title: Immunomodulation by blockade of the TRANCE co-stimulatory pathway in murine allogeneic islet transplantation.
abstract: We explore herein the effect of TNF-related activation-induced cytokine (TRANCE) co-stimulatory pathway blockade on islet survival after allograft transplantation. Expression of TRANCE on murine C57Bl/6 (B6) CD4+ T cells after allogeneic activation was analyzed by fluorescence-activated cell sorter (FACS). The effect of a TRANCE receptor fusion protein (TR-Fc) and anti-CD154 antibody (MR1) on B6 spleen cell proliferation after allogeneic activation was assessed by mixed lymphocyte reaction (MLR). Three groups of B6 mice were transplanted with allogeneic islets (DBA2): Control; short-term TR-Fc-treatment (days 0-4); and prolonged TR-Fc-treatment (days -1 to 13). Donor-specific transfusion (DST) was performed at the time of islet transplantation in one independent experiment. Transplantectomy samples were analyzed by immunohistochemistry. TRANCE expression was upregulated in stimulated CD4+ T cells in vitro. In MLR experiments, TR-Fc and MR1 both reduced spleen cell proliferation, but less than the combination of both molecules. Short-course TR-Fc treatment did not prolong islet graft survival when compared with controls (10.6 +/- 1.9 vs. 10.7 +/- 1.5 days) in contrast to prolonged treatment (20.7 +/- 3.2 days; P < 0.05). After DST, primary non function (PNF) was observed in half of control mice, but never in TR-Fc-treated mice. Immunofluorescence staining for Mac-1 showed a clear decrease in macrophage recruitment in the treated groups. TRANCE-targeting may be an effective strategy for the prolongation of allogeneic islet graft survival, thanks to its inhibitory effects on co-stimulatory signals and macrophage recruitment.
authors.affiliation: Cell Isolation and Transplantation Center, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Wojtusciszyn
authors.forename: Axel
authors.initials: A
authors.lastname: Andres
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.forename: Solange
authors.initials: S
authors.lastname: Charvier
authors.forename: Mathieu
authors.initials: M
authors.lastname: Armanet
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000096:biosynthesis; D002469:Cell Separation; D005434:Flow Cytometry; D006085:Graft Survival; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008954:Models, Biological; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D014184:Transplantation, Homologous
chemical_list: D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D023201:CD40 Ligand