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Title: Prolonged xenograft survival induced by inducible costimulator-Ig is associated with increased forkhead box P3(+) cells.
Austin Authors: Hodgson, Russell;Christiansen, Dale;Ziolkowski, Andrew;Mouhtouris, Effie ;Simeonovic, Charmaine J;Ierino, Francesco L;Sandrin, Mauro S 
Affiliation: Northern Health, Victoria, Australia
Surgery (University of Melbourne)
Issue Date: 27-May-2011
Publication information: Transplantation; 91(10): 1090-7
Abstract: Blockade of the inducible costimulator (ICOS) pathway has been shown to prolong allograft survival; however, its utility in xenotransplantation is unknown. We hypothesize that local expression of ICOS-Ig by the xenograft will suppress the T-cell response resulting in significant prolonged graft survival.Pig iliac artery endothelial cells (PIEC) secreting ICOS-Ig were generated and examined for the following: (1) inhibition of allogeneic and xenogeneic proliferation of primed T cells in vitro and (2) prolongation of xenograft survival in vivo. Grafts were examined for Tregs by flow cytometry and cytokine levels determined by quantitative reverse-transcriptase polymerase chain reaction.Soluble ICOS-Ig markedly decreased allogeneic and xenogeneic primed T-cell proliferation in a dose-dependent manner. PIEC-ICOS-Ig grafts were significantly prolonged compared with wild-type grafts (median survival, 34 and 12 days, respectively) with 20% of PIEC-ICOS-Ig grafts surviving more than 170 days. Histological examination showed a perigraft cellular accumulation of Forkhead box P3 (Foxp3(+)) cells in the PIEC-ICOS-Ig grafts, these were also shown to be CD3(+)CD4(+)CD25(+). Survival of wild-type PIEC grafts in a recipient simultaneously transplanted with PIEC-ICOS-Ig were also prolonged, with a similar accumulation of Foxp3(+) cells at the periphery of the graft demonstrating ICOS-Ig induces systemic graft prolongation. However, this prolongation was specific for the priming xenograft. Intragraft cytokine analysis showed an increase in interleukin-10 levels, suggesting a potential role in induction/function of CD4(+)CD25(+)Foxp3(+) cells.This study demonstrates prolonged xenograft survival by local expression of ICOS-Ig, we propose that the accumulation of CD4(+)CD25(+)Foxp3(+) cells at the periphery of the graft and secretion of interleukin-10 is responsible for this novel observation.
DOI: 10.1097/TP.0b013e31821774e0
Journal: Transplantation
Type: Journal Article
Subjects: Animals
Antigens, Differentiation, T-Lymphocyte.genetics.immunology
Cells, Cultured
Endothelial Cells.immunology.transplantation
Flow Cytometry
Forkhead Transcription Factors.metabolism
Gene Expression Regulation
Graft Rejection.immunology.prevention & control
Graft Survival
Immunoglobulin G.biosynthesis.immunology
Inducible T-Cell Co-Stimulator Protein
Interleukin-2 Receptor alpha Subunit.metabolism
Lymphocyte Culture Test, Mixed
Mice, Inbred BALB C
Mice, Inbred C57BL
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes, Regulatory.immunology
Time Factors
Transplantation, Heterologous
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