title: Prolonged islet allograft survival in diabetic NOD mice by targeting CD45RB and CD154.
abstract: Clinical islet transplantation is a successful procedure that can improve the quality of life in recipients with diabetes. A drawback of the procedure is the need for chronic administration of immunosuppressive drugs that, among other side effects, are potentially diabetogenic. Definition of immunosuppressive protocols that utilize nondiabetogenic compounds could further improve islet transplantation outcome. We used the NOD mouse to assess the effect of targeting the T-lymphocyte surface receptors CD45RB and CD154 in preventing loss of allogeneic islet grafts as a result of recurrence of autoimmunity and allorejection. Administration of the two antibodies led to significantly prolonged allograft survival, with a percentage of grafts surviving long-term. The therapeutic efficacy of the treatment was paralleled by a shift in CD45RB isoform expression on T-lymphocytes, increased in vitro responsiveness to interleukin-7, and increased in vitro gamma-interferon production after anti-CD3 antibody stimulation. Furthermore, graft infiltration by CD8+ T-cells was remarkably reduced. Recipient mice bearing functioning allografts were otherwise immunocompetent, as assessed in vivo and in vitro by numerous tests, including intragraft cytokine production, responsiveness to polyclonal stimulation and alloantigens, and analysis of cell subset phenotype. These data show that nondiabetogenic regimens of immunomodulation can lead to prolonged islet allograft survival in the challenging NOD mouse model.
authors.affiliation: Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: R Damaris
authors.initials: RD
authors.lastname: Molano
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.forename: Raffaella
authors.initials: R
authors.lastname: Poggioli
authors.forename: Elsie
authors.initials: E
authors.lastname: Zahr
authors.forename: Robert
authors.initials: R
authors.lastname: Oliver
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Basadonna
authors.forename: Luca
authors.initials: L
authors.lastname: Inverardi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017252:CD3 Complex / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006085:Graft Survival; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D015851:Interleukin-7 / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D012333:RNA, Messenger / Q000032:analysis; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007376:Interleukin-2; D015851:Interleukin-7; D012333:RNA, Messenger; D016753:Interleukin-10; D023201:CD40 Ligand; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens