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  • Review Article
  • Published:

Stem cell medicine encounters the immune system

Nature Reviews Immunology volume 2, pages 859–871 (2002)Cite this article

Key Points

  • Human embryonic (hES) stem cells are able to divide indefinitely and give rise to both undifferentiated stem cells and all types of fully functional, mature cell. Pluripotent hES-cell lines, derived from early human embryos, can be propagated continuously in vitro, or they can be encouraged to differentiate in vitro into specialized cell types.

  • Human ES cells might become a renewable source of differentiated cells for treating damaged or diseased tissues. For example, embryonic ectoderm-derived nerve cells might be used to treat Parkinson's disease or spinal-cord injuries, endodermal insulin-producing cells might be used to treat diabetes and mesodermal stem-cell derivatives might be used to treat leukaemias and heart disease.

  • Animal models of human diseases treated with ES-cell-derived tissues have shown encouraging results. However, hES-cell therapeutics is in its infancy; there is a long way to go to establish both the safety of transplanting differentiated derivatives of hES cells and the efficacy of conditions for deriving specialized tissues reproducibly from hES cells.

  • Immunological rejection is likely to be an important problem. Little attention has been paid to the immunogenicity of transplanted fetal or ES-cell-derived tissues or to the need for immunosuppression. Overcoming the immune response must have a prominent role in the development of hES-cell therapeutics.

  • Human ES cells express HLA class I, but not class II, molecules, and expression of these molecules increases with differentiation in vitro (to embryoid bodies) and in vivo (to teratomas). It is probable that fully differentiated stem-cell-derived tissues in vivo will express normal and cytokine-inducible levels of HLA class I and class II antigens.

  • In contrast to conventional tissue transplants, transplants derived from hES cells are likely to lack dendritic cells. Consequently, the indirect pathway of allorecognition will have an important role in the immune response.

  • Possible approaches to overcome rejection include 'therapeutic cloning' (nuclear transfer), genotyped hES-cell banking, genetic modification to create a 'universal donor' or a protected phenotype, use of non-specific immunosuppressive drugs, immunomodulation of the recipient and establishment of haematopoietic chimerism in the recipient.

  • Therapeutic cloning would require the creation of an hES-cell line for every patient, whereas hES-cell banking could provide well-matched tissues for most patients.

  • Matching and genetic alteration of hES cells or their derivatives would reduce the immune response, but probably not sufficiently to avoid the need for additional immunosuppression.

  • The induction of haematopoietic chimerism and transplantation of therapeutic tissues from the same hES-cell line offers the possibility of true transplantation tolerance.

Abstract

Recent progress in deriving human embryonic stem (hES) cells and defining their capacity to differentiate has inspired hope that they could become a source of replacement cells for damaged or diseased tissues. We review the immunological barriers to transplanting hES cells and consider several potential solutions, including stem-cell banking, modification of the immunogenicity of donor cells and induction of tolerance to the graft. We evaluate the probable efficacy of these approaches with a view to facilitating the use of hES cells in clinical practice.

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Figure 1: Alternative fates for an in vitro-fertilized zygote: intrauterine versus in vitro development.
Figure 2: Protocols for generating specialized tissues from embryonic stem cells and prospects for their therapeutic applications.
Figure 3: Direct and indirect T-cell allorecognition pathways.
Figure 4: Effector mechanisms mediating rejection of hES-cell-derived dendritic-cell-free allografts by T cells with indirect specificity for donor HLA molecules.
Figure 5: Genomic replacement (somatic-cell nuclear transfer) as a way of matching stem-cell-derived tissues with their intended recipient.
Figure 6: Mixed haematopoietic chimerism.

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Acknowledgements

We would like to thank C. J. Taylor for helpful discussions. Research in our laboratories is supported by grants from the British Heart Foundation, the Medical Research Council (UK) and the Wellcome Trust.

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Authors and Affiliations

  1. Department of Surgery, Cambridge University Clinical School, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK

    J. Andrew Bradley, Eleanor M. Bolton & Roger A. Pedersen

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  1. J. Andrew Bradley
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  2. Eleanor M. Bolton
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  3. Roger A. Pedersen
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Correspondence to J. Andrew Bradley.

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DATABASES

LocusLink

A20

β2-microglobulin

CD2

CD3

CD4

CD8

CD25

CD28

CD40

CD52

CD74

CD80

CD86

CD154

CIITA

FAS

FASL

HoxB4

ICAM1

IFN-α

IFN-β

IFN-γ

IL-10

LFA1

OCT4

RFX5

TAP

tapasin

TNF

FURTHER INFORMATION

NIH Human Embryonic Stem Cell Registry

UK Transplant

United Network for Organ Sharing

Glossary

EMBRYOID BODIES

Cellular aggregates that form in vitro when colonies of cultured embryonic stem (ES) cells are detached from the petri dish in which they are grown. ES cells in the resulting clumps begin the process of differentiation.

TERATOMA

A tumour that comprises disorganized tissues derived from all three embryonic germ layers (ectoderm, mesoderm and endoderm). It might arise spontaneously in the human gonads. Embryonic stem cells form teratomas when injected into an experimental animal, which confirms their pluripotency.

GRAFT-VERSUS-HOST DISEASE

(GVHD). An immune response mounted against the recipient of an allograft by immunocompetent donor T cells derived from the graft. Typically, it is seen in the context of allogeneic bone-marrow transplantation.

MYELOABLATION

Complete or partial elimination of the haematopoietic system of a graft recipient by the use of whole-body irradiation or cytotoxic drugs, before reconstitution with fresh autologous or allogeneic bone marrow or haematopoietic stem cells.

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Bradley, J., Bolton, E. & Pedersen, R. Stem cell medicine encounters the immune system. Nat Rev Immunol 2, 859–871 (2002). https://doi.org/10.1038/nri934

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  • DOI: https://doi.org/10.1038/nri934

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