Tolerant and rejecting T cell microarray. Mus musculus

anti-CD4, CD8 and CD40L treated versus control murine CD4+ T cells from micegrafted with hESC derived xenografts. Human embryonic stem cells (ESCs), by virtue of their capability to self-renew and differentiate into almost all body cell types, represent the first type of pluripotent stem cells (PSCs) to be used in clinical transplantation to humans in recent phase-I trials. As it is unlikely that any such cells or their progeny will survive in an allogeneic host, there is an urgent need to understand how to get long-term acceptance and functional differentiation with minimal immunosuppression. Here, we show that brief induction with combined monoclonal antibody-mediated coreceptor and costimulation blockade enables long-term survival and engraftment of murine ESCs, human ESCs, human induced PSCs, and human ESC-derived progenitor cells from all three embryonic germ layers. Tolerance induced to PSC-derived progenitors appears, remarkably, to extend to protection of their differentiated progenies, and sometimes even to different tissues derived from the same donor, suggesting linked-suppression as a likely operative mechanism. These results suggest that once tolerance has been established to PSC-derived progenitor cells, it can be extended to their differentiated progenies. Global gene expression profiling of graft infiltrating T-lymphocytes identifies gene sets that differ between rejecting and tolerant populations including gene upregulation in pathways associated with apoptosis, cell adhesion, transcription suppression and TGF synthesis; and gene downregulation in pathways associated with inflammation in recipients treated with combined coreceptor and costimulation blockade. Overall design: Mice grafted with hESC derived tissues and untreated (control) or tolerised via injections of anti-CD4, anti CD8 and CD40L. CD3+ T cells isolated from the gratfs 30 days later.