Open Access Early Islet Damage After Direct Exposure of Pig Islets to Blood:Has Humoral Immunity Been Underestimated?

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Abstract:

Currently, islet transplantation as a cell therapeutic option for type 1 diabetes occurs via islet injection into the portal vein. Direct contact between islets and blood is a pathophysiological “provocation” that results in the instant blood-mediated inflammatory reaction (IBMIR) and is associated with early islet loss. However, the nature of the various insults on the islets in the blood stream remains mostly unknown. To gain insight into the mechanisms, we utilized a simplified in vitro model in which islets were exposed to blood in different clinically relevant but increasingly challenging, autologous, allogeneic, and xenogeneic combinations. Irrespective of the blood type and species compatibility, islets triggered blood clotting. Islet damage was worse as islet, and blood compatibility diminished, with substantial islet injury after exposure of porcine islets to human blood. Islet damage involved membrane leakage, antibody deposition, complement activation, positive staining for the membrane attack complex, and mitochondrial dysfunction. Islet damage occurred even after exposure to plasma only, and specific complement inactivation and neutralization of IgM substantially prevented islet damage, indicating the importance of humoral immunity. Efficacious measures are needed to reduce this injury, especially in view of a potential clinical use of porcine islets to treat diabetes.

Keywords: Antibodies; Complement activation; Humoral immunity; IBMIR; Islet xenotransplantation

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368912X653011

Publication date: August 1, 2012

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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