title: Genetic strategies to bring islet xenotransplantation to the clinic.
abstract: Despite the benefits of islet and pancreas allotransplantation, their widespread use in type 1 diabetes is limited because of the paucity of suitable donors. Porcine xenotransplantation offers an alternative, and advances in genetic modification of pigs have opened up new potential for its clinical use. This review outlines the barriers to successful islet xenotransplantation, and genetic modifications that have been tested to overcome these.
  
  
  
  Islets from pigs lacking α1,3-galactosyltransferase, to prevent hyperacute rejection, are now used as a background strain for further genetic modifications. The instant blood-mediated inflammatory reaction is overcome by expressing complement regulators including CD46, CD55 and CD59. Prevention of immune-mediated rejection mediated by T cells, macrophages and natural killer cells remains a challenge. The use of immunosuppressive antibodies, such as anti-CD154 or anti-CD2, can be protective, and may be useful if they are produced by the islets themselves.
  
  
  
  The field of xenotransplantation has benefited enormously from the development of new genetic modification strategies. With the possibility of multiple genetic modifications in the same animal, and a detailed knowledge of the mechanism of xenograft rejection, the challenge now is to develop islets that provide long-term graft survival without systemic immunosuppression.
authors: aThe Centre for Transplant and Renal Research, The Westmead Institute bUniversity of Sydney at Westmead Hospital, Westmead, New South Wales cWalter and Eliza Hall Institute of Medical Research, Parkville dDepartment of Microbiology and Immunology, University of Melbourne eSt. Vincent's Institute of Medical Research fDepartment of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors: Wayne J
authors: WJ
authors: Hawthorne
authors: Andrew M
authors: AM
authors: Lew
authors: Helen E
authors: HE
authors: Thomas
mesh_terms: D000818:Animals; D005821:Genetic Techniques / Q000706:statistics & numerical data*; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods*