title: CD4-dependent generation of dominant transplantation tolerance induced by simultaneous perturbation of CD154 and LFA-1 pathways.
abstract: CD154 and LFA-1 (CD11a) represent conceptually distinct pathways of receptor/ligand interactions (costimulation and adhesion/homing, respectively) that have been effectively targeted to induce long-term allograft acceptance and tolerance. In the current study, we determined the relative efficacy and nature of tolerance induced by mAbs specific for these pathways. In vitro analysis indicated that simultaneous targeting of CD154 and LFA-1 resulted in profound inhibition of alloreactivity, suggesting that combined anti-CD154/anti-LFA-1 therapy could be highly effective in vivo. Thus, we evaluated combining mAb therapies targeting CD154 and LFA-1 for inducing transplantation tolerance to pancreatic islet allografts. Monotherapy with either anti-CD154 or anti-LFA-1 was partially effective for inducing long-term allograft survival, whereas the combination resulted in uniform allograft acceptance in high-responder C57BL/6 recipients. This combined therapy was not lymphocyte depleting and did not require the long-term deletion of donor-reactive T lymphocytes to maintain allograft survival. Importantly, combined anti-CD154/anti-LFA therapy uniquely resulted in "dominant" transplantation tolerance. Therefore, simultaneous perturbation of CD154 and LFA-1 molecules can result in profound tolerance induction not accomplished through individual monotherapy approaches. Furthermore, results show that such regulatory tolerance can coexist with the presence of robust anti-donor reactivity, suggesting that active tolerance does not require a corresponding deletion of donor-reactive T cells. Interestingly, although the induction of this regulatory state was highly CD4 dependent, the adoptive transfer of tolerance was less CD4 dependent in vivo.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver 80262, USA. mark.nicolls@uchsc.edu
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nicolls
authors.forename: Marilyne
authors.initials: M
authors.lastname: Coulombe
authors.forename: Joshua
authors.initials: J
authors.lastname: Beilke
authors.forename: H Carl
authors.initials: HC
authors.lastname: Gelhaus
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology* / Q000502:physiology; D017637:Clonal Deletion / Q000235:genetics; D004359:Drug Therapy, Combination; D016056:Immunodominant Epitopes / Q000276:immunology; D007274:Injections, Intraperitoneal; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D023001:Transplantation Tolerance / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D016056:Immunodominant Epitopes; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand