Engineering universal cells that evade immune detection

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Abstract

The prospect of transplanting cells and tissues without the risk of immune rejection or the need for powerful immunosuppressive drugs is the ‘holy grail’ of transplantation medicine. Now, with the advent of pluripotent stem cells, CRISPR–Cas9 and other gene-editing technologies, the race to create ‘off-the-shelf’ donor cells that are invisible to the immune system (‘universal cells’) has started. One important approach for creating such cells involves the manipulation of genes required for immune recognition, in particular HLA class I and II proteins. Other approaches leverage knowledge of immune-cloaking strategies used by certain bacteria, viruses, parasites, the fetus and cancer cells to induce tolerance to allogeneic cell-based therapies by modifying cells to express immune-suppressive molecules such as PD-L1 and CTLA4–Ig. Various academic groups as well as biotechnology and pharmaceutical companies are on the verge of bringing these therapies into the clinic.

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Fig. 1: Examples of disorders that could potentially be treated with different types of universal cells.
Fig. 2: HLA class I and II engineering strategies.
Fig. 3: Players in immune recognition and reactions to allografts.

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Acknowledgements

The authors thank J. Harding for his critical and helpful input.

Author information

The authors contributed equally to all aspects of the article.

Correspondence to Robert Lanza.

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Competing interests

R.L., D.W.R. and A.N. are employees and/or founders of the Astellas Institute for Regenerative Medicine, Universal Cells Inc. and panCELLa Inc., respectively, companies in the area of regenerative medicine, including the generation of cell therapies and universal cells.

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Peer review informationNature Reviews Immunology thanks Sonia Schrepfer, Xang Xu and Rainer Blasczyk for their contribution to the peer review of this work.

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Glossary

Intrabody

An antibody that works within cells to bind to a specific intracellular protein.

Cross-presentation

The uptake and presentation of antigens by cells that do not express those antigens themselves.

‘Direct recognition’ pathway

Host T cells can rapidly recognize a donor antigen that is being presented directly by donor antigen-presenting cells that are present during transplant. As opposed to indirect recognition, where host T cells recognize an antigen that is being presented by host antigen-presenting cells, which usually takes more time because the host has to acquire and process donor antigen.

iCasp9

The dimerizing small drug-inducible Caspase 9 system kills cells by initiating apoptosis.

Herpes simplex virus thymidine kinase

A commonly used suicide gene. Cells expressing herpes simplex virus thymidine kinase die in the presence of gancyclovir.

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