Prolonged xenograft survival induced by inducible costimulator-Ig Is associated with increased Forkhead Box P3+ Cells

Russell Hodgson, Dale Christiansen, Andrew Ziolkowski, Effie Mouhtouris, Charmaine J. Simeonovic, Francesco L. Ierino, Mauro S. Sandrin

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    10 Citations (Scopus)


    Background: 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. METHODS.: 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. Results: 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. Conclusions: 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.

    Original languageEnglish
    Pages (from-to)1090-1097
    Number of pages8
    Issue number10
    Publication statusPublished - 27 May 2011


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