title: Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft.
abstract: BACKGROUND
  Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia.
  
  
  METHODS
  Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags.
  
  
  RESULTS
  The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA-1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short-term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis.
  
  
  CONCLUSIONS
  Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment.
authors.affiliation: 1 Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA. 2 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA. 3 Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA. 4 Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC. 5 Department of Pathology, Emory University School of Medicine, Atlanta, GA. 6 Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, Madison, WI.
authors.forename: Jean
authors.initials: J
authors.lastname: Kwun
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Song
authors.forename: William T
authors.initials: WT
authors.lastname: Mahle
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Knechtle
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D015778:Minor Histocompatibility Antigens; C114320:anti-LFA-1 monoclonal antibody