Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts

Abstract

Given their self-renewing and pluripotent capabilities, human embryonic stem cells (hESCs) are well poised as a cellular source for tissue regeneration therapy. However, the host immune response against transplanted hESCs is not well characterized. In fact, controversy remains as to whether hESCs have immune-privileged properties. To address this issue, we used in vivo bioluminescent imaging to track the fate of transplanted hESCs stably transduced with a double-fusion reporter gene consisting of firefly luciferase and enhanced GFP. We show that survival after transplant is significantly limited in immunocompetent as opposed to immunodeficient mice. Repeated transplantation of hESCs into immunocompetent hosts results in accelerated hESC death, suggesting an adaptive donor-specific immune response. Our data demonstrate that transplanted hESCs trigger robust cellular and humoral immune responses, resulting in intragraft infiltration of inflammatory cells and subsequent hESC rejection. Moreover, we have found CD4 ؉ T cells to be an important modulator of hESC immunemediated rejection. Finally, we show that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days. Taken together, these data suggest that hESCs are immunogenic, trigger both cellular and humoral-mediated pathways, and, as a result, are rapidly rejected in xenogeneic hosts. This process can be mitigated by a combined immunosuppressive regimen as assessed by molecular imaging approaches. molecular imaging ͉ immunological response ͉ immunosuppression

Evaluation of 28 Human Embryonic Stem Cell Lines for Use as Unrelated Donors in Stem Cell Therapy: Implications of HLA and ABO Genotypes

“…In the last 10 years, more by injection of human peripheral blood leukocytes (13). In contrast, it was reported that hESCs transplanted into than 400 hESC lines have been established and studied worldwide (International stem cell registry, University immunocompetent mice were effectively recognized and rejected by the adaptive murine immune system (62 colony was cultured and mechanically dissected into small clumps every 5-6 days. ES cell colonies were culWe successfully determined the ABO genotypes of all hESC lines and obtained HLA-A, -B, -C, and -DR genotured in DMEM/F12 medium supplemented with 20% Knockout SR, 0.1 mM β-mercaptoethanol, 1% nonestype results from 27 of the 29 lines; the exceptions were two hESC lines that showed chromosomal triploidy/tetsential amino acids, 100 U/ml penicillin, 100 µg/ml streptomycin, and 4 ng/ml basic fibroblast growth factor raploidy, and HLA-A, -C, and -DR results were obtained in one of these two cell lines.…”

Engineering bone tissue substitutes from human induced pluripotent stem cells

“…Previous studies have demonstrated that human embryonic stem cells (hESCs) differentiate into osteogenic cells (6)(7)(8) and form compact bone tissue matrix when cultured on osteoconductive scaffolds in perfusion bioreactors (9). However, ethical controversy and concerns regarding immune properties of hESCs in allogeneic conditions hinder their clinical translation (10). Human-induced pluripotent stem cells (hiPSCs) reprogrammed using nonintegrating vectors (11,12) have the potential to overcome both limitations and be used to give rise to the cells of bone, vasculature, and adjacent tissues and to engineer autologous bone substitutes.…”

Human Dendritic Cell–Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic

“…Although other groups reported minimal or no immunogenicity of mouse syngenic iPSC lines and their cellular derivatives (15)(16)(17), these reports highlighted the need for an in-depth characterization of the inherent immunogenicity of hPSC. hESC lines express low levels of MHC class I molecules (18), exhibit immune-privileged properties (19,20), and are rejected in immune-competent mice through a T cellmediated allograft-rejection process (19,21,22); however, the inherent immunogenicity of human iPSC lines has not been examined carefully. In this article, we show that the terminally differentiated gold standard for human immunogenic cells, DC, can be successfully dedifferentiated into the iPSC state using Sendai virus, a nonintegrating RNA virus.…”