title: The effect of simultaneous CD154 and LFA-1 blockade on the survival of allogeneic islet grafts in nonobese diabetic mice.
abstract: BACKGROUND
  The rate of success in clinical transplantation of islets of Langerhans has dramatically improved with perspectives of wide-scale applicability for patients with type 1 diabetes. One drawback is the need for lifelong immunosuppression, which is associated with significant side effects. Immunomodulatory strategies devoid of side effects and with tolerogenic potential, such as co-stimulatory blockade, would be a great improvement if successful. In this study, the authors have explored the effect of simultaneous blockade of CD40/CD154 and intercellular adhesion molecule (ICAM)/lymphocyte function-associated antigen (LFA)-1 interactions.
  
  
  METHODS
  Spontaneously diabetic nonobese diabetic (NOD) mice underwent transplantation with allogeneic (C57BL/6) islets and were treated with anti-CD154 monoclonal antibody (mAb) (500 microg, three doses), anti-LFA-1 mAb (100 microg, three doses), or a combination of both in the early peritransplant period. In another set of experiments, LFA-1 engagement was impaired by transplanting islets isolated from ICAM-1-knockout (KO) mice.
  
  
  RESULTS
  Untreated animals rejected their grafts within 10 days. LFA-1 blockade alone did not result in improved islet graft survival, whereas CD154 blockade alone increased graft survival to 18 days. Simultaneous blockade of both pathways led to significantly improved islet graft survival to 30 days (ICAM-1-KO islets plus anti-CD154), 35 days (anti-LFA-1 plus anti-CD154), and 44 days (ICAM-1-KO islets plus anti-LFA-1 plus anti-CD154).
  
  
  CONCLUSIONS
  These data suggest that a synergistic effect for prolonged graft survival can be obtained by simultaneously targeting CD154 and LFA-1 in the challenging model of islet allotransplantation in NOD mice. The observation of similar results with anti-LFA-1 mAb and with ICAM-1-KO grafts suggests a key role of direct antigen presentation for the activation of LFA-1-driven signaling.
authors.affiliation: Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: R Damaris
authors.initials: RD
authors.lastname: Molano
authors.forename: Raffaella
authors.initials: R
authors.lastname: Poggioli
authors.forename: Elsie
authors.initials: E
authors.lastname: Zahr
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Luca
authors.initials: L
authors.lastname: Inverardi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000601:surgery; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D066298:In Vitro Techniques; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand