Properties of Immune-Privileged STO-Progenitor Cells

描述(申请人提供)：本R21申请的长期目标是鉴定胚胎瑞士小鼠STO和STO细胞衍生(SCO)祖细胞系的几个关键生物学和免疫学特性，以确定这些细胞作为祖细胞分化和植入非免疫抑制哺乳动物宿主的新型模型系统的实用性。在没有免疫抑制的情况下，STO和SCO细胞系的肝内移植在二肽基肽酶IV阴性(DPPIV)的德国F344大鼠或其野生型DPPIV*对应的大鼠中至少存活了三个月。绿色荧光蛋白标记的SCO细胞系(3(8)21-EGFP)在没有免疫抑制的情况下，作为成年C57BL/6J小鼠的包膜下移植肾和成年F344大鼠的硬膜下异种移植，也可以存活至少一个月。供体小鼠STO和SCO细胞表现出与免疫豁免一致的表型(MHCI类[LOW1(H-2Kd[low])/Class 11-(L-ADH)；CD80-和CD86-)；在大鼠肝脏和损伤的大鼠脊髓模型中，它们在体内分别分化为肝脏和轴突诱导的神经胶质细胞系，并在小鼠肾被膜下分化为导管样结构。这些新的和意想不到的发现表明，STO和SCO细胞可能为非免疫抑制受者的通用组织移植提供免疫优势的多潜能祖细胞样材料。因此，STO和SCD细胞将被用于：1)体外研究肝细胞前体细胞的潜力；2)研究非免疫抑制野生型和转基因H-2b小鼠的肝细胞前体细胞潜力和同种异体存活；3)鉴定非免疫抑制同种异体小鼠的免疫原性和抗原性；以及4)阐明共刺激分子CD80和CD86不表达的机制。将开发细胞和分子生物学、生物化学、免疫学、移植和小鼠遗传学的标准程序，以及实时EGFP成像。到目前为止研究的供体细胞和受体模型的特性表明，开发非人类来源的免疫特异祖细胞用于移植而不受免疫抑制是一种新的可能性。作为这些拟议研究的结果，新的细胞试剂将可用于再生和移植医学的新模型。

DESCRIPTION (provided by applicant): The long-term objectives of this R21 application are to characterize several key biological and immunological properties of embryonic Swiss mouse STO- and STO cell-derived (SCO) progenitor cell lines to determine the utility of these cells as novel model systems of progenitor cell differentiation and engraftment into non- immunosuppressed mammalian hosts. Intrahepatic xenografts of STO and SCO cell lines survive without immunosuppression for at least three months in either dipeptidylpeptidase IV-negative (DPPIV) German F344 rats or in their wild type DPPIV* counterparts. An EGFP-labeled SCO cell line (3(8)21-EGFP) also survives without immunosuppression for at least one month as a subcapsular renal allograft in adult C57BL/6J mice, and as a subdural xenograft in C3-lesioned spinal cords in adult F344 rats. Donor mouse STO and SCO cells display phenotypes (MHC class I+[LOW1 (H-2Kd[LOW]) / class ll-negative (l-AdH); CD80- and CD86-negative) consistent with immune privilege; they differentiate into hepatic and axon-inducing neuroglial lineages in the rat liver and lesioned rat spinal cord models in vivo, respectively, and into duct-like structures under mouse renal capsules. These novel and unexpected findings suggest the hypothesis that STO and SCO cells might provide immune-privileged pluripotential progenitor cell-like material for universal tissue grafts in non-immunosuppressed recipients. Accordingly, STO and SCD cells will be used to: 1] investigate in vitro hepatocytic progenitor cell potential; 2] investigate in vivo hepatocytic progenitor cell potential and allogeneic survival in non-immunosuppressed wild type and genetically injured knockout and transgenic H-2b mice; 3] characterize immunogenicity and antigenicity in non-immunosuppressed allogeneic mice; and, 4] delineate mechanisms of non-expression of costimulatory molecules CD80 and CD86. Standard procedures of cell and molecular biology, biochemistry, immunology, transplantation and mouse genetics will be exploited, along with real-time EGFP imaging. The properties of the donor cells and recipient models examined thus far suggest novel possibilities for developing nonhuman sources of immune privileged progenitor cells for transplantation without immunosuppression. As a result of these proposed studies, new cellular reagents will be available for new models for regenerative and transplantation medicine.