Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance
Nathan J. Robertson,F. A. Brook,Richard L. Gardner,Stephen P. Cobbold,Herman Waldmann,Paul J. Fairchild +5 more
TLDR
It is shown that even expression of minor histocompatibility (mH) antigens is sufficient to provoke acute rejection of tissues differentiated from ES cells, suggesting the natural privileged status of ES cell-derived tissues may be harnessed effectively for the induction of dominant tolerance with minimal therapeutic intervention.Abstract:
Although human embryonic stem (ES) cells may one day provide a renewable source of tissues for cell replacement therapy (CRT), histoincompatibility remains a significant barrier to their clinical application. Current estimates suggest that surprisingly few cell lines may be required to facilitate rudimentary tissue matching. Nevertheless, the degree of disparity between donor and recipient that may prove acceptable, and the extent of matching that is therefore required, remain unknown. To address this issue using a mouse model of CRT, we have derived a panel of ES cell lines that differ from CBA/Ca recipients at defined genetic loci. Here, we show that even expression of minor histocompatibility (mH) antigens is sufficient to provoke acute rejection of tissues differentiated from ES cells. Nevertheless, despite their immunogenicity in vivo, transplantation tolerance may be readily established by using minimal host conditioning with nondepleting monoclonal antibodies specific for the T cell coreceptors, CD4 and CD8. This propensity for tolerance could be attributed to the paucity of professional antigen-presenting cells and the expression of transforming growth factor (TGF)-β2. Together, these factors contribute to a state of acquired immune privilege that favors the polarization of infiltrating T cells toward a regulatory phenotype. Although the natural privileged status of ES cell-derived tissues is, therefore, insufficient to overcome even mH barriers, our findings suggest it may be harnessed effectively for the induction of dominant tolerance with minimal therapeutic intervention.read more
Citations
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Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts
Rutger-Jan Swijnenburg,Sonja Schrepfer,Johannes A. Govaert,Feng Cao,Katie Ransohoff,Ahmad Y. Sheikh,Munif Haddad,Andrew J. Connolly,Mark M. Davis,Robert C. Robbins,Joseph C. Wu +10 more
TL;DR: It is shown that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days.
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Immunogenicity of Pluripotent Stem Cells and Their Derivatives
TL;DR: This approach to overcome immunologic barriers to stem cell therapy can take advantage of the validated knowledge acquired from decades of hematopoietic stem cell transplantation and develop safe, effective strategies to bypass them.
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Glutamatergic Neuronal Differentiation of Mouse Embryonic Stem Cells after Transient Expression of Neurogenin 1 and Treatment with BDNF and GDNF: In Vitro and In Vivo Studies
Jeannie H. Reyes,K. Sue O'Shea,Noel L. Wys,J. Matthew Velkey,Diane M. Prieskorn,Karolina Wesolowski,Josef M. Miller,Richard A. Altschuler +7 more
TL;DR: This is the first study to report a high percentage of ES cell differentiation into a glutamatergic phenotype and sets the stage for cell replacement of auditory nerve.
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Izhak Kehat,Leonid Khimovich,Oren Caspi,Amira Gepstein,Rona Shofti,Gil Arbel,Irit Huber,Jonathan Satin,Joseph Itskovitz-Eldor,Lior Gepstein +9 more
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