Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance

Abstract

Although human embryonic stem (ES) cells may one day provide a renewable source of tissues for cell replacement therapy (CRT), histoincompatibility remains a significant barrier to their clinical application. Current estimates suggest that surprisingly few cell lines may be required to facilitate rudimentary tissue matching. Nevertheless, the degree of disparity between donor and recipient that may prove acceptable, and the extent of matching that is therefore required, remain unknown. To address this issue using a mouse model of CRT, we have derived a panel of ES cell lines that differ from CBA/Ca recipients at defined genetic loci. Here, we show that even expression of minor histocompatibility (mH) antigens is sufficient to provoke acute rejection of tissues differentiated from ES cells. Nevertheless, despite their immunogenicity in vivo, transplantation tolerance may be readily established by using minimal host conditioning with nondepleting monoclonal antibodies specific for the T cell coreceptors, CD4 and CD8. This propensity for tolerance could be attributed to the paucity of professional antigen-presenting cells and the expression of transforming growth factor (TGF)-␤2. Together, these factors contribute to a state of acquired immune privilege that favors the polarization of infiltrating T cells toward a regulatory phenotype. Although the natural privileged status of ES cell-derived tissues is, therefore, insufficient to overcome even mH barriers, our findings suggest it may be harnessed effectively for the induction of dominant tolerance with minimal therapeutic intervention.cell replacement therapy ͉ acquired immune privilege ͉ regulatory T cell

Immunogenicity of human embryonic stem cell-derived beta cells

“…Low expression of HLA by hESCs and hESC-derived cells underlies the hypoimmunogenicity observed in most published studies, effectively hiding cells from T cell recognition and alloreactive antibodies, while differentiation can upregulate HLA and increase vulnerability to immunity [17][18][19][20][21]. In our study, immunogenicity to alloreactive and peptide (CMV)-specific responses was related to HLA expression.…”

“…Preproinsulin (PPI)-specific T cell clone 1E6 generation was described previously [23]. Briefly, PBMCs from an individual with type 1 diabetes were stimulated with PPI [15][16][17][18][19][20][21][22][23][24] peptide. PPI-specific cytotoxic T lymphocytes (CTLs) were sorted by FACS and expanded.…”

“…However, differentiation of hESCs to other cell types can result in the loss of this immunological privilege [17][18][19][20][21]. Insights into the immunogenicity of the alternative sources of beta cells can help to guide the choice of immune-protective strategies and the relevant immune monitoring to be employed in clinical introduction.…”

Privilege revisited: an evaluation of the eye's defence mechanisms

“…Recently, the immunoregulatory functions of tissues have been brought to centre stage and has been developed as a concept equal in importance to the canonical central and peripheral tolerance mechanisms, rehearsed ad infinitum by immunologists. 4,[65][66][67] In reality, tissue immunregulatory properties are another way of describing immune privilege, ie, ways in which the tissues and its secreted products can control immune responses. It is even possible to induce immune privilege in certain sites such as in accepted grafts or in tumours, where T regulatory cells are induced by the tissue.…”

Concise Review: Epidermal Grafting: The Case for Pluripotent Stem Cells

“…Whether pluripotent stem cell therapy products will request the same type of immunosuppressive treatment as that currently needed for organ transplant is an important issue because this will be an essential parameter in the eventual extension of the technique to a large number of patients. There have been indications that, altogether, pluripotent stem cell derivatives may be much better tolerated than other tissues [26]. Our own study has demonstrated that keratinocytes derived from hESCs express low level of Major Histocompatibility Complex (MHC) antigens suggesting a low immunogenicity of the skin substitute [5].…”