title: Induction of xenogeneic neonatal tolerance to transgenic human leukocyte antigen class I grafts.
abstract: BACKGROUND
  The immune response against xenografts is vigorous and poorly controlled with conventional immunosuppressants. Therefore, success in xenotransplantation will depend on developing additional approaches such as induction of immunologic unresponsiveness or tolerance. Although classic protocols of neonatal tolerance induction in mice are very tolerogenic in many allogeneic models, they have generally failed in xenogeneic models. The purpose of these studies was to determine whether failure results from an intrinsic property of xenogenic major histocompatibility complex (MHC) molecules themselves or, instead, is caused by some limitation in species-specific molecular interactions distinct from the polymorphic domains of xenogenic MHC molecules.
  
  
  METHODS
  Our approach was to test the ability of lymphoid cells from a transgenic (Tg) mouse donor expressing a xeno-MHC class I molecule encoding the polymorphic alpha1/alpha2 for human leukocyte antigen (HLA)-B7 to induce neonatal tolerance in non-Tg syngeneic C57BL/6 recipients. Because the donor and recipient strains are genetically identical (C57BL/6, H-2b) except for Tg human MHC HLA-B7, any species-specific molecular incompatibility in this mouse anti-human class I xeno-combination that could potentially interfere with induction of tolerance has been eliminated.
  
  
  RESULTS
  Our results show that HLA-B7 Tg-, but not C57BL/6 syngeneic-, injected neonates were unresponsive as adults to HLA-B7-expressing target cells in vitro and specifically accepted HLA-B7-expressing Tg skin grafts. In addition, neonatal injection of donor cells resulted in peripheral chimerism.
  
  
  CONCLUSIONS
  These experiments demonstrate that, as long as species-specific molecular interactions are maintained, recognition of the polymorphic domains of xenogeneic MHC does not represent a barrier to neonatal tolerance induction.
authors.affiliation: Research Institute, Program in Infection, Immunity, Injury and Repair, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Borenstein
authors.forename: Kesheng S
authors.initials: KS
authors.lastname: Tao
authors.forename: Michael
authors.initials: M
authors.lastname: Mendicino
authors.forename: Ningjie
authors.initials: N
authors.lastname: Hu
authors.forename: Lori J
authors.initials: LJ
authors.lastname: West
authors.forename: John W
authors.initials: JW
authors.lastname: Chamberlain
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D005434:Flow Cytometry; D015793:HLA-B7 Antigen / Q000235:genetics* / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D013154:Spleen / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D015793:HLA-B7 Antigen; D015395:Histocompatibility Antigens Class I