title: Failure of neonatal B-cell tolerance induction by ABO-incompatible kidney grafts in piglets.
abstract: BACKGROUND
  ABO-incompatible (ABOi) infant heart transplantation results in B-cell tolerance to graft A/B antigens, confirming human susceptibility to acquired immunologic or "neonatal" tolerance as described originally in murine models. Starting with this clinical observation, we sought to model neonatal ABOi organ transplantation to allow mechanistic studies of tolerance.
  
  
  METHODS
  Plasma anti-A/B antibodies were measured over time in piglets to establish developmental antibody kinetics. Blood group O piglets received kidney allografts from group A (AO-incompatible) or group O (AO-compatible) donors under cyclosporine immunosuppression. Anti-A antibodies were measured serially after transplantation; A/H antigen expression and allograft rejection were assessed in graft biopsies.
  
  
  RESULTS
  Anti-A antibodies developed in naïve piglets in a kinetic pattern analogous to human infants; anti-B remained low. After transplantation, anti-A antibodies developed similarly in AO-incompatible and AO-compatible groups and were not suppressed by cyclosporine. A/H antigen expression was persistent in all graft biopsies; however, A/H antigens were not detected in vascular endothelium. Cellular and antibody-mediated rejection was absent or minimal in early and late biopsies in both groups, with one exception.
  
  
  CONCLUSIONS
  Naturally delayed isohemagglutinin production in piglets is analogous to the developmental kinetics in human infants. However, in contrast to deficient anti-A antibody production as seen long-term after "A-into-O" infant heart transplant recipients, normal anti-A antibody production after "A-into-O" piglet kidney transplantation indicates that tolerance did not develop despite graft A antigen persistence. These findings suggest that the impact on the host immune system of exposure to nonself ABH antigens during early life in human heart versus porcine kidney grafts may depend on expression in vascular endothelium.
authors.affiliation: 1 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. 2 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. 3 Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Alberta, Canada. 4 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada. 5 Address correspondence to: Lori J. West, M.D., D.Phil., F.R.C.P.C., 6-002 Li Ka Shing Health Research Centre East, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Mylvaganam
authors.initials: M
authors.lastname: Jeyakanthan
authors.forename: Xianpei
authors.initials: X
authors.lastname: Zhou
authors.forename: KeSheng
authors.initials: K
authors.lastname: Tao
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.forename: Ray V
authors.initials: RV
authors.lastname: Rajotte
authors.forename: Ingrid
authors.initials: I
authors.lastname: Larsen
authors.forename: Lori J
authors.initials: LJ
authors.lastname: West
mesh_terms: D000017:ABO Blood-Group System / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn; D001402:B-Lymphocytes / Q000276:immunology*; D001706:Biopsy; D001787:Blood Group Incompatibility / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival; D006648:Histocompatibility / Q000187:drug effects; D006650:Histocompatibility Testing; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007518:Isoantibodies / Q000097:blood; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D007700:Kinetics; D023421:Models, Animal; D034421:Sus scrofa; D023001:Transplantation Tolerance
chemical_list: D000017:ABO Blood-Group System; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D016572:Cyclosporine