Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning

Abstract

Hematopoietic stem cells have been successfully employed for tolerance induction in a variety of rodent and large animal studies. However, clinical transplantation of fully allogeneic bone marrow or blood-borne stem cells is still associated with major obstacles, such as graft-versus-host disease or cytoreductive conditioning-related toxicity. Here we show that when rat embryonic stem cell-like cells of WKY origin are injected intraportally into fully MHC-mismatched DA rats, they engraft permanently (>150 days) without supplementary host conditioning. This deviation of a potentially alloreactive immune response sets the basis for long-term graft acceptance of second-set transplanted WKY cardiac allografts. Graft survival was strictly correlated with a state of mixed chimerism, which required functional thymic host competence. Our results provide a rationale for using preimplantation-stage stem cells as vehicles in gene therapy and for the induction of long-term graft acceptance.

The contribution of farm animals to human health

“…A particularly promising strategy for long-term graft acceptance is the induction of a permanent chimerism via intraportal injection of embryonic stem cells [40].…”

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

“…There are several reports of a robust immune-privileged ('tolerogenic') state of ESC of mice, humans and rats after engraftment [1][2][3], while others described an increase of immunogenicity following transplantation with proceeding differentiation [4,5]. Expression of structures recognized by the host immune system varies between the species, e.g.…”

“…MHC class II and costimulatory molecules are generally not expressed by ESC. Another 'tolerogenic' feature of these cells is the profound expression of Fas ligand (FasL) that would induce T-cell apoptosis via Fas-FasL interaction [1,3]. The major obstacle following transplantation is the recognition of donor antigens on the graft by the recipient's immune cells.…”

Detection and Characterization of Hepatic Engraftment of Embryonic Stem Derived Cells by Fluorescent Stereomicroscopy

“…Previous studies of engraftment efficiency have used several molecular and immunohistochemical methods including: flow cytometry [24][25][26][27][28], histological and immunostaining techniques [28][29][30], b-gal staining analysis of whole liver and tissue sections [31], different types of PCR analysis [32][33][34][35] and/or a combination of several of these methods [36]. As the use of such methods has proven to be labor intensive and costly, we examined past attempts at detection and evaluation of cellular structural function and liver sinusoidal architecture to determine if similar strategies could be applied to our models.…”