Could Heme-Oxygenase-1 Have a Role in Modulating the Recipient Immune Response to Embryonic Stem Cells?

Abstract

Pluripotent human embryonic stem cells (hESCs) may provide a potential source of cellular therapies, but as allogeneic cells may require evading the recipient's immune response. Using an NIH-registry hESC line, it was found that undifferentiated hESCs induce a reduced proliferative response compared to PBMC and demonstrate that this diminished response correlates with the activity of heme oxygenase-1 (HO-1). Inhibition of HO-1 significantly increases T cell proliferation against hESC, indicating the potential suppression of these cells during transplantation of allogeneic hESC. These data suggest the hypothesis that HO-1 provides a mechanism for protecting hESCs in vivo.

Human Embryonic Stem Cells Suppress T Cell Responses via Arginase I-Dependent Mechanism

“…Previous reports mainly studied the immunogenicity of hESCs (10) and their capability to trigger an immune response (5,6,9). In the present study, we focused on the potential of hESCs to suppress the activation of T cells in response to potent stimulators.…”

“…TGF-b was suggested to play a role in immunosuppression mediated by mESCs and their CM (22). The small products biliverdin and carbon monoxide, of hemoxygenase I enzymatic activity in hESCs, were also shown to regulate T cell proliferation by their anti-inflammatory and antiapoptotic properties (9). In addition, arginase I activity in ESCs could potentially also inhibit immune responses by metabolites of L-arginine, such as spermidine, spermine, and putrescine, which were shown to have a role in cell cycle control and in regulating the secretion of proinflammatory cytokines by monocytes (18).…”

“…Accordingly, hESCs inhibit proliferation of PBMCs (5,9), express low levels of class I MHC molecules, do not express class II MHC, and do not induce NK cell lysis activity (5,7,10).…”

Immune regulation by non-lymphoid cells in transplantation

“…Heart transplantation in mice [71] ESC Low MHC expression [73] Production of HO-1 [75] Transplantation of ESC for tissue repair [134] NSC n.d. Intracerebral injection of neuronal precursors in EAE [78] AAMF TGF-b [80] Arginase I [80] Suppression of T cell proliferation [99] IFN-g-MdC Induction of Treg, CD40 and IFN-g-dependent [104] Heart transplantation in mice Mouse DSS-induced colitis [104] MDSC Release of nitric oxide [122] Action of arginase I [123] Kidney transplantation in rats [131] AAMF, alternatively activated macrophages; DC, dendritic cell; DSS, dextran sulphate sodium; EAE, experimental autoimmune encephalomyelitis; ESC, embryonic stem cells; IFN-g-MdC, interferon (IFN)-g-stimulated monocyte-derived cells; MDSC, myeloid-derived suppressor cells; MSC, mesenchymal stem cells; n.d., not defined; NSC, neural stem cells; IDO, indoleamine 2,3-dioxygenase; HO-1, haem oxygenase; PGE2, prostaglandin E2; IL, interleukin; IFN, interferon; TGF, transforming growth factor; Treg, T regulatory cells.…”

“…ESC express low levels of MHC class I and class II molecules [73], albeit sufficient in quantity to elicit their rejection by cytotoxic T cells [74]. The reason for their immunomodulatory properties resides in their synthesis of HO-1, which reduces proliferative responses in vitro [75]. Neural stem cell (NSC) transplantation or transplantation of ESC-derived neural precursors has also been proposed as a means of cell replacement therapy.…”