Locally expressed CTLA4-Ig in a pancreatic beta-cell line suppresses accelerated graft rejection response induced by donor-specific transfusion

Diabetologia. 2002 Jun;45(6):831-40. doi: 10.1007/s00125-002-0844-3. Epub 2002 May 25.

Abstract

Aims/hypothesis: 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.

Conclusion/interpretation: A beta-cell line genetically engineered to secrete CTLA4-Ig can protect a graft locally from the alloimmune response induced by donor-specific transfusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / genetics*
  • Antigens, Differentiation / metabolism
  • Blood Glucose / metabolism
  • COS Cells
  • CTLA-4 Antigen
  • Cell Line
  • Chlorocebus aethiops
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / therapy*
  • Graft Rejection / immunology*
  • Graft Rejection / prevention & control
  • Immunoconjugates*
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / metabolism
  • Insulinoma
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Islets of Langerhans Transplantation / immunology*
  • Lymphocyte Transfusion
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms
  • Recombinant Proteins / metabolism
  • Spleen / immunology
  • Transfection
  • Transplantation, Homologous
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Blood Glucose
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Immunoglobulin Fc Fragments
  • Recombinant Proteins
  • Abatacept