title: Anti-CD154 mAb treatment but not recipient CD154 deficiency leads to long-term survival of xenogeneic islet grafts.
abstract: The aim of the study was to evaluate the role of recipient CD40 and CD154 in the rejection process of concordant and discordant islets xenotransplantation (Tx). Diabetic C57BL/6 mice, CD40- or CD154-knockout (KO) and complement C3-deficient (C3-/-) mice were transplanted with either rat or human islets. Group 1, C57BL/6 Tx without therapy; Group 2, C57BL/6 Tx with anti-CD154 monoclonal antibody (mAb) (MR1) therapy; Group 3, CD40-KO; and Group 4, CD154-KO Tx without therapy; Group 5, C3-/- Tx without therapy and Group 6, C3-/-Tx with MR1 therapy. Mixed lymphocyte reactions (MLR) were performed. Compared to Group 1, MR1 induced long-term survival of xenografts in Group 2, but not in Group 6, survival of islets was not prolonged significantly in Groups 3 and 4. MLR responses in Group 2 were reduced approximately 50% compared to Group 1. In Groups 3, 4 and 6, MLR responses were not modified by the absence of CD40 or CD154 molecules, or MR1 and were similar to Group 1. Improved graft survival and reduced MLR responses in Group 2, but not in Group 6, could be explained by specific targeting of activated T cells with inactivation by complement- or cellular-mediated mechanisms. Rejection of xenografts and strong MLR responses in Groups 3 and 4 are possible through efficient activation of alternate pathways of costimulation.
authors.affiliation: Surgical Research Unit, Department of Surgery, University Hospital Geneva, Switzerland.
authors.forename: Gang
authors.initials: G
authors.lastname: Mai
authors.forename: Pascal
authors.initials: P
authors.lastname: Bucher
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.forename: Jie
authors.initials: J
authors.lastname: Mei
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Axel
authors.initials: A
authors.lastname: Andres
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Mathe
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.forename: Leo H
authors.initials: LH
authors.lastname: Bühler
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001835:Body Weight; D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D003176:Complement C3 / Q000235:genetics / Q000502:physiology; D006084:Graft Rejection; D006085:Graft Survival; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D003176:Complement C3; D023201:CD40 Ligand