Low-molecular weight dextran sulfate abrogates the instant blood-mediated inflammatory reaction induced by adult porcine islets both in vitro and in vivo.
BACKGROUND
One of the main obstacles to clinical application of islet xenotransplantation is the injurious inflammatory reaction elicited by porcine islets when they are exposed to fresh human blood in vitro and in vivo. This instant blood-mediated inflammatory reaction (IBMIR) causes rapid binding of platelets to the islet surface, activation of the coagulation and complement systems, and leukocyte infiltration of the islets. As a consequence of IBMIR, morphological destruction of porcine islets occurs within the first few hours after transplantation.


METHODS
In the present study, by analyzing the plasma samples and performing immunohistochemical investigation, we assessed the effect of adding low-molecular weight dextran sulfate (LMW-DS) at 0.01-1 mg/mL to an in vitro tubing loop assay in which porcine islets were exposed to fresh human blood. The effect of LMW-DS also was investigated in an in vivo model using diabetic athymic mice, which provides an innate inflammatory milieu without influence of T cells. The possible toxicity of LMW-DS was assessed by culturing pig islets in the presence or absence of LMW-DS for 3 days.


RESULTS
In the in vitro study, in the presence of LMW-DS at 0.01 mg/mL, platelet consumption, coagulation, and complement activation were reduced, and, at 0.1 mg/mL, LMW-DS totally prevented IBMIR. Immunohistochemical investigation showed that leukocyte infiltration was totally abrogated at the highest dose. A similar finding was observed in the in vivo study. No adverse effect of LMW-DS was observed on the quality of the islets.


CONCLUSIONS
LMW-DS appears to be an effective drug candidate that is able to control the strong innate immune response induced by pig islets in contact with human blood.
Goto
M
M
Department of Radiology, Oncology and Clinical Immunology, Division of Clinical Immunology, Rudbeck Laboratory, University Hospital, Uppsala, Sweden. gotokichi@aol.com
Johansson
H
H
Maeda
A
A
Elgue
G
G
Korsgren
O
O
Nilsson
B
B
D000818:Animals; D001769:Blood; D016264:Dextran Sulfate / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D013552:Swine; D014183:Transplantation, Heterologous
D016264:Dextran Sulfate