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a Robarts Research Institute, Krembil Centre for Stem Cell Biology and Regenerative Medicine and FOCIS Centre for Clinical Immunology and Immunotherapeutics, London, Ontario, Canada;" r/ ]6 P* Q+ h. B, X. A
* d5 J- h& t6 e% Ib Geron Corporation, Menlo Park, California;6 [+ `% d! q( J& ^7 L, F/ _$ l
& l5 s* T( g3 _5 }4 qc The University of Western Ontario, Department of Microbiology and Immunology and Medicine, London, Ontario, Canada.0 b* @4 E) V& {; G
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Key Words. Human embryonic stem cells ? Immune response ? Transplantation ? Tolerance ? T-cell proliferation& s9 s L! z+ { ^, A% `
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Correspondence: Mickie Bhatia, M.D., Robarts Research Institute, Krembil Centre for Stem Cell Biology and Regenerative Medicine, 100 Perth Drive, London, Ontario, Canada, N6A5K8. Telephone: 519-663-5777 ext. 34166; Fax: 519-663-2982; e-mail: mbhatia@robarts.ca+ m' a% C7 C. |5 j# N& A
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ABSTRACT/ \6 _6 l; L6 S1 u/ S0 n+ m
n1 Z ]- R& L% }; j8 QFor nearly 50 years, transplantation medicine has focused on innovative strategies to prevent rejection of donor alloanti-gens . In addition to whole organ transplants, the emergence of cellular transplantation in the evolving field of regenerative medicine must now also be cognizant of potential rejection and the potential requirement of immune tolerance induction in the recipient . The isolation of human embryonic stem cells (hESCs) provides an unlimited source of cells capable of producing a wide spectrum of cell types for replacement of degenerating tissue . Efforts to overcome rejection of hESCs include nuclear transfer to create compatible cells and development of hESC banks representing the broadest diversity of human major histocompatabil-ity complex (MHC) polymorphorisms . Despite the continued exploration into approaches to avoid rejection of transplanted cells, immune responses to hESCs have yet to be evaluated.
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9 H: w) }& @/ {5 R7 }Survival of transplanted cells correlates with the number of differences in major histocompatibility (MHC) antigens between donor and recipient that triggers T-cell responses and rejection of cells with disparate MHC profiles . One exception to this rule is maternal tolerance to the fetal conceptus expressing paternal antigens . In spite of our growing understanding of the immune system, the mechanism of immune privilege exhibited by fetal tissue remains unknown . Accordingly, it is reasonable to assume that immune responses to human embryonic cells may reveal unanticipated results, and therefore must be examined experimentally.
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" I/ T1 P! G2 R/ T9 ]+ v4 nImmunosuppressive drugs allow the majority of transplant recipients to accept allogeneic donated tissue and prevent acute graft rejection. However, immunosuppression has complications, including the increased susceptibility to infections . Our study indicates that hESCs possess mechanisms that counteract immune responses, thereby providing protection to hESC-derived allografts while allowing locally inhibited T cells to respond to other foreign antigens. However, this same beneficial property also reveals the risk of seeding transplanted hosts with hESCs capable of neoplastic growth./ Z7 h, D1 O+ a6 \& b0 p
7 K1 k. S% o" U/ S8 RThe immunologically privileged state of the human embryo has been attributed to a unique relationship between the maternal host and fetal tissue that is dependent on the physiology and structure of the placenta . Based on our current observations using hESCs as a model, the lack of maternal immuno-genic response to the human embryo may be independent of complex in vivo interactions mediated by the placental barrier but instead is due to unique properties of embryonic human cells that inhibit local immune responses to the fetus.
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/ O7 B# x! o$ C- ~+ e v( ~) t5 p# bThe combination of regenerative medicine strategies using stem cells and evidence for the lack of immune response to undifferentiated and differentiated hESCs suggests that a scientific branch of immunology is evolving . Further study into "stem cell immunobiology" will reveal the exact mechanisms that account for the unique immunological properties of human stem cells and will likely have an impact on both our basic understanding of immune response and future approaches of cell replacement therapy.- s6 G" }( T# d$ h" }
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; u3 l$ X/ @/ AThis work was supported in part by a grant from the Multiple Organ Transplant Initiative, Geron Corporation, London Health Sciences Centre, and a Canadian Research Chair in Stem Cell Biology and Regenerative Medicine to M.B. and in Transplantation and Immunology to J.M. We would like to thank Christina Bhatia, Krysta Levac, and Francis Karanu for insights leading to completion of this study. The authors confirm that there are no conflicts of interest related to commercial affiliations regarding this work.
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发表于 2009-3-5 10:37
发表于 2015-5-21 16:10
