Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants

Anabel S. de la Garza-Rodea, Marieke Verweij, Hester Boersma, Ietje van der Velde-van Dijke, Antoine A F de Vries, Rob C. Hoeben, Dirk W. van Bekkum, Emmanuel J H J Wiertz, Shoshan Knaän-Shanzer

Research output: Contribution to journalArticle

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Abstract

Background: Mesenchymal stem cells (MSCs) are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs) are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected. Methodology/Principal Findings: We aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC) class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID) mice could be attained provided that recipients' natural killer (NK) cells were depleted prior to cell transplantation. Conclusions/Significance: Our findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs nonimmunogenic and thereby universally transplantable.

Original languageEnglish (US)
Article numbere14493
JournalPLoS One
Volume6
Issue number1
DOIs
StatePublished - 2011
Externally publishedYes

Fingerprint

immune evasion
Immune Evasion
Transplants
Herpesviridae
Stem cells
Mesenchymal Stromal Cells
stem cells
immune response
major histocompatibility complex
Major Histocompatibility Complex
natural killer cells
Tissue
Natural Killer Cells
Down-Regulation
proteins
retroviral vectors
Human herpesvirus 5
cytolysis
cell transplantation
Inbred NOD Mouse

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

de la Garza-Rodea, A. S., Verweij, M., Boersma, H., van der Velde-van Dijke, I., de Vries, A. A. F., Hoeben, R. C., ... Knaän-Shanzer, S. (2011). Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants. PLoS One, 6(1), [e14493]. https://doi.org/10.1371/journal.pone.0014493

Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants. / de la Garza-Rodea, Anabel S.; Verweij, Marieke; Boersma, Hester; van der Velde-van Dijke, Ietje; de Vries, Antoine A F; Hoeben, Rob C.; van Bekkum, Dirk W.; Wiertz, Emmanuel J H J; Knaän-Shanzer, Shoshan.

In: PLoS One, Vol. 6, No. 1, e14493, 2011.

Research output: Contribution to journalArticle

de la Garza-Rodea, AS, Verweij, M, Boersma, H, van der Velde-van Dijke, I, de Vries, AAF, Hoeben, RC, van Bekkum, DW, Wiertz, EJHJ & Knaän-Shanzer, S 2011, 'Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants', PLoS One, vol. 6, no. 1, e14493. https://doi.org/10.1371/journal.pone.0014493
de la Garza-Rodea AS, Verweij M, Boersma H, van der Velde-van Dijke I, de Vries AAF, Hoeben RC et al. Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants. PLoS One. 2011;6(1). e14493. https://doi.org/10.1371/journal.pone.0014493
de la Garza-Rodea, Anabel S. ; Verweij, Marieke ; Boersma, Hester ; van der Velde-van Dijke, Ietje ; de Vries, Antoine A F ; Hoeben, Rob C. ; van Bekkum, Dirk W. ; Wiertz, Emmanuel J H J ; Knaän-Shanzer, Shoshan. / Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants. In: PLoS One. 2011 ; Vol. 6, No. 1.
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