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Thread: We need Wise's comment on this one

  1. #11
    Immunogenicity of Induced Pluripotent Stem Cells
    16 May 2011
    Wise Young

    On May 15, Nature magazine published an article entitled “Immunogenicity of induced pluripotent stem cell” by Tongbiao Zhao, Zhen-Ning Zhang, Zhili Rong, and Yang Xu from the Section of Molecular Biology, Division of Biological Sciences, University of California in San Diego (UCSD). The article caused consternation in the stem cell field because it challenged a widely held assumption that induced pluripotent stem (iPS) cells would not be immune-rejected if the cells were transplanted into a syngeneic individual. Since 2007, when Shinya Yamanaka and colleagues described pluripotent cells induced by expressing four genes in skin cells, scientists have assumed that these cells would be immune compatible with the individual from which skin cells came. Now, Zhao, et al. at UCSD has reported that mouse iPS cells transplanted into syngeneic mice (with the same genes) are immune-rejected whereas embryonic stem cells derived from the same strain of mice are not immune-rejected and form teratomas or stem cell tumors. What does this mean for the stem cell field? Does this mean that iPS cells are not immune compatible?

    Let me first describe the experiments done by Zhao, et al. They created iPS cells using a new method called episomal iPS cells (EiPSC). Using a single retroviral vector, they insert 3 (Oct4/Sox2/Klf4) or 4 genes (Oct4/Sox2/Klf4/myc) into mouse embryonic fibroblasts. They isolated four independent iPS cell lines and transplanted these cells into mice from the same strain C57/BL6 (B6) or a different strain 129/sVJ (129). The iPS cells not only did not form teratomas but were immune rejected from the animals, accompanied by T-cell infiltration and massive necrosis of the transplanted cells. In contrast, embryonic stem cells (ESC) transplanted into syngeneic mice survived and formed stem cell tumor called teratomas but not when transplanted to allogeneic (another strain) mice. When they transplanted the iPS cells into immunodeficient mice (NOD/SKID), the cells were not be rejected, suggesting that the cells were rejected by the immune system. The immune rejection was associated with CD4-positive T-cells infiltration into the transplant.

    So, what could be the cause of this immune rejection? After all, the transplanted iPS cells should have the same genes as the host. The authors hypothesized that iPS cells may be expressing certain genes that are normally not expressed by embryonic stem cells or other cells in the body of the mice and therefore may be subject to immune rejection. Using gene chips, they identified 9 genes that the iPS cells express but are not as highly expressed by ESC. They then expressed these genes in ESC and found that two of the genes (Zg16 and Hormad1) resulted in immune rejection, i.e. Zg16-ESC and Hormad1-ESC. To show that the cells were rejected by lymphocytes, they showed that the iPS cells, as well as Zg16-ESC and Hormad1-ESC, were not rejected by mice deficient for CD4 or CD8 lymphocytes. They concluded that the cells were rejected by an immune mechanism that involve CD4 and CD8 lymphocytes. They further showed that dendritic cells (a kind of lymphocyte that presents antigens for immune rejection) expressing Zg16 or Hormad1 elicited interferon expression by T-cells, indicating that these two proteins contribute to immunogenicity. Finally, the authors found that immunogenicity of iPS cells derived from B6 is less than iPS cells derived from 129 mouse strain, suggesting that there are strain differences.

    This study provides convincing data that mouse iPS cells can be immunogenic when transplanted into syngeneic mice. They even identified two possible genes (Zg16 and Hormad1) that may contribute to immunogenicity of the iPS cells. The induction of immunogenic genes may explain why many investigators have had trouble forming teratomas with iPS cells whereas ESC cells more easily and consistently produce teratomas. Control cells, transfected with the empty vectors, did not elicit similar immune responses. By showing that the rejection did not occur in NOD/SKID immunodeficient mice, as well as CD4-/- and CD8-/- mice, they authors make a convincing case that the iPS cells are capable of growth and teratoma formation. Finally, ESC cells expressing Zg16 and Hormad1 were rejected with the same pattern and iPS cells. So, the data is very convincing. In addition to Zg16 and Hormad1, the authors pointed out that Dohdapkar, et al. (2010) have reported natural immunity to Oct4, one of the four pluripotency genes used to create iPS cells.

    However, several caveats should be kept in mind before the results of this study can be generalized to other species, including human.
    • The induced immunogenicity may vary amongst species. The authors found significant strain variations. It is not clear that such immunogenicity would be present in human or that human iPS cells would express Zg16 or Hormad1.
    • The host mice had to have existing immunity to the Zg16 or Hormad1 expressed by iPS cells. Even in mice that where teratomas did not regress, CD4+ lymphocytes rapidly infiltrated the tumor almost as soon as the tumor developed.
    • Other epigenetic differences between iPS and ESC may be responsible for the immune rejection. For example, iPS cells may have been grown in different media as the ESCs, including the possibility of fetal bovine serum.

    Much evidence suggests that many stem cells, including ESC cells, may express genes that suppress immune responses. ESC express anti-immune molecules that iPS cells may not. Although both iPS and ESC are known to have reduced major histocompatability complex (MHC) gene expression [2], ESC express the non-classical HLA-G molecule which induces tolerance by acting on cells of both innate and adaptive immunity [3]. HLA-G is expressed in oocytes, cleavage stage embryos, blastocysts, and inner cell mass cells, as well as ESC [4]. HLA-G expression is controlled by DNA methylation. Thus, one important potential explanation of the difference between iPS and ESC may be the latter’s expression of HLA-G and anti-immune factors.

    In summary, Zhao, et al. from UCSD has reported that mouse iPS cells can cause immune rejection whereas mouse ESC do not when transplanted into mice of the same strain. It is important to point out that more data is necessary to show that this occurs in humans. While they identified two genes that appear to contribute to the immunogenicity of mouse iPS cells, it is not clear that all iPS cells express these genes, that human iPS cells express these genes, or that many people have existing immunity against these genes. Much evidence suggest that ESC not only express low levels of MHC antigens but may express high levels of non-classical anti-immune HLA-G, that may not be expressed by iPS cells. More work needs to be done to confirm the mechanism of this immunogenicity and to show that it occurs in human iPS as well.

    References Cited
    1. Dhodapkar KM, et al. Natural immunity to pluripotency antigen OCT4 in humans. Proc. Natl. Acad. Sci. 107-8718-8723 (2010).
    2. Suarez-Alvarez B, et al. Epigenetic mechanisms regualte MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells. PLOS One 5: e10192.
    3. Rizzo, R, et al. The importance of HLA-G expression embryos, trophoblast cells, and embryonic stem cells. Cell Mol. Life. Sci. 68: 341-52.
    4. Verloes, A. HLA-G expression in human embryonic teem cells and pre-implantation embryos. J. Immunol. 186: 2663-71.
    Last edited by Wise Young; 05-16-2011 at 06:54 PM.

  2. #12
    I merged the two threads on this subject.
    Last edited by Wise Young; 05-17-2011 at 08:46 AM.

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