α-1-Antitrypsin Gene Delivery Reduces Inflammation, Increases T-Regulatory Cell Population Size and Prevents Islet Allograft Rejection
Copyright policy )α-1-Antitrypsin Gene Delivery Reduces Inflammation, Increases T-Regulatory Cell Population Size and Prevents Islet Allograft Rejection
Antiinflammatory clinical-grade, plasma-derived human α-1 antitrypsin (hAAT) protects islets from allorejection as well as from autoimmune destruction. hAAT also interferes with disease progression in experimental autoimmune encephalomyelitis (EAE) and in collagen-induced arthritis (CIA) mouse models. hAAT increases IL-1 receptor antagonist expression in human mononuclear cells and T-regulatory (Treg) cell population size in animal models. Clinical-grade hAAT contains plasma impurities, multiple hAAT isoforms and various states of inactive hAAT. We thus wished to establish islet-protective activities and effect on Treg cells of plasmid-derived circulating hAAT in whole animals. Islet function was assessed in mice that received allogeneic islet transplants after mice were given hydrodynamic tail-vein injection with pEF-hAAT, a previously described Epstein-Barr virus (EBV) plasmid construct containing the EBV nuclear antigen 1 (EBNA1) and the family of repeat EBNA1 binding site components (designated "EF") alongside the hAAT gene. Sera collected from hAAT-expressing mice were added to lipopolysaccharide (LPS)-stimulated macrophages to assess macrophage responsiveness. Also, maturation of peritoneal cells from hAAT-expressing mice was evaluated. hAAT-expressing mice accepted islet allografts (n = 11), whereas phosphate-buffered saline-injected animals (n = 11), as well as mice treated with truncated-hAAT-plasmid (n = 6) and untreated animals (n = 20) rapidly rejected islet allografts. In hAAT-expressing animals, local Treg cells were abundant at graft sites, and the IL-1 receptor antagonist was elevated in grafts and circulation. Sera from hAAT-expressing mice, but not control mice, inhibited macrophage responses. Finally, peritoneal cells from hAAT-expressing mice exhibited a semimature phenotype. We conclude that plasmid-derived circulating hAAT protects islet allografts from acute rejection, and human plasma impurities are unrelated to islet protection. Future studies may use this in vivo approach to examine the structure-function characteristics of the protective activities of AAT by manipulation of the hAAT plasmid.
- Ben-Gurion University of the Negev Israel
- Soroka Medical Center Israel
Graft Rejection, Inflammation, Lipopolysaccharides, Reverse Transcriptase Polymerase Chain Reaction, Immune Sera, Macrophages, Blotting, Western, Gene Transfer Techniques, Islets of Langerhans Transplantation, Genetic Therapy, T-Lymphocytes, Regulatory, Cell Line, Mice, Inbred C57BL, Mice, alpha 1-Antitrypsin, Animals, Humans, Transplantation, Homologous, Lymphocyte Count, Plasmids
Graft Rejection, Inflammation, Lipopolysaccharides, Reverse Transcriptase Polymerase Chain Reaction, Immune Sera, Macrophages, Blotting, Western, Gene Transfer Techniques, Islets of Langerhans Transplantation, Genetic Therapy, T-Lymphocytes, Regulatory, Cell Line, Mice, Inbred C57BL, Mice, alpha 1-Antitrypsin, Animals, Humans, Transplantation, Homologous, Lymphocyte Count, Plasmids
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