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  • Several approaches exist to prevent allogeneic cell

    2018-10-24

    Several approaches exist to prevent allogeneic cell transplantation-related immune rejection. One is immune suppression therapy using a combination of several different types of immunosuppressants. Others are the use of major histocompatibility complex (MHC)-matched donor cells to reduce immunogenicity, or the suppression of MHC expression via genetic modification. MHC molecules function by binding to pathogen-derived peptide fragments and displaying them on their cell surface for T cell recognition; this process is affected by the high polymorphism of MHC genes. The recognition of non-self MHC molecules causes the rejection of allogeneic organs and tissues (Janeway et al., 2001); therefore, donor/recipient MHC matching can decrease the rate of rejection in organ transplantation (Flomenberg et al., 2004). For these approaches, the establishment of iPSC lines from healthy donors with homozygous MHC AEG 3482 is useful for minimizing the number of banked iPSC lines (Nakatsuji et al., 2008; Taylor et al., 2012). The cynomolgus macaque is a non-human primate that is taxonomically more closely related to humans than other experimental primates. Cynomolgus macaques have a nearly identical genomic organization of the MHC region and drug metabolizing capacity similar to that of humans (Kita et al., 2009; Sano et al., 2006), thus making them a good model for organ transplantation and immunogenicity studies. At least 15 homozygous or semi-homozygous haplotypes (HT1–15) have been identified in a Philippines macaque population (Shiina et al., 2015), with the most frequent haplotype, HT1, detected in 5%–10%.
    Results
    Discussion The efficacy and limitations of MHC-matched transplantation are related to the role of MHC in allogeneic cell transplantation. Theoretically, the main mechanism of MHC-matched transplantation is prevention of the host immune reaction through MHC-restricted direct recognition for the donor cells as self by the recipient immunocompetent cells, e.g., T cells. In general, approximately 1%–10% of naive T cells are activated by non-self MHC molecules, but not by self MHC molecules via such a “direct pathway” (Janeway et al., 2001). Therefore, MHC-matched transplantation might decrease the initial population of T cells activated by transplanted cell MHCs by recognizing them as self. In this study, the less severe rejection effected by MHC-matched versus mismatched iPSC-CM transplantation suggested that immune rejection via the direct pathway might have been minimal in the former. In addition, allogeneic iPSC-CMs caused severe rejection in MHC-mismatched transplantation with combined immune suppression within 1 month, even though organ transplantation, including heart, lung, liver, and kidney transplantations, is usually performed in an MHC-mismatched manner without severe rejection under the appropriate immunosuppression therapy. Therefore, MHC-matched transplantation of iPSC-CMs represents a promising approach for clinical applications to avoid immunosuppression-related problems. In contrast, MHC-matched transplantation might not have substantial effects on the prevention of allogeneic cell transplantation rejection in the indirect pathway, in which the transplanted cell antigens are presented after being phagocytosed and digested by recipient antigen-presenting cells to activate recipient T cells, as observed in animal 6 or 7. This might arise because the peptide antigens would be derived from MHC proteins and other non-self peptides, acting as minor antigens. In this study, GFP might represent one of the minor antigens, as has previously been reported (Stripecke et al., 1999), or non-peptide antigens such as cell surface glycans, which have been reported to be highly expressed in iPSC-CMs (Kawamura et al., 2014, 2015), might serve as well. The antigen causing rejection in MHC-matched transplantation will need to be identified in further studies to overcome this limitation of allogeneic iPSC-CM transplantation.