title: Perturbation of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 results in differential outcomes in cardiac vs islet allograft survival.
abstract: BACKGROUND
  Various studies indicate the requirements for tolerance induction may vary between different transplanted tissues and organs. Consequently, we compared the efficacy of anti-leukocyte function-associated antigen-1 (LFA-1)/anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody therapy for facilitating cardiac vs islet long-term allograft acceptance in mice.
  
  
  METHODS
  BALB/c (H-2d) mouse cardiac or islet allografts were transplanted into recipient CBA/J (H-2k) mice. Monoclonal anti-body therapy with anti-LFA-1, anti-ICAM-1, the combination, or control rat immunoglobulin (Ig) was administered intraperitoneally on Days 0 to 5. Cardiac allograft function was assessed by palpation and islet graft function by blood glucose monitoring. Mixed lymphocyte assays were performed to assess proliferation of CD4 and CD8 T-cells under conditions of stimulator-cell ICAM-1 and/or LFA-1 deficiency.
  
  
  RESULTS
  Anti-ICAM-1 therapy resulted in a modest prolongation of cardiac allografts but in pronounced survival of islet allografts. Anti-LFA-1 therapy promoted significant long-term survival of both cardiac and islet allografts. Surprisingly, combined anti-LFA-1/anti-ICAM-1 therapy abrogated long-term islet, but not cardiac, allograft acceptance relative to either monotherapy. Mixed lymphocyte reactions demonstrated complete blockade of CD4 and CD8 T-cell proliferation under conditions of ICAM-1 deficiency alone or in combination with anti-LFA-1 therapy.
  
  
  CONCLUSIONS
  These results indicate that optimal therapies for some allografts (vascularized-heart) may not translate to other types of allografts (cellular-islet). Thus, the type of transplant represents an independent variable for optimizing strategies to promote indefinite allograft acceptance. Complete inhibition of CD4 and CD8 T-cell proliferation during ICAM-1/LFA-1 blockade suggests a threshold signal may be dependent upon ICAM-1/LFA-1 for regulatory tolerance to occur and that this signal may be lost under conditions of minimal graft cellular mass.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, The Children's Hospital, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Todd.Grazia@uchsc.edu
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Grazia
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
authors.forename: H Carl
authors.initials: HC
authors.lastname: Gelhaus
authors.forename: An N
authors.initials: AN
authors.lastname: Doan
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Sleater
authors.forename: Biagio A
authors.initials: BA
authors.lastname: Pietra
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1