation of the coagulation and complement systems, and leukocyte infiltration of the islets when the islets are exposed to blood. METHODS: This study assesses the effect of low molecular weight dextran sulfate (LMW-DS) on IBMIR induced by porcine islets in an in vitro tubing loop assay using human blood and in an in vivo model using diabetic athymic mice. RESULTS: In vitro experiments demonstrated that platelet consumption, coagulation, and complement activation were already reduced in the presence of LMW-DS at 0.01 mg/mL, and that at 0.1 mg/mL, LMW-DS prevented IBMIR. Immunohistochemical investigation showed that the leukocyte infiltration was abrogated at the highest dose. In vivo experiments showed that the transplanted pig islets survived for a significantly longer period in recipients treated with LMW-DS, and morphologic examination of transplanted islets showed a reduction in IBMIR analogous to that demonstrated by in vitro studies. CONCLUSIONS: Given that LMW-DS has been used in clinical studies without serious adverse reactions, it has potential as a drug candidate that can control the strong innate immune response induced by pig islets when transplanted through the portal vein.
BACKGROUND: One of the main obstacles to clinical islet xenotransplantation is the injurious instant blood-mediated inflammatory reaction (IBMIR) that causes rapid binding of platelets to the islet surface, activation of the coagulation and complement systems, and leukocyte infiltration of the islets when the islets are exposed to blood. METHODS: This study assesses the effect of low molecular weight dextran sulfate (LMW-DS) on IBMIR induced by porcine islets in an in vitro tubing loop assay using human blood and in an in vivo model using diabetic athymic mice. RESULTS: In vitro experiments demonstrated that platelet consumption, coagulation, and complement activation were already reduced in the presence of LMW-DS at 0.01 mg/mL, and that at 0.1 mg/mL, LMW-DS prevented IBMIR. Immunohistochemical investigation showed that the leukocyte infiltration was abrogated at the highest dose. In vivo experiments showed that the transplanted pig islets survived for a significantly longer period in recipients treated with LMW-DS, and morphologic examination of transplanted islets showed a reduction in IBMIR analogous to that demonstrated by in vitro studies. CONCLUSIONS: Given that LMW-DS has been used in clinical studies without serious adverse reactions, it has potential as a drug candidate that can control the strong innate immune response induced by pig islets when transplanted through the portal vein.
Authors: Stephen T Bartlett; James F Markmann; Paul Johnson; Olle Korsgren; Bernhard J Hering; David Scharp; Thomas W H Kay; Jonathan Bromberg; Jon S Odorico; Gordon C Weir; Nancy Bridges; Raja Kandaswamy; Peter Stock; Peter Friend; Mitsukazu Gotoh; David K C Cooper; Chung-Gyu Park; Phillip OʼConnell; Cherie Stabler; Shinichi Matsumoto; Barbara Ludwig; Pratik Choudhary; Boris Kovatchev; Michael R Rickels; Megan Sykes; Kathryn Wood; Kristy Kraemer; Albert Hwa; Edward Stanley; Camillo Ricordi; Mark Zimmerman; Julia Greenstein; Eduard Montanya; Timo Otonkoski Journal: Transplantation Date: 2016-02 Impact factor: 4.939
Authors: Andrew M Jackson; Mazhar A Kanak; Ellen K Grishman; Damien Chaussabel; Marlon F Levy; Bashoo Naziruddin Journal: Islets Date: 2012-07-01 Impact factor: 2.694