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The challenge of immunogenicity in the quest for induced pluripotency

Nature Reviews Immunology volume 10, pages 868–875 (2010)Cite this article

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Abstract

Few advances have been so widely acclaimed in biology as the seminal demonstration that adult somatic cells can be induced to acquire the phenotype and differentiation potential of embryonic stem cells. The capacity to produce patient-specific stem cells that are truly pluripotent has raised prospects for the treatment of many degenerative diseases through replacement of the affected cell types. In the race to the clinic, however, questions surrounding the potential immunogenicity of such cells have been largely overlooked. Here, I explore the extent of the challenges ahead and suggest that the induction of tolerance to such cells will be crucial to the future success of induced pluripotency.

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Figure 1: Pathways to pluripotency.
Figure 2: Applications of disease-specific iPSCs.
Figure 3: Induction of tolerance to the products of corrected genes.

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Acknowledgements

I am indebted to K. Silk, T. Davies, N. Ichiryu, S. Hackett, S. Cobbold and H. Waldmann for helpful discussions. Work on iPSCs in my laboratory is supported by seed-funding from the Oxford Stem Cell Institute and grant G0802538 from the Medical Research Council (UK).

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  1. Paul J. Fairchild is at the Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Paul.Fairchild@path.ox.ac.uk,

    Paul J. Fairchild

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Glossary

Blastocyst

The structure formed after the successive cell divisions of a fertilized zygote, giving rise to between 70 and 100 cells. The blastocyst consists of an outer layer, known as the trophectoderm, surrounding a central cavity (the blastocoel) and the inner cell mass. The trophectoderm gives rise to the extraembryonic tissues, including the placenta. After implantation into the endometrium of the uterus, the embryo proper develops from a portion of the inner cell mass, known as the epiblast.

Epiblast

The portion of the inner cell mass of a blastocyst that is capable of establishing the body plan of the developing embryo after implantation. As such, cells that make up the epiblast are fully pluripotent.

Human embryonic stem cells

Lines of cells derived from the epiblast of supernumerary blastocysts. Their significance lies in their ability to self-renew indefinitely under appropriate culture conditions in vitro, while retaining their inherent pluripotency.

Implantation

An event that occurs within the first few days after conception in which the blastocyst attaches to the wall of the uterus. This leads to invasion of the endometrium by trophoblasts, which subsequently form the placenta and extraembryonic tissues that support development of the embryo proper.

Induced pluripotent stem cells

Lines of self-renewing, pluripotent stem cells derived by the transient introduction of transgenes encoding transcription factors such as OCT4, SOX2, KLF4 and MYC, or the gene products themselves, into adult somatic cells. Only transient expression of the transgenes is required because the reprogramming factors upregulate expression of their endogenous counterparts, which subsequently maintain pluripotency.

Insertional mutagenesis

A type of mutation caused by the disruption of a gene following the random integration of heterologous genetic material that is required for the genetic modification of the cell.

Lysosomal storage diseases

A broad group of diseases that have a common aetiology involving a deficiency in crucial enzymes required for lysosome function. Symptoms are associated with the accumulation of the enzyme substrate, leading, ultimately, to cell death. For example, the mental retardation, motor dysfunction and infantile death associated with Sandhoff disease are caused by a deletion in the β-chain of β-hexosaminidase that results in the accumulation of gangliosides in lysosomes throughout the central nervous system.

Mitochondrial genes

The complement of genes, inherited maternally, that are encoded by the episomal DNA located in the mitochondria. Mitochondrial genes have considerable diversity between individuals and are, therefore, an important source of minor histocompatibility antigens.

Nuclear transfer embryonic stem cells

Embryonic stem cell lines derived from the epiblast of cloned blastocysts, which are created through the process of somatic cell nuclear transfer.

Pluripotent

The term used to describe cells displaying the capacity to give rise to cell types from each of the three embryonic germ layers (endoderm, ectoderm and mesoderm) and, hence, to generate a viable embryo in the tetraploid complementation assay.

Primitive and definitive haematopoiesis

Primitive haematopoiesis occurs mainly in the yolk sac during the earliest stages of ontogeny and is characterized by the generation of myeloid cells and nucleated erythrocytes, but the failure to differentiate along the lymphoid lineage. After relocating to intraembryonic sites, haematopoiesis becomes definitive, supporting the development of both myeloid and lymphoid lineages and giving rise to enucleated erythrocytes.

Somatic cell nuclear transfer

The process of injecting into an enucleated donor oocyte the diploid nucleus from a terminally differentiated somatic cell. Stimulation of the resulting construct can induce cell division and the eventual formation of a blastocyst, from which nuclear transfer embryonic stem cells can be derived.

Teratoma

A benign tumour formed by the dysregulated proliferation and differentiation of pluripotent stem cells. Teratomas typically contain a wide range of tissues derived from each of the three embryonic germ layers (endoderm, ectoderm and mesoderm), organized chaotically within the tumour mass.

Tetraploid complementation

The most rigorous assay for the demonstration of pluripotency; it involves the microinjection of stem cells into a tetraploid blastocyst containing four sets of chromosomes. The tetraploid blastocyst is produced when the two blastomeres, generated by the first division of a fertilized zygote, are fused. Under these circumstances, the tetraploid epiblast of the resulting blastocyst fails to contribute to the developing embryo which is, therefore, derived entirely from the injected diploid stem cells.

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Fairchild, P. The challenge of immunogenicity in the quest for induced pluripotency. Nat Rev Immunol 10, 868–875 (2010). https://doi.org/10.1038/nri2878

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