title: Locally expressed CTLA4-Ig in a pancreatic beta-cell line suppresses accelerated graft rejection response induced by donor-specific transfusion.
abstract: OBJECTIVE
  This study examined whether locally expressed CTLA4-Ig can suppress the accelerated islet allograft rejection that is induced by donor-specific transfusion.
  
  
  METHODS
  CTLA4-Ig-transfected or parental MIN6 cells were transplanted subcutaneously into the right flank of streptozotocin-induced diabetic C3H/Hej mice with or without donor-specific transfusion. For donor-specific transfusion, spleen cells from C57BL/6 mice were injected i.v. at the time of transplantation. In other experiments, CTLA4-Ig-transfected and parental MIN6 cells were transplanted separately into each flank, together with donor-specific transfusion. Rejection was defined as a blood glucose concentration of more than 300 mg/dl in two consecutive measurements, and graft survival was confirmed by hyperglycaemia after the grafts were removed. The effect of an anti-CTLA4 antibody on the survival of CTLA4-Ig-transfected MIN6 cells was also examined.
  
  
  RESULTS
  In 7 of 12 donor-specific transfusion sensitised mice, CTLA4-Ig-transfected MIN6 cells remained viable 20 days after grafting, whereas all parental MIN6 cells ( n = 10) were rejected promptly, within 14 days. The prolonged allograft survival was observed even in the absence of detectable levels of serum CTLA4-Ig, while the surviving allografts continued to produce CTLA4-Ig in situ. This protection was abrogated by an anti-CTLA4 antibody, but not by a control antibody. Furthermore, six animals that maintained normoglycaemia after the separate transplantation of parental and CTLA4-Ig-transfected MIN6 cells into each flank all showed abrupt hyperglycaemia after the CTLA4-Ig/MIN6 graft was removed, suggesting that this protection operated locally.
  
  
  CONCLUSIONS
  A beta-cell line genetically engineered to secrete CTLA4-Ig can protect a graft locally from the alloimmune response induced by donor-specific transfusion.
authors.affiliation: Molecular and Cellular Recognition, Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Kimura
authors.forename: M
authors.initials: M
authors.lastname: Gotoh
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
authors.forename: J
authors.initials: J
authors.lastname: Miyazaki
authors.forename: T
authors.initials: T
authors.lastname: Uede
authors.forename: M
authors.initials: M
authors.lastname: Monden
authors.forename: M
authors.initials: M
authors.lastname: Miyasaka
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D019556:COS Cells; D060908:CTLA-4 Antigen; D002460:Cell Line; D002522:Chlorocebus aethiops; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology / Q000628:therapy*; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D007340:Insulinoma; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms; D011994:Recombinant Proteins / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D014162:Transfection; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D001786:Blood Glucose; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D011994:Recombinant Proteins; D000069594:Abatacept