Human Embryonic Stem Cells and Their Differentiated Derivatives Are Less Susceptible to Immune Rejection Than Adult Cells

Abstract

Differentiated cell types derived from human embryonic stem cells (hESCs) may serve in the future to treat various human diseases. A crucial step toward their successful clinical application is to examine the immune response that might be launched against them after transplantation. We used two experimental platforms to examine the in vivo leukocyte response toward hESCs. First, immunocompetent and immunodeficient mouse strains were used to identify T cells as the major component that causes xenorejection of hESCs. Second, mice that were conditioned to carry peripheral blood leukocytes from human origin were used to test the human leukocyte alloresponse toward undifferentiated and differentiated hESCs. Using this model, we have detected only a minute immune response toward undifferentiated as well as differentiated hESCs over the course of 1 month, although control adult grafts were repeatedly infiltrated with lymphocytes and destroyed. Our data show that the cells evade immune destruction due to a low immunostimulatory potential. Nevertheless, a human cytotoxic T lymphocyte clone that was specifically prepared to recognize two hESC lines could lyse the cells after major histocompatibility complex class I (MHC-I) induction. Although MHC-I levels in hESCs are sufficient for rejection by cytotoxic T cells, our data suggest that the immunostimulatory capacity of the cells is very low. Thus, immunosuppressive regimens for hESC-based therapeutics could be highly reduced compared with conventional organ transplantation because direct allorejection processes of hESCs and their derivatives are considerably weaker. STEM CELLS 2006;24:221-229

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

“…It was shown that human ES cells express MHC class I at low levels and that stimulation by IFNγ upregulates the level of expression and induces MHC class II [22]. In vitro studies with human ES cells also demonstrated that cytotoxic immune responses by T cells were exclusively induced following IFNγ stimulation and that natural killer (NK) cell response was negligible [23,24]. In some studies mouse ES cells exhibited a strong humoral and cellular immune response after in vivo application into injured myocardium in allogeneic settings [4,5].…”

Deciphering the β‐adrenergic response in human embryonic stem cell‐derived‐cardiac myocytes: closer to clinical use?

“…Another serious issue that needs to be solved is the immunological compatibility between donor and grafted tissues, lack of which leads to ES cell rejection after transplantation. Recent work has yielded encouraging results on this point, demonstrating that lower levels of the class I major histocompatibility complex on hESC might make the derived cardiac myocytes less immunogenic (Drukker et al, 2006). Furthermore, the development of chemically defined culture media supplemented with recombinant cytokines and growth factors is a crucial requirement if these cells are to have clinical applications.…”

Progress and prospects: gene transfer into embryonic stem cells

“…Li et al 68 have shown that hESCs and their derivatives can evade both in vivo xenogenic and in vitro allogeneic immune responses despite normal levels of MHCI. It was later unequivocally confirmed that hES and hES-derived cells can in some cases evade allogenic immune responses 69 based on a careful study performed in a NOD/SCID-based chimeric mouse-human model.…”