Acute cellular rejection after human heart transplantation is associated with ICOS+ graft-infiltrating T lymphocytes and increased endothelial expression of inducible costimulator ligand (ICOSL)

Abstract

The novel costimulatory molecule inducible costimulator (ICOS) mediates effector T cell differentiation and function. Inhibition of the ICOS/ICOS ligand pathway in animal models of heart transplantation led to prolonged engraftment in recent studies. We have recently demonstrated constitutive expression of ICOSL and its upregulation by proinflammatory cytokines on human vascular endothelial cells in vitro. However, no data concerning human heart transplantation are available to date. This pilot study examined the cellular expression pattern of ICOS and ICOS ligand in human cardiac allograft rejection. Immunohistochemical staining was performed on endomyocardial biopsy specimens from individual patients (n = 8 in each group) with histological evidence of moderate (ISHLT 3A) acute cellular rejection comparing it to specimens from patients without signs of rejection (ISHLT 0). ICOS expression was detected on graft-infiltrating T lymphocytes during acute rejection. ICOS ligand (ICOSL) showed a distinct expression restricted to vascular endothelial cells. ICOSL was present on 18 % of vessels (mean) identified by CD31 staining in non-rejecting specimens compared to 55 % of vessels in specimens with evidence of moderate rejection (p = 0.0357). This is the first report implicating the ICOS/ICOSL pathway in human cardiac allograft rejection. Coroborating previous in vitro data, ICOSL is expressed on endothelial cells suggesting a role as antigen-presenting cells, regulated by inflammatory cytokines. Quantitative analysis suggests that ICOSL expression on endothelial cells is correlated with histologically significant acute cellular rejection.