title: Nonobese diabetic natural killer cells: a barrier to allogeneic chimerism that can be reduced by rapamycin.
abstract: BACKGROUND
  Induction of allogeneic hematopoietic chimerism is a promising strategy to induce tolerance to donor islets for treating type 1 diabetes. Successful induction of chimerism requires overcoming host alloimmunity. In diabetes-prone nonobese diabetic (NOD) mice, this is challenging due to their general tolerance resistance. Although the adaptive alloimmunity of NOD mice is a known barrier to allogeneic chimerism, whether NOD natural killer (NK) cells are an additional barrier has not been examined. Because NOD NK cells exhibit functional defects, they may not inhibit chimerism generation.
  
  
  METHODS
  Antibody depletion of NK cells in vivo, or transplantation of F1 hybrid donor cells to eliminate the "missing-self" trigger of NK cells, was preformed to test the NK-mediated rejection of donor bone marrow cells. We also studied the capacity of rapamycin to block the NK cell response against allogeneic cells in vivo.
  
  
  RESULTS
  Depleting NK cells or rendering them unresponsive to the donor greatly improved the level of chimerism obtained in NOD mice. Rapamycin significantly reduced the resistance to allogeneic chimerism mounted by NOD NK cells; however, it was much less effective than NK cell depletion by antibodies.
  
  
  CONCLUSIONS
  Contrary to the view that NOD NK cells are defective, we found these cells to be a substantial barrier to allogeneic chimerism in the presence or absence of adaptive immunity. Moreover, rapamycin will need to be combined with other approaches to fully overcome the NK cell barrier.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David P
authors.initials: DP
authors.lastname: Al-Adra
authors.forename: William F N
authors.initials: WF
authors.lastname: Chan
authors.forename: Colin C
authors.initials: CC
authors.lastname: Anderson
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000818:Animals; D046528:Chimerism / Q000187:drug effects*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology* / Q000601:surgery*; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation; D007694:Killer Cells, Natural / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D020123:Sirolimus / Q000494:pharmacology*; D018183:Transplantation Chimera / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus