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    • Regulatory immune cell therapy including regulatory T

    2018-10-24

    Regulatory immune cell therapy, including regulatory T cells (Tregs) (Bradley, 2014; McMurchy et al., 2011), regulatory dendritic pde inhibitors (DCregs) (Ezzelarab and Thomson, 2011; Moreau et al., 2012), and immature DCs (iDCs) (Roncarolo et al., 2001), is an emerging strategy for the prevention of allograft rejection by promoting antigen-specific tolerance and the elimination of IS drug use (Raich-Regue et al., 2014; Wood et al., 2012). Because DCregs play essential roles in maintaining immune homeostasis (Morelli and Thomson, 2007), they are usually the target of rejection treatment. However, the lack of stable therapeutic DCregs has been the biggest problem in clinical application. Induced pluripotent stem cells (iPSCs), created by Yamanaka and colleagues in 2006, can propagate indefinitely and differentiate into various cells just like embryonic stem cells (ESCs) (Takahashi et al., 2007; Takahashi and Yamanaka, 2006). Notably, unlike ESCs, iPSCs can be generated from adult cells, which overcomes ethical issues and patient-matching limitations. In our previous study (Zhang et al., 2014), we established a novel approach for generating a sufficient quantity of high-quality functional DCregs from iPSCs (iPS-DCregs), which could be kept in a “stable immature stage” even under strong stimulation. Harnessing this characteristic, we hypothesized that donor-type iPS-DCregs expressing donor antigen worked as an immune suppressive vaccine to generate alloantigen-specific Tregs, and induced permanent acceptance of mouse cardiac allografts.
    Results
    Discussion Donor-specific tolerance that does not compromise the overall immune response is the ultimate goal in the transplantation field. DCregs-based therapies could potentially promote donor-specific tolerance to prevent allograft rejection and graft-versus-host disease (Bonham et al., 2002; DePaz et al., 2003; Garrovillo et al., 2001; Lan et al., 2006; Lutz et al., 2000; Min et al., 2000; Mirenda et al., 2004; Morelli and Thomson, 2007; Sato et al., 2003b; Turnquist et al., 2007; Zhang et al., 2008). Both donor-type DCregs (Bonham et al., 2002; DePaz et al., 2003; Fu et al., 1996; Lan et al., 2006; Lu et al., 1997; Lutz et al., 2000; Min et al., 2000; Taner et al., 2005; Zhang et al., 2008) and recipient-type DCregs (loaded with donor antigen) (Ali et al., 2000; Beriou et al., 2005; Garrovillo et al., 1999; Oluwole et al., 2001; Peche et al., 2005; Sato et al., 2003b) were reported to be able to prolong allograft survival through different pathways (direct, indirect, semi-direct). However, most of these studies are based on murine/rat bone marrow stem cells and human blood mononuclear cell-derived DCs, which require a large number of progenitor cells. Also, the quantity and quality of cultured DCs were inconsistent because of different ages, health conditions, and other variables among the sample. Recently, Kudo et al. (2014) differentiated donor-type macrophage-like IS cells from mouse ESCs, and these cells were found to prolong allograft survival. However, the ethical issues and patient-matched limitations of ESCs prevented them from being used in the clinical setting. In our previous study, we successfully differentiated DCregs from iPSCs (Zhang et al., 2014). The present study addressed the hypothesis of whether the administration of donor-type iPS-DCregs was capable of generating donor-specific tolerance. Several conclusions can be drawn from the current study. First, iPS-DCregs not only indicate a high purity of CD11b+CD11c+ cells, but also retain a stable “immature” phenotype, even in the presence of strong maturational stimulus, IFN-γ. Many groups treated recipients with at least 2 × 106 bone marrow-derived DCregs, immature DCs, or other suppressive cells (such as myeloid-deprived suppressor cells) to achieve prolonged allograft survival (Arakawa et al., 2014; Fu et al., 1996; Rastellini et al., 1995; Tiao et al., 2005). In this study, 1 × 106 iPS-DCregs induced permanent allograft acceptance while BM-DCregs did not. The co-stimulator (CD40, CD80, CD86) and MHC-II molecule expressions in the CD11b+CD11c+ population were not significantly different between BM-DCregs and iPS-DCregs. However, iPS-DCregs have a significantly higher percentage of CD11c+ in the CD11b+ population compared with BM-DCregs. We thought that the high CD11b+CD11c+ purity of iPS-DCregs was the reason why the same dose of BM-DCregs and iPS-DCregs led to a different outcome. The number of administered CD11b+CD11c+ cells is known to directly affect the tolerance-inducing reaction (Morelli and Thomson, 2007). Recipients treated with a half-dose of iPS-DCregs indicated a graft survival similar to that with a full-dose of BM-DCregs, which was identified in our hypothesis. Our findings suggest that the addition of iPS-DCregs into MLR culture and PLN significantly suppressed the T cell proliferative response. These characteristics engineered iPS-DCregs as important “regulatory cellular vaccines” in the allogeneic transplantation model (Morelli and Thomson, 2007; Sato et al., 2003a, 2003b; Thomson et al., 2009).